Targeting Abnormal PI3K/AKT/mTOR Signaling in Intracerebral Hemorrhage:
A Systematic Review on Potential Drug Targets and Influences
of Signaling Modulators on Other Neurological Disorders

Kuldeep   Singh   Jadaun; Aarti      Sharma; Ehraz   Mehmood   Siddiqui; Sidharth      Mehan
doi:10.2174/1574884716666210726110021
Abstract

PI3K/AKT/mTOR (phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin) signaling pathway is an important signal transduction pathway mediated by enzyme-linked receptors with many biological functions in mammals. This pathway modulates the epigenetic modification of DNA and target gene histones and plays a significant role in regulating biological activity, disease progression, oncogenesis, and cancer progression. PI3K/AKT/mTOR signaling pathway involves and mediates many cellular processes such as nutrient uptake, proliferation, anabolic reactions, and cell survival. Several studies have shown that PI3K/AKT/mTOR has been a promising therapeutic approach to intracerebral hemorrhage (ICH). ICH is characterized by the progressive development of hematoma, which leads to the structural destabilization of the neurons and glial cells, leading to neuronal deformation, further contributing to mitochondrial dysfunction, membrane depolarization, oligaemia, and neurotransmitter imbalance. Partial suppression of cell metabolism and necrosis can occur, depending on the degree of mitochondrial dysfunction. Therefore in the following review, we discuss whether or not the activation of the PI3K/AKT/mTOR signaling pathway could minimize neuronal dysfunction following ICH. We further elaborate the review by discussing the updated pathophysiology of brain hemorrhage and the role of molecular targets in other neurodegenerative diseases. This review provides current approachable disease treatment in various disease states, single and dual PI3K/AKT/mTOR signaling pathway modulators.
Keywords: PI3K/AKT/mTOR signaling, intracerebral hemorrhage, neurodegeneration, neuronal metabolism, neuroprotection, drug targets.
« Previous Next »
Graphical Abstract

[1] 
Caceres JA, Goldstein JN. Intracranial hemorrhage. Emerg Med Clin North Am  2012; 30(3): 771-94.
[http://dx.doi.org/10.1016/j.emc.2012.06.003] [PMID:  22974648] 
[2] 
Liao R, Wood TR, Nance E. Nanotherapeutic modulation of excitotoxicity and oxidative stress in acute brain injury. Nanobiomedicine (Rij)  2020; 7: 1849543520970819.
[http://dx.doi.org/10.1177/1849543520970819] 
[3] 
Pandian JD, Sudhan P. Stroke epidemiology and stroke care services in India. 2013; 15(3): 128-34.
[4] 
An SJ, Kim TJ, Yoon BW. Epidemiology, risk factors, and clinical features of intracerebral hemorrhage: An update. J Stroke  2017; 19(1): 3-10.
[http://dx.doi.org/10.5853/jos.2016.00864] [PMID:  28178408] 
[5] 
Gong C, Hoff JT, Keep RF. Acute inflammatory reaction following experimental intracerebral hemorrhage in rat. Brain Res  2000; 871(1): 57-65.
[http://dx.doi.org/10.1016/S0006-8993(00)02427-6] [PMID:  10882783] 
[6] 
Hua Y, Xi G, Keep RF, Hoff JT. Complement activation in the brain after experimental intracerebral hemorrhage. J Neurosurg  2000; 92(6): 1016-22.
[http://dx.doi.org/10.3171/jns.2000.92.6.1016] [PMID:  10839264] 
[7] 
Wagner KR, Sharp FR, Ardizzone TD, Lu A, Clark JF. Heme and iron metabolism: role in cerebral hemorrhage. J Cereb Blood Flow Metab  2003; 23(6): 629-52.
[http://dx.doi.org/10.1097/01.WCB.0000073905.87928.6D] [PMID:  12796711] 
[8] 
Wang J, Rogove AD, Tsirka AE, Tsirka SE. Protective role of tuftsin fragment 1-3 in an animal model of intracerebral hemorrhage. Ann Neurol  2003; 54(5): 655-64.
[http://dx.doi.org/10.1002/ana.10750] [PMID:  14595655] 
[9] 
Xi G, Fewel ME, Hua Y, Thompson BG Jr, Hoff JT, Keep RF. Intracerebral hemorrhage: pathophysiology and therapy. Neurocrit Care  2004; 1(1): 5-18.
[http://dx.doi.org/10.1385/NCC:1:1:5] [PMID:  16174894] 
[10] 
D’Astous M, Mendez P, Morissette M, Garcia-Segura LM, Di Paolo T. Implication of the phosphatidylinositol-3 kinase/protein kinase B signaling pathway in the neuroprotective effect of estradiol in the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mice. Mol Pharmacol  2006; 69(4): 1492-8.
[http://dx.doi.org/10.1124/mol.105.018671] [PMID:  16434614] 
[11] 
Salman M, Tabassum H, Parvez S. Nrf2/HO-1 mediates the neuroprotective effects of pramipexole by attenuating oxidative damage and mitochondrial perturbation after traumatic brain injury in rats. Dis Model Mech  2020; 13(8): dmm045021.
[http://dx.doi.org/10.1242/dmm.045021] [PMID:  32540990] 
[12] 
Wang Z, Guo S, Wang J, Shen Y, Zhang J, Wu Q. Nrf2/HO-1 mediates the neuroprotective effect of mangiferin on early brain injury after subarachnoid hemorrhage by attenuating mitochondria-related apoptosis and neuroinflammation. Sci Rep  2017; 7(1): 11883.
[http://dx.doi.org/10.1038/s41598-017-12160-6] [PMID:  28928429] 
[13] 
Kaizaki A, Tanaka S, Ishige K, Numazawa S, Yoshida T. The neuroprotective effect of heme oxygenase (HO) on oxidative stress in HO-1 siRNA-transfected HT22 cells. Brain Res  2006; 1108(1): 39-44.
[http://dx.doi.org/10.1016/j.brainres.2006.06.011] [PMID:  16828716] 
[14] 
Arai S, Katai N, Ohta K, et al. The mechanism of neuroprotective
effect of heme oxygenase on retinal ischemia-reperfusion injury in
rats. Arvo annual meeting abstract search & program planner
abstract. Fort Lauderdale, Florida. 
[15] 
Qureshi AI, Suri MF, Ostrow PT, et al. Apoptosis as a form of cell death in intracerebral hemorrhage. Neurosurgery  2003; 52(5): 1041-7.
[PMID:  12699545] 
[16] 
Qureshi AI, Ali Z, Suri MF, et al. Extracellular glutamate and other amino acids in experimental intracerebral hemorrhage: an in vivo microdialysis study. Crit Care Med  2003; 31(5): 1482-9.
[http://dx.doi.org/10.1097/01.CCM.0000063047.63862.99] [PMID:  12771622] 
[17] 
Lusardi TA, Wolf JA, Putt ME, Smith DH, Meaney DF. Effect of acute calcium influx after mechanical stretch injury in vitro on the viability of hippocampal neurons. J Neurotrauma  2004; 21(1): 61-72.
[http://dx.doi.org/10.1089/089771504772695959] [PMID:  14987466] 
[18] 
Graham DI, McIntosh TK, Maxwell WL, Nicoll JA. Recent advances in neurotrauma. J Neuropathol Exp Neurol  2000; 59(8): 641-51.
[http://dx.doi.org/10.1093/jnen/59.8.641] [PMID:  10952055] 
[19] 
Nakamura T, Xi G, Park JW, Hua Y, Hoff JT, Keep RF. Holo-transferrin and thrombin can interact to cause brain damage. Stroke  2005; 36(2): 348-52.
[http://dx.doi.org/10.1161/01.STR.0000153044.60858.1b] [PMID:  15637325] 
[20] 
Xi G, Keep RF, Hoff JT. Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol  2006; 5(1): 53-63.
[http://dx.doi.org/10.1016/S1474-4422(05)70283-0] [PMID:  16361023] 
[21] 
Nakamura T, Keep RF, Hua Y, Nagao S, Hoff JT, Xi G. Iron-induced oxidative brain injury after experimental intracerebral hemorrhage. Acta Neurochir Suppl (Wien)  2006; 96: 194-8.
[http://dx.doi.org/10.1007/3-211-30714-1_42] [PMID:  16671453] 
[22] 
Wagner KR, Packard BA, Hall CL, et al. Protein oxidation and heme oxygenase-1 induction in porcine white matter following intracerebral infusions of whole blood or plasma. Dev Neurosci  2002; 24(2-3): 154-60.
[http://dx.doi.org/10.1159/000065703] [PMID:  12401953] 
[23] 
Taylor RA, Sansing LH. Microglial responses after ischemic stroke and intracerebral hemorrhage. Clin Dev Immunol  2013; 2013: 746068.
[http://dx.doi.org/10.1155/2013/746068] [PMID:  24223607] 
[24] 
Alvarez-Sabín J, Delgado P, Abilleira S, et al. Temporal profile of matrix metalloproteinases and their inhibitors after spontaneous intracerebral hemorrhage: relationship to clinical and radiological outcome. Stroke  2004; 35(6): 1316-22.
[http://dx.doi.org/10.1161/01.STR.0000126827.69286.90] [PMID:  15087562] 
[25] 
Aronowski J, Hall CE. New horizons for primary intracerebral hemorrhage treatment: experience from preclinical studies. Neurol Res  2005; 27(3): 268-79.
[http://dx.doi.org/10.1179/016164105X25225] [PMID:  15845210] 
[26] 
Hua Y, Wu J, Keep RF, Nakamura T, Hoff JT, Xi G. Tumor necrosis factor-alpha increases in the brain after intracerebral hemorrhage and thrombin stimulation. Neurosurgery  2006; 58(3): 542-50.
[http://dx.doi.org/10.1227/01.NEU.0000197333.55473.AD] [PMID:  16528196] 
[27] 
Gong C, Boulis N, Qian J, Turner DE, Hoff JT, Keep RF. Intracerebral hemorrhage-induced neuronal death. Neurosurgery  2001; 48(4): 875-82.
[PMID:  11322448] 
[28] 
Matz PG, Lewén A, Chan PH. Neuronal, but not microglial, accumulation of extravasated serum proteins after intracerebral hemolysate exposure is accompanied by cytochrome c release and DNA fragmentation. J Cereb Blood Flow Metab  2001; 21(8): 921-8.
[http://dx.doi.org/10.1097/00004647-200108000-00004] [PMID:  11487727] 
[29] 
Yang S, Nakamura T, Hua Y, et al. The role of complement C3 in intracerebral hemorrhage-induced brain injury. J Cereb Blood Flow Metab  2006; 26(12): 1490-5.
[http://dx.doi.org/10.1038/sj.jcbfm.9600305] [PMID:  16552422] 
[30] 
Fujii Y, Takeuchi S, Harada A, Abe H, Sasaki O, Tanaka R. Hemostatic activation in spontaneous intracerebral hemorrhage. Stroke  2001; 32(4): 883-90.
[http://dx.doi.org/10.1161/01.STR.32.4.883] [PMID:  11283387] 
[31] 
Broderick JP, Diringer MN, Hill MD, et al. Determinants of intracerebral hemorrhage growth: an exploratory analysis. Stroke  2007; 38(3): 1072-5.
[http://dx.doi.org/10.1161/01.STR.0000258078.35316.30] [PMID:  17290026] 
[32] 
Davis SM, Broderick J, Hennerici M, et al. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology  2006; 66(8): 1175-81.
[http://dx.doi.org/10.1212/01.wnl.0000208408.98482.99] [PMID:  16636233] 
[33] 
Qureshi AI, Harris-Lane P, Kirmani JF, et al. Treatment of acute hypertension in patients with intracerebral hemorrhage using American Heart Association guidelines. Crit Care Med  2006; 34(7): 1975-80.
[http://dx.doi.org/10.1097/01.CCM.0000220763.85974.E8] [PMID:  16641615] 
[34] 
Kazui S, Minematsu K, Yamamoto H, Sawada T, Yamaguchi T. Predisposing factors to enlargement of spontaneous intracerebral hematoma. Stroke  1997; 28(12): 2370-5.
[http://dx.doi.org/10.1161/01.STR.28.12.2370] [PMID:  9412616] 
[35] 
Gebel JM Jr, Jauch EC, Brott TG, et al. Natural history of perihematomal edema in patients with hyperacute spontaneous intracerebral hemorrhage. Stroke  2002; 33(11): 2631-5.
[http://dx.doi.org/10.1161/01.STR.0000035284.12699.84] [PMID:  12411653] 
[36] 
Inaji M, Tomita H, Tone O, Tamaki M, Suzuki R, Ohno K. Chronological changes of perihematomal edema of human intracerebral hematoma. Acta Neurochir Suppl (Wien)  2003; 86: 445-8.
[http://dx.doi.org/10.1007/978-3-7091-0651-8_91] [PMID:  14753483] 
[37] 
Butcher KS, Baird T, MacGregor L, Desmond P, Tress B, Davis S. Perihematomal edema in primary intracerebral hemorrhage is plasma derived. Stroke  2004; 35(8): 1879-85.
[http://dx.doi.org/10.1161/01.STR.0000131807.54742.1a] [PMID:  15178826] 
[38] 
Gebel JM Jr, Jauch EC, Brott TG, et al. Relative edema volume is a predictor of outcome in patients with hyperacute spontaneous intracerebral hemorrhage. Stroke  2002; 33(11): 2636-41.
[http://dx.doi.org/10.1161/01.STR.0000035283.34109.EA] [PMID:  12411654] 
[39] 
Qureshi AI, Hanel RA, Kirmani JF, Yahia AM, Hopkins LN. Cerebral blood flow changes associated with intracerebral hemorrhage. Neurosurg Clin N Am  2002; 13(3): 355-70.
[http://dx.doi.org/10.1016/S1042-3680(02)00012-8] [PMID:  12486925] 
[40] 
Siddique MS, Fernandes HM, Wooldridge TD, Fenwick JD, Slomka P, Mendelow AD. Reversible ischemia around intracerebral hemorrhage: a single-photon emission computerized tomography study. J Neurosurg  2002; 96(4): 736-41.
[http://dx.doi.org/10.3171/jns.2002.96.4.0736] [PMID:  11990815] 
[41] 
Kim-Han JS, Kopp SJ, Dugan LL, Diringer MN. Perihematomal mitochondrial dysfunction after intracerebral hemorrhage. Stroke  2006; 37(10): 2457-62.
[http://dx.doi.org/10.1161/01.STR.0000240674.99945.4e] [PMID:  16960094] 
[42] 
Carhuapoma JR, Wang PY, Beauchamp NJ, Keyl PM, Hanley DF, Barker PB. Diffusion-weighted MRI and proton MR spectroscopic imaging in the study of secondary neuronal injury after intracerebral hemorrhage. Stroke  2000; 31(3): 726-32.
[http://dx.doi.org/10.1161/01.STR.31.3.726] [PMID:  10700511] 
[43] 
Zazulia AR, Diringer MN, Videen TO, et al. Hypoperfusion without ischemia surrounding acute intracerebral hemorrhage. J Cereb Blood Flow Metab  2001; 21(7): 804-10.
[http://dx.doi.org/10.1097/00004647-200107000-00005] [PMID:  11435792] 
[44] 
Schellinger PD, Fiebach JB, Hoffmann K, et al. Stroke MRI in intracerebral hemorrhage: is there a perihemorrhagic penumbra? Stroke  2003; 34(7): 1674-9.
[http://dx.doi.org/10.1161/01.STR.0000076010.10696.55] [PMID:  12805502] 
[45] 
Orakcioglu B, Fiebach JB, Steiner T, et al. Evolution of early perihemorrhagic changes-ischemia vs. edema: an MRI study in rats. Exp Neurol  2005; 193(2): 369-76.
[http://dx.doi.org/10.1016/j.expneurol.2005.01.017] [PMID:  15869939] 
[46] 
Qureshi AI, Wilson DA, Hanley DF, Traystman RJ. No evidence for an ischemic penumbra in massive experimental intracerebral hemorrhage. Neurology  1999; 52(2): 266-72.
[http://dx.doi.org/10.1212/WNL.52.2.266] [PMID:  9932942] 
[47] 
Ng SY, Lee AYW. Traumatic brain injuries: Pathophysiology and potential therapeutic targets. Front Cell Neurosci  2019; 13: 528.
[http://dx.doi.org/10.3389/fncel.2019.00528] [PMID:  31827423] 
[48] 
Luo CL, Chen XP, Yang R, et al. Cathepsin B contributes to traumatic brain injury-induced cell death through a mitochondria-mediated apoptotic pathway. J Neurosci Res  2010; 88(13): 2847-58.
[http://dx.doi.org/10.1002/jnr.22453] [PMID:  20653046] 
[49] 
Dudek H, Datta SR, Franke TF, et al. Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science  1997; 275(5300): 661-5.
[http://dx.doi.org/10.1126/science.275.5300.661] [PMID:  9005851] 
[50] 
Datta SR, Dudek H, Tao X, et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell  1997; 91(2): 231-41.
[http://dx.doi.org/10.1016/S0092-8674(00)80405-5] [PMID:  9346240] 
[51] 
Brunet A, Bonni A, Zigmond MJ, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell  1999; 96(6): 857-68.
[http://dx.doi.org/10.1016/S0092-8674(00)80595-4] [PMID:  10102273] 
[52] 
Zheng L, Ren JQ, Li H, Kong ZL, Zhu HG. Downregulation of wild-type p53 protein by HER-2/neu mediated PI3K pathway activation in human breast cancer cells: its effect on cell proliferation and implication for therapy. Cell Res  2004; 14(6): 497-506.
[http://dx.doi.org/10.1038/sj.cr.7290253] [PMID:  15625017] 
[53] 
Xu X, Cao Z, Cao B, et al. Carbamylated erythropoietin protects the myocardium from acute ischemia/reperfusion injury through a PI3K/Akt-dependent mechanism. Surgery  2009; 146(3): 506-14.
[http://dx.doi.org/10.1016/j.surg.2009.03.022] [PMID:  19715808] 
[54] 
Hirsch E, Costa C, Ciraolo E. Phosphoinositide 3-kinases as a common platform for multi-hormone signaling. J Endocrinol  2007; 194(2): 243-56.
[http://dx.doi.org/10.1677/JOE-07-0097] [PMID:  17641274] 
[55] 
Jean S, Kiger AA. Classes of phosphoinositide 3-kinases at a glance. J Cell Sci  2014; 127(Pt 5): 923-8.
[http://dx.doi.org/10.1242/jcs.093773] [PMID:  24587488] 
[56] 
Falasca M, Maffucci T. Regulation and cellular functions of class II phosphoinositide 3-kinases. Biochem J  2012; 443(3): 587-601.
[http://dx.doi.org/10.1042/BJ20120008] [PMID:  22507127] 
[57] 
Devereaux K, Dall’Armi C, Alcazar-Roman A, et al. Regulation of mammalian autophagy by class II and III PI 3-kinases through PI3P synthesis. PLoS One  2013; 8(10): e76405.
[http://dx.doi.org/10.1371/journal.pone.0076405] [PMID:  24098492] 
[58] 
Trejo JL, Pons S. Phosphatidylinositol-3-OH kinase regulatory subunits are differentially expressed during development of the rat cerebellum. J Neurobiol  2001; 47(1): 39-50.
[http://dx.doi.org/10.1002/neu.1014] [PMID:  11257612] 
[59] 
Jaworski J, Spangler S, Seeburg DP, Hoogenraad CC, Sheng M. Control of dendritic arborization by the phosphoinositide-3′-kinase-Akt-mammalian target of rapamycin pathway. J Neurosci  2005; 25(49): 11300-12.
[http://dx.doi.org/10.1523/JNEUROSCI.2270-05.2005] [PMID:  16339025] 
[60] 
Chan CB, Ye K. Multiple functions of phosphoinositide-3 kinase enhancer (PIKE). ScientificWorldJournal  2010; 10: 613-23.
[http://dx.doi.org/10.1100/tsw.2010.64] [PMID:  20419274] 
[61] 
Cuesto G, Enriquez-Barreto L, Caramés C, et al. Phosphoinositide-3-kinase activation controls synaptogenesis and spinogenesis in hippocampal neurons. J Neurosci  2011; 31(8): 2721-33.
[http://dx.doi.org/10.1523/JNEUROSCI.4477-10.2011] [PMID:  21414895] 
[62] 
Horwood JM, Dufour F, Laroche S, Davis S. Signalling mechanisms mediated by the phosphoinositide 3-kinase/Akt cascade in synaptic plasticity and memory in the rat. Eur J Neurosci  2006; 23(12): 3375-84.
[http://dx.doi.org/10.1111/j.1460-9568.2006.04859.x] [PMID:  16820027] 
[63] 
Rivière J-B, Mirzaa GM, O’Roak BJ, et al. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat Genet  2012; 44(8): 934-40.
[http://dx.doi.org/10.1038/ng.2331] [PMID:  22729224] 
[64] 
Xiao Z, Peng J, Yang L, Kong H, Yin F. Interleukin-1β plays a role in the pathogenesis of mesial temporal lobe epilepsy through the PI3K/Akt/mTOR signaling pathway in hippocampal neurons. J Neuroimmunol  2015; 282: 110-7.
[http://dx.doi.org/10.1016/j.jneuroim.2015.04.003] [PMID:  25903737] 
[65] 
Brandt C, Hillmann P, Noack A, et al. The novel, catalytic mTORC1/2 inhibitor PQR620 and the PI3K/mTORC1/2 inhibitor PQR530 effectively cross the blood-brain barrier and increase seizure threshold in a mouse model of chronic epilepsy. Neuropharmacology  2018; 140: 107-20.
[http://dx.doi.org/10.1016/j.neuropharm.2018.08.002] [PMID:  30081001] 
[66] 
Heras-Sandoval D, Pérez-Rojas JM, Hernández-Damián J, Pedraza-Chaverri J. The role of PI3K/AKT/mTOR pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration. Cell Signal  2014; 26(12): 2694-701.
[http://dx.doi.org/10.1016/j.cellsig.2014.08.019] [PMID:  25173700] 
[67] 
Agyeman AS, Jun WJ, Proia DA, et al. Hsp90 inhibition results in glucocorticoid receptor degradation in association with increased sensitivity to paclitaxel in triple-negative breast cancer. Horm Cancer  2016; 7(2): 114-26.
[http://dx.doi.org/10.1007/s12672-016-0251-8] [PMID:  26858237] 
[68] 
Santi SA, Lee H. The Akt isoforms are present at distinct subcellular locations. Am J Physiol Cell Physiol  2010; 298(3): C580-91.
[http://dx.doi.org/10.1152/ajpcell.00375.2009] [PMID:  20018949] 
[69] 
Downward J. Mechanisms and consequences of activation of protein kinase B/Akt. Curr Opin Cell Biol  1998; 10(2): 262-7.
[http://dx.doi.org/10.1016/S0955-0674(98)80149-X] [PMID:  9561851] 
[70] 
Huang J, Manning BD. A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans  2009; 37(Pt 1): 217-22.
[http://dx.doi.org/10.1042/BST0370217] [PMID:  19143635] 
[71] 
Niswender KD, Morrison CD, Clegg DJ, et al. Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus: a key mediator of insulin-induced anorexia. Diabetes  2003; 52(2): 227-31.
[http://dx.doi.org/10.2337/diabetes.52.2.227] [PMID:  12540590] 
[72] 
Obici S, Zhang BB, Karkanias G, Rossetti L. Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med  2002; 8(12): 1376-82.
[http://dx.doi.org/10.1038/nm1202-798] [PMID:  12426561] 
[73] 
Oh H, Boghossian S, York DA, Park-York M. The effect of high fat diet and saturated fatty acids on insulin signaling in the amygdala and hypothalamus of rats. Brain Res  2013; 1537: 191-200.
[http://dx.doi.org/10.1016/j.brainres.2013.09.025] [PMID:  24076449] 
[74] 
Pardini AW, Nguyen HT, Figlewicz DP, et al. Distribution of insulin receptor substrate-2 in brain areas involved in energy homeostasis. Brain Res  2006; 1112(1): 169-78.
[http://dx.doi.org/10.1016/j.brainres.2006.06.109] [PMID:  16925984] 
[75] 
Agostini M, Romeo F, Inoue S, et al. Metabolic reprogramming during neuronal differentiation. Cell Death Differ  2016; 23(9): 1502-14.
[http://dx.doi.org/10.1038/cdd.2016.36] [PMID:  27058317] 
[76] 
Pearson-Leary J, Jahagirdar V, Sage J, McNay EC. Insulin modulates hippocampally-mediated spatial working memory via glucose transporter-4. Behav Brain Res  2018; 338: 32-9.
[http://dx.doi.org/10.1016/j.bbr.2017.09.033] [PMID:  28943428] 
[77] 
Zhang T, Shi Z, Wang Y, et al. Akt3 deletion in mice impairs spatial cognition and hippocampal CA1 long long-term potentiation through downregulation of mTOR. Acta Physiol (Oxf)  2019; 225(1): e13167.
[http://dx.doi.org/10.1111/apha.13167] [PMID:  30053339] 
[78] 
Kim J-I, Lee H-R, Sim SE, et al. PI3Kγ is required for NMDA receptor-dependent long-term depression and behavioral flexibility. Nat Neurosci  2011; 14(11): 1447-54.
[http://dx.doi.org/10.1038/nn.2937] [PMID:  22019731] 
[79] 
Choi J-H, Park P, Baek G-C, et al. Effects of PI3Kγ overexpression in the hippocampus on synaptic plasticity and spatial learning. Mol Brain  2014; 7: 78.
[http://dx.doi.org/10.1186/s13041-014-0078-6] [PMID:  25373491] 
[80] 
Lin CH, Yeh SH, Lin CH, et al. A role for the PI-3 kinase signaling pathway in fear conditioning and synaptic plasticity in the amygdala. Neuron  2001; 31(5): 841-51.
[http://dx.doi.org/10.1016/S0896-6273(01)00433-0] [PMID:  11567621] 
[81] 
Seitz C, Hugle M, Cristofanon S, Tchoghandjian A, Fulda S. The dual PI3K/mTOR inhibitor NVP-BEZ235 and chloroquine synergize to trigger apoptosis via mitochondrial-lysosomal cross-talk. Int J Cancer  2013; 132(11): 2682-93.
[http://dx.doi.org/10.1002/ijc.27935] [PMID:  23151917] 
[82] 
Liu Q, Qiu J, Liang M, et al. Akt and mTOR mediate programmed necrosis in neurons. Cell Death Dis  2014; 5: e1084.
[http://dx.doi.org/10.1038/cddis.2014.69] [PMID:  24577082] 
[83] 
Cai WJ, Chen Y, Shi LX, et al. AKT-GSK3β Signaling Pathway Regulates Mitochondrial Dysfunction-Associated OPA1 Cleavage Contributing to Osteoblast Apoptosis: Preventative Effects of Hydroxytyrosol. Oxid Med Cell Longev  2019; 2019: 4101738.
[http://dx.doi.org/10.1155/2019/4101738] [PMID:  31281574] 
[84] 
Kim DI, Lee KH, Gabr AA, et al. Aβ-Induced Drp1 phosphorylation through Akt activation promotes excessive mitochondrial fission leading to neuronal apoptosis. Biochim Biophys Acta  2016; 1863(11): 2820-34.
[http://dx.doi.org/10.1016/j.bbamcr.2016.09.003] [PMID:  27599716] 
[85] 
Lim SL, Rodriguez-Ortiz CJ, Kitazawa M. Infection, systemic inflammation, and Alzheimer’s disease. Microbes Infect  2015; 17(8): 549-56.
[http://dx.doi.org/10.1016/j.micinf.2015.04.004] [PMID:  25912134] 
[86] 
Avila-Muñoz E, Arias C. When astrocytes become harmful: functional and inflammatory responses that contribute to Alzheimer’s disease. Ageing Res Rev  2014; 18: 29-40.
[http://dx.doi.org/10.1016/j.arr.2014.07.004] [PMID:  25078115] 
[87] 
Medeiros R, LaFerla FM. Astrocytes: conductors of the Alzheimer disease neuroinflammatory symphony. Exp Neurol  2013; 239: 133-8.
[http://dx.doi.org/10.1016/j.expneurol.2012.10.007] [PMID:  23063604] 
[88] 
Heneka MT, O’Banion MK, Terwel D, Kummer MP. Neuroinflammatory processes in Alzheimer’s disease. J Neural Transm (Vienna)  2010; 117(8): 919-47.
[http://dx.doi.org/10.1007/s00702-010-0438-z] [PMID:  20632195] 
[89] 
Olson L, Humpel C. Growth factors and cytokines/chemokines as surrogate biomarkers in cerebrospinal fluid and blood for diagnosing Alzheimer’s disease and mild cognitive impairment. Exp Gerontol  2010; 45(1): 41-6.
[http://dx.doi.org/10.1016/j.exger.2009.10.011] [PMID:  19853649] 
[90] 
McGeer EG, McGeer PL. Inflammatory processes in Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry  2003; 27(5): 741-9.
[http://dx.doi.org/10.1016/S0278-5846(03)00124-6] [PMID:  12921904] 
[91] 
Troutman TD, Bazan JF, Pasare C. Toll-like receptors, signaling adapters and regulation of the pro-inflammatory response by PI3K. Cell Cycle  2012; 11(19): 3559-67.
[http://dx.doi.org/10.4161/cc.21572] [PMID:  22895011] 
[92] 
Aksoy E, Taboubi S, Torres D, et al. The p110δ isoform of the kinase PI(3)K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock. Nat Immunol  2012; 13(11): 1045-54.
[http://dx.doi.org/10.1038/ni.2426] [PMID:  23023391] 
[93] 
Byfield MP, Murray JT, Backer JM. hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase. J Biol Chem  2005; 280(38): 33076-82.
[http://dx.doi.org/10.1074/jbc.M507201200] [PMID:  16049009] 
[94] 
Zhou F, Yang Y, Xing D. Bcl-2 and Bcl-xL play important roles in the crosstalk between autophagy and apoptosis. FEBS J  2011; 278(3): 403-13.
[http://dx.doi.org/10.1111/j.1742-4658.2010.07965.x] [PMID:  21182587] 
[95] 
Komatsu M, Ichimura Y. Selective autophagy regulates various cellular functions. Genes Cells  2010; 15(9): 923-33.
[http://dx.doi.org/10.1111/j.1365-2443.2010.01433.x] [PMID:  20670274] 
[96] 
Gerónimo-Olvera C, Montiel T, Rincon-Heredia R, Castro-Obregón S, Massieu L. Autophagy fails to prevent glucose deprivation/glucose reintroduction-induced neuronal death due to calpain-mediated lysosomal dysfunction in cortical neurons. Cell Death Dis  2017; 8(6): e2911.
[http://dx.doi.org/10.1038/cddis.2017.299] [PMID:  28661473] 
[97] 
Issman-Zecharya N, Schuldiner O. The PI3K class III complex promotes axon pruning by downregulating a Ptc-derived signal via endosome-lysosomal degradation. Dev Cell  2014; 31(4): 461-73.
[http://dx.doi.org/10.1016/j.devcel.2014.10.013] [PMID:  25458013] 
[98] 
Weigl W, Milej D, Janusek D, et al. Application of optical methods in the monitoring of traumatic brain injury: A review. J Cereb Blood Flow Metab  2016; 36(11): 1825-43.
[http://dx.doi.org/10.1177/0271678X16667953] [PMID:  27604312] 
[99] 
Feng Y, Cui Y, Gao JL, et al. Resveratrol attenuates neuronal autophagy and inflammatory injury by inhibiting the TLR4/NF-κB signaling pathway in experimental traumatic brain injury. Int J Mol Med  2016; 37(4): 921-30.
[http://dx.doi.org/10.3892/ijmm.2016.2495] [PMID:  26936125] 
[100] 
McKnight NC, Zhong Y, Wold MS, et al. Beclin 1 is required for neuron viability and regulates endosome pathways via the UVRAG-VPS34 complex. PLoS Genet  2014; 10(10): e1004626.
[http://dx.doi.org/10.1371/journal.pgen.1004626] [PMID:  25275521] 
[101] 
Li X, Li J, Zhang Y, Zhou Y. Di-n-butyl phthalate induced hypospadias relates to autophagy in genital tubercle via the PI3K/Akt/mTOR pathway. J Occup Health  2017; 59(1): 8-16.
[http://dx.doi.org/10.1539/joh.16-0089-OA] [PMID:  27885243] 
[102] 
Li Y, Yang W, Quinones-Hinojosa A, et al. Interference with protease-activated receptor 1 alleviates neuronal cell death induced by lipopolysaccharide- Stimulated microglial cells through the PI3K/Akt pathway. Sci Rep  2016; 6: 38247.
[http://dx.doi.org/10.1038/srep38247] [PMID:  27910893] 
[103] 
Chen A, Xiong LJ, Tong Y, Mao M. Neuroprotective effect of brain-derived neurotrophic factor mediated by autophagy through the PI3K/Akt/mTOR pathway. Mol Med Rep  2013; 8(4): 1011-6.
[http://dx.doi.org/10.3892/mmr.2013.1628] [PMID:  23942837] 
[104] 
Kitagishi Y, Matsuda S. Diets involved in PPAR and PI3K/AKT/PTEN pathway may contribute to neuroprotection in a traumatic brain injury. Alzheimers Res Ther  2013; 5(5): 42.
[http://dx.doi.org/10.1186/alzrt208] [PMID:  24074163] 
[105] 
Wu YT, Tan HL, Huang Q, Ong CN, Shen HM. Activation of the PI3K-Akt-mTOR signaling pathway promotes necrotic cell death via suppression of autophagy. Autophagy  2009; 5(6): 824-34.
[http://dx.doi.org/10.4161/auto.9099] [PMID:  19556857] 
[106] 
Luo CL, Li BX, Li QQ, et al. Autophagy is involved in traumatic brain injury-induced cell death and contributes to functional outcome deficits in mice. Neuroscience  2011; 184: 54-63.
[http://dx.doi.org/10.1016/j.neuroscience.2011.03.021] [PMID:  21463664] 
[107] 
Sun LQ, Gao JL, Cui CM, et al. Astrocytic p-connexin 43 regulates neuronal autophagy in the hippocampus following traumatic brain injury in rats. Mol Med Rep  2014; 9(1): 77-82.
[http://dx.doi.org/10.3892/mmr.2013.1787] [PMID:  24220542] 
[108] 
Ciuffreda L, Di Sanza C, Incani UC, Milella M. The mTOR pathway: a new target in cancer therapy. Curr Cancer Drug Targets  2010; 10(5): 484-95.
[http://dx.doi.org/10.2174/156800910791517172] [PMID:  20384580] 
[109] 
Liao Q, Shi DH, Zheng W, Xu XJ, Yu YH. Antiproliferation of cardamonin is involved in mTOR on aortic smooth muscle cells in high fructose-induced insulin resistance rats. Eur J Pharmacol  2010; 641(2-3): 179-86.
[http://dx.doi.org/10.1016/j.ejphar.2010.05.024] [PMID:  20566415] 
[110] 
Pignataro G, Capone D, Polichetti G, et al. Neuroprotective, immunosuppressant and antineoplastic properties of mTOR inhibitors: current and emerging therapeutic options. Curr Opin Pharmacol  2011; 11(4): 378-94.
[http://dx.doi.org/10.1016/j.coph.2011.05.003] [PMID:  21646048] 
[111] 
Liu HQ, An YW, Hu AZ, et al. Critical roles of the PI3K-Akt-mTOR signaling pathway in apoptosis and autophagy of astrocytes induced by methamphetamine. Open Chem  2019; 17(1): 96-104.
[http://dx.doi.org/10.1515/chem-2019-0015] 
[112] 
Shen M, Wang S, Wen X, et al. Dexmedetomidine exerts neuroprotective effect via the activation of the PI3K/Akt/mTOR signaling pathway in rats with traumatic brain injury. Biomed Pharmacother  2017; 95: 885-93.
[http://dx.doi.org/10.1016/j.biopha.2017.08.125] [PMID:  28903184] 
[113] 
Hou Y, Wang K, Wan W, Cheng Y, Pu X, Ye X. Resveratrol provides neuroprotection by regulating the JAK2/STAT3/PI3K/AKT/mTOR pathway after stroke in rats. Genes Dis  2018; 5(3): 245-55.
[http://dx.doi.org/10.1016/j.gendis.2018.06.001] [PMID:  30320189] 
[114] 
Kilic U, Caglayan AB, Beker MC, et al. Particular phosphorylation of PI3K/Akt on Thr308 via PDK-1 and PTEN mediates melatonin’s neuroprotective activity after focal cerebral ischemia in mice. Redox Biol  2017; 12: 657-65.
[http://dx.doi.org/10.1016/j.redox.2017.04.006] [PMID:  28395173] 
[115] 
Zhao M, Gao J, Cui C, Zhang Y, Jiang X, Cui J. Inhibition of PTEN Ameliorates Secondary Hippocampal Injury and Cognitive Deficits after Intracerebral Hemorrhage: Involvement of AKT/FoxO3a/ATG-Mediated Autophagy. Oxid Med Cell Longev  2021; 2021: 5472605.
[http://dx.doi.org/10.1155/2021/5472605] [PMID:  33777313] 
[116] 
Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell  2012; 149(2): 274-93.
[http://dx.doi.org/10.1016/j.cell.2012.03.017] [PMID:  22500797] 
[117] 
Khaleghpour K, Pyronnet S, Gingras AC, Sonenberg N. Translational homeostasis: eukaryotic translation initiation factor 4E control of 4E-binding protein 1 and p70 S6 kinase activities. Mol Cell Biol  1999; 19(6): 4302-10.
[http://dx.doi.org/10.1128/MCB.19.6.4302] [PMID:  10330171] 
[118] 
Tee AR. The target of Rapamycin and mechanisms of cell growth. Int J Mol Sci  2018; 19(3): 880.
[http://dx.doi.org/10.3390/ijms19030880] [PMID:  29547541] 
[119] 
Sharma A, Mehan S. Targeting PI3K-AKT/mTOR signaling in the prevention of autism. Neurochem Int  2021; 147: 105067.
[http://dx.doi.org/10.1016/j.neuint.2021.105067] [PMID:  33992742] 
[120] 
Duarte A, Silveira GG, Soave DF, Costa JPO, Silva AR. The role of the LY294002-a non-selective inhibitor of phosphatidylinositol 3-kinase (PI3K) pathway-in cell survival and proliferation in cell line SCC-25. Asian Pac J Cancer Prev  2019; 20(11): 3377-83.
[http://dx.doi.org/10.31557/APJCP.2019.20.11.3377] [PMID:  31759362] 
[121] 
Bavelloni A, Focaccia E, Piazzi M, et al. Therapeutic potential of nvp-bkm120 in human osteosarcomas cells. J Cell Physiol  2019; 234(7): 10907-17.
[http://dx.doi.org/10.1002/jcp.27911] [PMID:  30536897] 
[122] 
Hainsworth JD, Becker KP, Mekhail T, et al. Phase I/II study of bevacizumab with BKM120, an oral PI3K inhibitor, in patients with refractory solid tumors (phase I) and relapsed/refractory glioblastoma (phase II). J Neurooncol  2019; 144(2): 303-11.
[http://dx.doi.org/10.1007/s11060-019-03227-7] [PMID:  31392595] 
[123] 
Weinberg MA. RES-529: a PI3K/AKT/mTOR pathway inhibitor that dissociates the mTORC1 and mTORC2 complexes. Anticancer Drugs  2016; 27(6): 475-87.
[http://dx.doi.org/10.1097/CAD.0000000000000354] [PMID:  26918392] 
[124] 
Kaley TJ, Panageas KS, Mellinghoff IK, et al. Phase II trial of an AKT inhibitor (perifosine) for recurrent glioblastoma. J Neurooncol  2019; 144(2): 403-7.
[http://dx.doi.org/10.1007/s11060-019-03243-7] [PMID:  31325145] 
[125] 
Peng K, Fan X, Li Q, et al. IRF-1 mediates the suppressive effects of mTOR inhibition on arterial endothelium. J Mol Cell Cardiol  2020; 140: 30-41.
[http://dx.doi.org/10.1016/j.yjmcc.2020.02.006] [PMID:  32087218] 
[126] 
Méndez-Gómez M, Castro-Mercado E, Peña-Uribe CA, Reyes-de la Cruz H, López-Bucio J, García-Pineda E. TARGET OF RAPAMYCIN signaling plays a role in Arabidopsis growth promotion by Azospirillum brasilense Sp245. Plant Sci  2020; 293: 110416.
[http://dx.doi.org/10.1016/j.plantsci.2020.110416] [PMID:  32081264] 
[127] 
Brakemeier S, Arns W, Lehner F, et al. Everolimus in de novo kidney transplant recipients participating in the Eurotransplant senior program: Results of a prospective randomized multicenter study (SENATOR). PLoS One  2019; 14(9): e0222730.
[http://dx.doi.org/10.1371/journal.pone.0222730] [PMID:  31536556] 
[128] 
Schotz U, Balzer V, Brandt FW, et al. Dual PI3K/mTOR inhibitor NVP-BEZ235 enhances radiosensitivity of head and neck squamous cell carcinoma (HNSCC) cell lines due to suppressed double-strand break (DSB) repair by non-homologous end joining. Cancers (Basel)  2020; 12(2): 467.
[129] 
Affoo RH, Foley N, Rosenbek J, Kevin Shoemaker J, Martin RE. Swallowing dysfunction and autonomic nervous system dysfunction in Alzheimer’s disease: a scoping review of the evidence. J Am Geriatr Soc  2013; 61(12): 2203-13.
[http://dx.doi.org/10.1111/jgs.12553] [PMID:  24329892] 
[130] 
Caricasole A, Copani A, Caruso A, et al. The Wnt pathway, cell-cycle activation and beta-amyloid: novel therapeutic strategies in Alzheimer’s disease? Trends Pharmacol Sci  2003; 24(5): 233-8.
[http://dx.doi.org/10.1016/S0165-6147(03)00100-7] [PMID:  12767722] 
[131] 
Ksiezak-Reding H, Pyo HK, Feinstein B, Pasinetti GM. Akt/PKB kinase phosphorylates separately Thr212 and Ser214 of tau protein in vitro. Biochim Biophys Acta  2003; 1639(3): 159-68.
[http://dx.doi.org/10.1016/j.bbadis.2003.09.001] [PMID:  14636947] 
[132] 
Howes AL, Arthur JF, Zhang T, et al. Akt-mediated cardiomyocyte survival pathways are compromised by G alpha q-induced phosphoinositide 4,5-bisphosphate depletion. J Biol Chem  2003; 278(41): 40343-51.
[http://dx.doi.org/10.1074/jbc.M305964200] [PMID:  12900409] 
[133] 
Ksiezak-Reding H, Pyo HK, Feinstein B, Pasinetti GM. Akt/PKB kinase phosphorylates separately Thr212 and Ser214 of tau protein in vitro. Biochim Biophys Acta  2003; 1639(3): 159-68.
[134] 
Lee CW, Lau KF, Miller CC, Shaw PC. Glycogen synthase kinase-3 beta-mediated tau phosphorylation in cultured cell lines. Neuroreport  2003; 14(2): 257-60.
[http://dx.doi.org/10.1097/00001756-200302100-00020] [PMID:  12598741] 
[135] 
Wen Y, Planel E, Herman M, et al. Interplay between cyclin-dependent kinase 5 and glycogen synthase kinase 3 beta mediated by neuregulin signaling leads to differential effects on tau phosphorylation and amyloid precursor protein processing. J Neurosci  2008; 28(10): 2624-32.
[http://dx.doi.org/10.1523/JNEUROSCI.5245-07.2008] [PMID:  18322105] 
[136] 
Bhaskar K, Miller M, Chludzinski A, Herrup K, Zagorski M, Lamb BT. The PI3K-Akt-mTOR pathway regulates Abeta oligomer induced neuronal cell cycle events. Mol Neurodegener  2009; 4(1): 14.
[http://dx.doi.org/10.1186/1750-1326-4-14] [PMID:  19291319] 
[137] 
Do TD, Economou NJ, Chamas A, Buratto SK, Shea JE, Bowers MT. Interactions between amyloid-β and Tau fragments promote aberrant aggregates: implications for amyloid toxicity. J Phys Chem B  2014; 118(38): 11220-30.
[http://dx.doi.org/10.1021/jp506258g] [PMID:  25153942] 
[138] 
Kitagishi Y, Nakanishi A, Ogura Y, Matsuda S. Dietary regulation of PI3K/AKT/GSK-3β pathway in Alzheimer’s disease. Alzheimers Res Ther  2014; 6(3): 35.
[http://dx.doi.org/10.1186/alzrt265] [PMID:  25031641] 
[139] 
Carrarini C, Russo M, Dono F, et al. A stage-based approach to therapy in Parkinson’s Disease. Biomolecules  2019; 9(8): E388.
[http://dx.doi.org/10.3390/biom9080388] [PMID:  31434341] 
[140] 
AlDakheel A, Kalia LV, Lang AE. Pathogenesis-targeted, disease-modifying therapies in Parkinson disease. Neurotherapeutics  2014; 11(1): 6-23.
[http://dx.doi.org/10.1007/s13311-013-0218-1] [PMID:  24085420] 
[141] 
Luo S, Kang SS, Wang ZH, et al. Akt phosphorylates NQO1 and triggers its degradation, abolishing its antioxidative activities in Parkinson’s Disease. J Neurosci  2019; 39(37): 7291-305.
[http://dx.doi.org/10.1523/JNEUROSCI.0625-19.2019] [PMID:  31358653] 
[142] 
Leikas JV, Kohtala S, Theilmann W, Jalkanen AJ, Forsberg MM, Rantamäki T. Brief isoflurane anesthesia regulates striatal AKT-GSK3β signaling and ameliorates motor deficits in a rat model of early-stage Parkinson’s disease. J Neurochem  2017; 142(3): 456-63.
[http://dx.doi.org/10.1111/jnc.14066] [PMID:  28488766] 
[143] 
Jia Y, Mo SJ, Feng QQ, et al. EPO-dependent activation of PI3K/Akt/FoxO3a signalling mediates neuroprotection in in vitro and in vivo models of Parkinson’s disease. J Mol Neurosci  2014; 53(1): 117-24.
[http://dx.doi.org/10.1007/s12031-013-0208-0] [PMID:  24390959] 
[144] 
Jaworski T, Banach-Kasper E, Gralec K. GSK-3β at the Intersection of Neuronal Plasticity and Neurodegeneration. Neural Plast  2019; 2019: 4209475.
[http://dx.doi.org/10.1155/2019/4209475] [PMID:  31191636] 
[145] 
Yang L, Wang H, Liu L, Xie A. The role of insulin/IGF-1/PI3K/Akt/GSK3beta signaling in Parkinson’s disease dementia. Front Neurosci  2018; 12: 73.
[http://dx.doi.org/10.3389/fnins.2018.00073] [PMID:  29515352] 
[146] 
Zhang W, He H, Song H, et al. Neuroprotective effects of salidroside in the MPTP mouse model of Parkinson’s disease: involvement of the PI3K/Akt/GSK3beta pathway. Parkinsons Dis  2016; 2016: 9450137.
[http://dx.doi.org/10.1155/2016/9450137] [PMID:  27738547] 
[147] 
Gong J, Zhang L, Zhang Q, et al. Lentiviral vector-mediated SHC3 silencing exacerbates oxidative stress injury in nigral dopamine neurons by regulating the PI3K-AKT-FoxO signaling pathway in rats with Parkinson’s disease. Cell Physiol Biochem  2018; 49(3): 971-84.
[http://dx.doi.org/10.1159/000493228] [PMID:  30184529] 
[148] 
Jha SK, Jha NK, Kar R, Ambasta RK, Kumar P. p38 MAPK and PI3K/AKT signalling cascades in Parkinson’s disease. Int J Mol Cell Med  2015; 4(2): 67-86.
[PMID:  26261796] 
[149] 
Giacoppo S, Bramanti P, Mazzon E. Triggering of inflammasome by impaired autophagy in response to acute experimental Parkinson’s disease: involvement of the PI3K/Akt/mTOR pathway. Neuroreport  2017; 28(15): 996-1007.
[http://dx.doi.org/10.1097/WNR.0000000000000871] [PMID:  28902711] 
[150] 
Chen WF, Wu L, Du ZR, et al. Neuroprotective properties of icariin in MPTP-induced mouse model of Parkinson’s disease: Involvement of PI3K/Akt and MEK/ERK signaling pathways. Phytomedicine  2017; 25: 93-9.
[http://dx.doi.org/10.1016/j.phymed.2016.12.017] [PMID:  28190476] 
[151] 
Ribeiro M, Rosenstock TR, Oliveira AM, Oliveira CR, Rego AC. Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington’s disease knock-in striatal cells. Free Radic Biol Med  2014; 74: 129-44.
[http://dx.doi.org/10.1016/j.freeradbiomed.2014.06.023] [PMID:  24992836] 
[152] 
Bathina S, Das UN. Brain-derived neurotrophic factor and its clinical implications. Arch Med Sci  2015; 11(6): 1164-78.
[http://dx.doi.org/10.5114/aoms.2015.56342] [PMID:  26788077] 
[153] 
Vaillant AR, Mazzoni I, Tudan C, Boudreau M, Kaplan DR, Miller FD. Depolarization and neurotrophins converge on the phosphatidylinositol 3-kinase-Akt pathway to synergistically regulate neuronal survival. J Cell Biol  1999; 146(5): 955-66.
[http://dx.doi.org/10.1083/jcb.146.5.955] [PMID:  10477751] 
[154] 
Silva A, Naia L, Dominguez A, et al. Overexpression of BDNF and full-length TrkB receptor ameliorate striatal neural survival in Huntington’s disease. Neurodegener Dis  2015; 15(4): 207-18.
[http://dx.doi.org/10.1159/000375447] [PMID:  25896770] 
[155] 
Fernández-Nogales M, Cabrera JR, Santos-Galindo M, et al. Huntington’s disease is a four-repeat tauopathy with tau nuclear rods. Nat Med  2014; 20(8): 881-5.
[http://dx.doi.org/10.1038/nm.3617] [PMID:  25038828] 
[156] 
Saavedra A, García-Martínez JM, Xifró X, et al. PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt pro-survival pathway in Huntington’s disease striatum. Cell Death Differ  2010; 17(2): 324-35.
[http://dx.doi.org/10.1038/cdd.2009.127] [PMID:  19745829] 
[157] 
L’Episcopo F, Drouin-Ouellet J, Tirolo C, et al. GSK-3β-induced Tau pathology drives hippocampal neuronal cell death in Huntington’s disease: involvement of astrocyte-neuron interactions. Cell Death Dis  2016; 7: e2206.
[http://dx.doi.org/10.1038/cddis.2016.104] [PMID:  27124580] 
[158] 
Nath FP, Jenkins A, Mendelow AD, Graham DI, Teasdale GM. Early hemodynamic changes in experimental intracerebral hemorrhage. J Neurosurg  1986; 65(5): 697-703.
[http://dx.doi.org/10.3171/jns.1986.65.5.0697] [PMID:  3772459] 
[159] 
Rajdev K, Mehan S. Neuroprotective methodologies of Co-enzyme Q10 associated mitochondrial dysfunction in post brain haemorrhagic treatment: clinical and pre-clinical findings. CNS Neurol Disord Drug Targets  2019; 18(6): 446-65.
[http://dx.doi.org/10.2174/1871527318666190610101144] [PMID:  31187715] 
[160] 
Miller JH, Wardlaw JM, Lammie GA. Intracerebral haemorrhage and cerebral amyloid angiopathy: CT features with pathological correlation. Clin Radiol  1999; 54(7): 422-9.
[http://dx.doi.org/10.1016/S0009-9260(99)90825-5] [PMID:  10437691] 
[161] 
Kirkman MA, Allan SM, Parry-Jones AR. Experimental intracerebral hemorrhage: avoiding pitfalls in translational research. J Cereb Blood Flow Metab  2011; 31(11): 2135-51.
[http://dx.doi.org/10.1038/jcbfm.2011.124] [PMID:  21863040] 
[162] 
Yang GY, Betz AL, Chenevert TL, Brunberg JA, Hoff JT. Experimental intracerebral hemorrhage: relationship between brain edema, blood flow, and blood-brain barrier permeability in rats. J Neurosurg  1994; 81(1): 93-102.
[http://dx.doi.org/10.3171/jns.1994.81.1.0093] [PMID:  8207532] 
[163] 
Xue M, Del Bigio MR. Comparison of brain cell death and inflammatory reaction in three models of intracerebral hemorrhage in adult rats. J Stroke Cerebrovasc Dis  2003; 12(3): 152-9.
[http://dx.doi.org/10.1016/S1052-3057(03)00036-3] [PMID:  17903920] 
[164] 
Iida S, Baumbach GL, Lavoie JL, Faraci FM, Sigmund CD, Heistad DD. Spontaneous stroke in a genetic model of hypertension in mice. Stroke  2005; 36(6): 1253-8.
[http://dx.doi.org/10.1161/01.str.0000167694.58419.a2] [PMID:  15914769] 
[165] 
Merrill DC, Thompson MW, Carney CL, et al. Chronic hypertension and altered baroreflex responses in transgenic mice containing the human renin and human angiotensinogen genes. J Clin Invest  1996; 97(4): 1047-55.
[http://dx.doi.org/10.1172/JCI118497] [PMID:  8613528] 
[166] 
Herzig MC, Winkler DT, Burgermeister P, et al. Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nat Neurosci  2004; 7(9): 954-60.
[http://dx.doi.org/10.1038/nn1302] [PMID:  15311281] 
[167] 
Elfenbein HA, Rosen RF, Stephens SL, et al. Cerebral beta-amyloid angiopathy in aged squirrel monkeys. Histol Histopathol  2007; 22(2): 155-67.
[PMID:  17149688] 
[168] 
Davis J, Xu F, Deane R, et al. Early-onset and robust cerebral microvascular accumulation of amyloid β-protein in transgenic mice expressing low levels of a vasculotropic Dutch/Iowa mutant form of amyloid β-protein precursor. J Biol Chem  2004; 279(19): 20296-306.
[http://dx.doi.org/10.1074/jbc.M312946200] [PMID:  14985348] 
[169] 
Coomaraswamy J, Kilger E, Wölfing H, et al. Modeling familial Danish dementia in mice supports the concept of the amyloid hypothesis of Alzheimer’s disease. Proc Natl Acad Sci USA  2010; 107(17): 7969-74.
[http://dx.doi.org/10.1073/pnas.1001056107] [PMID:  20385796] 
[170] 
Winkler DT, Bondolfi L, Herzig MC, et al.  Spontaneous haemorrhagic
stroke in a mouse model of cerebral amyloid angiopathy. J
Neurosci. 2001; 21(5): 1619– 27.155.
[171] 
Clark W, Gunion-Rinker L, Lessov N, Hazel K, Macdonald RL. Citicoline treatment for experimental intracerebral haemorrhage in mice editorial comment. Stroke  1998; 29: 2136-40.
[http://dx.doi.org/10.1161/01.STR.29.10.2136] [PMID:  9756595] 
[172] 
Rosenberg GA, Mun-Bryce S, Wesley M, Kornfeld M. Collagenase-induced intracerebral hemorrhage in rats. Stroke  1990; 21(5): 801-7.
[http://dx.doi.org/10.1161/01.STR.21.5.801] [PMID:  2160142] 
[173] 
Wang J, Tsirka SE. Tuftsin fragment 1-3 is beneficial when delivered after the induction of intracerebral hemorrhage. Stroke  2005; 36(3): 613-8.
[http://dx.doi.org/10.1161/01.STR.0000155729.12931.8f] [PMID:  15692122] 
[174] 
Manaenko A, Chen H, Zhang JH, Tang J. Comparison of different preclinical models of intracerebral hemorrhage. Acta Neurochir Suppl (Wien)  2011; 111: 9-14.
[http://dx.doi.org/10.1007/978-3-7091-0693-8_2] [PMID:  21725724] 
[175] 
Leonardo CC, Robbins S, Doré S. Translating basic science research to clinical application: models and strategies for intracerebral hemorrhage. Front Neurol  2012; 3: 85.
[http://dx.doi.org/10.3389/fneur.2012.00085] [PMID:  22661966] 
[176] 
Sinar EJ, Mendelow AD, Graham DI, Teasdale GM. Experimental intracerebral hemorrhage: effects of a temporary mass lesion. J Neurosurg  1987; 66(4): 568-76.
[http://dx.doi.org/10.3171/jns.1987.66.4.0568] [PMID:  3559723] 
[177] 
Lopez Valdes E, Hernandez Lain A, Calandre L, Grau M, Cabello A, Gomez-Escalonilla C. Time window for clinical effectiveness of mass evacuation in a rat balloon model mimicking an intraparenchymatous hematoma. J Neurol Sci  2000; 174(1): 40-6.
[http://dx.doi.org/10.1016/S0022-510X(99)00288-9] [PMID:  10704978] 
[178] 
Nakashima K, Yamashita K, Uesugi S, Ito H. Temporal and spatial profile of apoptotic cell death in transient intracerebral mass lesion of the rat. J Neurotrauma  1999; 16(2): 143-51.
[http://dx.doi.org/10.1089/neu.1999.16.143] [PMID:  10098959] 
[179] 
Siaw-Debrah F, Nyanzu M, Ni H, et al. Preclinical Studies and Translational Applications of Intracerebral Hemorrhage. BioMed Res Int  2017; 2017: 5135429.
[http://dx.doi.org/10.1155/2017/5135429] [PMID:  28698874] 
[180] 
Giansily-Blaizot M, Schved JF. Recombinant human factor VIIa (rFVIIa) in hemophilia: mode of action and evidence to date. Ther Adv Hematol  2017; 8(12): 345-52.
[http://dx.doi.org/10.1177/2040620717737701] [PMID:  29204261] 
[181] 
Konkle BA, Ebbesen LS, Erhardtsen E, et al. Randomized, prospective clinical trial of recombinant factor VIIa for secondary prophylaxis in hemophilia patients with inhibitors. J Thromb Haemost  2007; 5(9): 1904-13.
[http://dx.doi.org/10.1111/j.1538-7836.2007.02663.x] [PMID:  17723130] 
[182] 
Marsh K, Green D, Raco V, Papadopoulos J, Ahuja T. Antithrombotic and hemostatic stewardship: evaluation of clinical outcomes and adverse events of recombinant factor VIIa (Novoseven®) utilization at a large academic medical center. Ther Adv Cardiovasc Dis  2020; 14: 1753944720924255.
[http://dx.doi.org/10.1177/1753944720924255] [PMID:  32449469] 
[183] 
Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med  2005; 352(8): 777-85.
[http://dx.doi.org/10.1056/NEJMoa042991] [PMID:  15728810] 
[184] 
Mayer SA, Brun NC, Begtrup K, et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med  2008; 358(20): 2127-37.
[http://dx.doi.org/10.1056/NEJMoa0707534] [PMID:  18480205] 
[185] 
Mary V, Wahl F, Uzan A, Stutzmann JM. Enoxaparin in experimental stroke: neuroprotection and therapeutic window of opportunity. Stroke  2001; 32(4): 993-9.
[http://dx.doi.org/10.1161/01.STR.32.4.993] [PMID:  11283402] 
[186] 
Kase CS, Albers GW, Bladin C, et al. Neurological outcomes in patients with ischemic stroke receiving enoxaparin or heparin for venous thromboembolism prophylaxis: subanalysis of the Prevention of VTE after Acute Ischemic Stroke with LMWH (PREVAIL) study. Stroke  2009; 40(11): 3532-40.
[http://dx.doi.org/10.1161/STROKEAHA.109.555003] [PMID:  19696423] 
[187] 
Nonaka Y, Tsuruma K, Shimazawa M, Yoshimura S, Iwama T, Hara H. Cilostazol protects against hemorrhagic transformation in mice transient focal cerebral ischemia-induced brain damage. Neurosci Lett  2009; 452(2): 156-61.
[http://dx.doi.org/10.1016/j.neulet.2009.01.039] [PMID:  19383431] 
[188] 
Uchiyama S, Sakai N. Cilostazol-aspirin therapy against recurrent
stroke with intracranial artery stenosis. In:  2006. Available from: http://clinicaltrials.gov/show/NCT00333164
[189] 
Ding G, Jiang Q, Zhang L, et al. Analysis of combined treatment of embolic stroke in rat with r-tPA and a GPIIb/IIIa inhibitor. J Cereb Blood Flow Metab  2005; 25(1): 87-97.
[http://dx.doi.org/10.1038/sj.jcbfm.9600010] [PMID:  15678115] 
[190] 
Pancioli AM, Adeoye OM. Study of the combination therapy of rt-
PA and eptifibatide to treat acute ischemic stroke (CLEAR-ER). In:  2009. Available from: http://clinicaltrials.gov/show/NCT00894
803
[191] 
O’Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW. 1,026 experimental treatments in acute stroke. Ann Neurol  2006; 59(3): 467-77.
[http://dx.doi.org/10.1002/ana.20741] [PMID:  16453316] 
[192] 
Tissue plasminogen activator for acute ischemic stroke. The national institute of neurological disorders and stroke rt-PA stroke study group. N Engl J Med  1995; 333: 1581-7.
[http://dx.doi.org/10.1056/NEJM199512143332401] 
[193] 
Lee KY, Kim DI, Kim SH, et al. Sequential combination of intravenous recombinant tissue plasminogen activator and intra-arterial urokinase in acute ischemic stroke. AJNR Am J Neuroradiol  2004; 25(9): 1470-5.
[PMID:  15502123] 
[194] 
Nategh M, Shaveisi K, Shabanzadeh AP, Sadr SSh, Parviz M, Ghabaei M. Systemic hyperthermia masks the neuroprotective effects of MK-801, but not rosiglitazone in brain ischaemia. Basic Clin Pharmacol Toxicol  2010; 107(3): 724-9.
[http://dx.doi.org/10.1111/j.1742-7843.2010.00570.x] [PMID:  20406202] 
[195] 
Kocaeli H, Korfali E, Oztürk H, Kahveci N, Yilmazlar S. MK-801 improves neurological and histological outcomes after spinal cord ischemia induced by transient aortic cross-clipping in rats. Surg Neurol  2005; 64(Suppl. 2): S22-6.
[http://dx.doi.org/10.1016/j.surneu.2005.07.034] [PMID:  16256835] 
[196] 
Horn J, de Haan RJ, Vermeulen M, Luiten PG, Limburg M. Nimodipine in animal model experiments of focal cerebral ischemia: a systematic review. Stroke  2001; 32(10): 2433-8.
[http://dx.doi.org/10.1161/hs1001.096009] [PMID:  11588338] 
[197] 
Zhang J, Yang J, Zhang C, Jiang X, Zhou H, Liu M. Calcium antagonists for acute ischemic stroke. Cochrane Database Syst Rev  2012; 5(5): CD001928.
[PMID:  22592678] 
[198] 
Mullins ME, Empey M, Jaramillo D, Sosa S, Human T, Diringer MN. A prospective randomized study to evaluate the antipyretic effect of the combination of acetaminophen and ibuprofen in neurological ICU patients. Neurocrit Care  2011; 15(3): 375-8.
[http://dx.doi.org/10.1007/s12028-011-9533-8] [PMID:  21503807] 
[199] 
Polson J, Lee WM. AASLD position paper: the management of acute liver failure. Hepatology  2005; 41(5): 1179-97.
[http://dx.doi.org/10.1002/hep.20703] [PMID:  15841455] 
[200] 
Zhao Z, Cheng M, Maples KR, Ma JY, Buchan AM. NXY-059, a novel free radical trapping compound, reduces cortical infarction after permanent focal cerebral ischemia in the rat. Brain Res  2001; 909(1-2): 46-50.
[http://dx.doi.org/10.1016/S0006-8993(01)02618-X] [PMID:  11478919] 
[201] 
Sydserff SG, Borelli AR, Green AR, Cross AJ. Effect of NXY-059 on infarct volume after transient or permanent middle cerebral artery occlusion in the rat; studies on dose, plasma concentration and therapeutic time window. Br J Pharmacol  2002; 135(1): 103-12.
[http://dx.doi.org/10.1038/sj.bjp.0704449] [PMID:  11786485] 
[202] 
Peeling J, Del Bigio MR, Corbett D, Green AR, Jackson DM. Efficacy of disodium 4-[(tert-butylimino)methyl]benzene-1,3-disulfonate N-oxide (NXY-059), a free radical trapping agent, in a rat model of hemorrhagic stroke. Neuropharmacology  2001; 40(3): 433-9.
[http://dx.doi.org/10.1016/S0028-3908(00)00170-2] [PMID:  11166336] 
[203] 
Lyden PD, Shuaib A, Lees KR, et al. Safety and tolerability of NXY-059 for acute intracerebral hemorrhage: the chant Trial. Stroke  2007; 38(8): 2262-9.
[http://dx.doi.org/10.1161/STROKEAHA.106.472746] [PMID:  17569876] 
[204] 
Diener H-C, Lees KR, Lyden P, et al. NXY-059 for the treatment of acute stroke: pooled analysis of the SAINT I and II Trials. Stroke  2008; 39(6): 1751-8.
[http://dx.doi.org/10.1161/STROKEAHA.107.503334] [PMID:  18369171] 
[205] 
Kellner CP, Connolly ES Jr. Neuroprotective strategies for intracerebral hemorrhage: trials and translation. Stroke  2010; 41(10)(Suppl.): S99-S102.
[http://dx.doi.org/10.1161/STROKEAHA.110.597476] [PMID:  20876519] 
[206] 
Lapchak PA, Araujo DM. Development of the nitrone-based spin trap agent NXY-059 to treat acute ischemic stroke. CNS Drug Rev  2003; 9(3): 253-62.
[http://dx.doi.org/10.1111/j.1527-3458.2003.tb00252.x] [PMID:  14530797] 
[207] 
Sturgeon JD, Folsom AR, Longstreth WT Jr, Shahar E, Rosamond WD, Cushman M. Risk factors for intracerebral hemorrhage in a pooled prospective study. Stroke  2007; 38(10): 2718-25.
[http://dx.doi.org/10.1161/STROKEAHA.107.487090] [PMID:  17761915] 
[208] 
Orken DN, Kenangil G, Celik M, et al. Association of low cholesterol with primary intracerebral haemorrhage: a case control study. Acta Neurol Scand  2009; 119(3): 151-4.
[http://dx.doi.org/10.1111/j.1600-0404.2008.01083.x] [PMID:  18684213] 
[209] 
Amarenco P, Bogousslavsky J, Callahan A III, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med  2006; 355(6): 549-59.
[http://dx.doi.org/10.1056/NEJMoa061894] [PMID:  16899775] 
[210] 
Sironi L, Cimino M, Guerrini U, et al. Treatment with statins after induction of focal ischemia in rats reduces the extent of brain damage. Arterioscler Thromb Vasc Biol  2003; 23(2): 322-7.
[http://dx.doi.org/10.1161/01.ATV.0000044458.23905.3B] [PMID:  12588778] 
[211] 
Laufs U, Gertz K, Dirnagl U, Böhm M, Nickenig G, Endres M. Rosuvastatin, a new HMG-CoA reductase inhibitor, upregulates endothelial nitric oxide synthase and protects from ischemic stroke in mice. Brain Res  2002; 942(1-2): 23-30.
[http://dx.doi.org/10.1016/S0006-8993(02)02649-5] [PMID:  12031849] 
[212] 
Amin-Hanjani S, Stagliano NE, Yamada M, Huang PL, Liao JK, Moskowitz MA. Mevastatin, an HMG-CoA reductase inhibitor, reduces stroke damage and upregulates endothelial nitric oxide synthase in mice. Stroke  2001; 32(4): 980-6.
[http://dx.doi.org/10.1161/01.STR.32.4.980] [PMID:  11283400] 
[213] 
Seyfried D, Han Y, Lu D, Chen J, Bydon A, Chopp M. Improvement in neurological outcome after administration of atorvastatin following experimental intracerebral hemorrhage in rats. J Neurosurg  2004; 101(1): 104-7.
[http://dx.doi.org/10.3171/jns.2004.101.1.0104] [PMID:  15255259] 
[214] 
Jung KH, Chu K, Jeong SW, et al. HMG-CoA reductase inhibitor, atorvastatin, promotes sensorimotor recovery, suppressing acute inflammatory reaction after experimental intracerebral hemorrhage. Stroke  2004; 35(7): 1744-9.
[http://dx.doi.org/10.1161/01.STR.0000131270.45822.85] [PMID:  15166393] 
[215] 
Karki K, Knight RA, Han Y, et al. Simvastatin and atorvastatin improve neurological outcome after experimental intracerebral hemorrhage. Stroke  2009; 40(10): 3384-9.
[http://dx.doi.org/10.1161/STROKEAHA.108.544395] [PMID:  19644071] 
[216] 
Lu D, Qu C, Goussev A, et al. Statins increase neurogenesis in the dentate gyrus, reduce delayed neuronal death in the hippocampal CA3 region, and improve spatial learning in rat after traumatic brain injury. J Neurotrauma  2007; 24(7): 1132-46.
[http://dx.doi.org/10.1089/neu.2007.0288] [PMID:  17610353] 
[217] 
Shi Y, Pan H, Zhang HZ, Zhao XY, Jin J, Wang HY. Lipoxin A4 mitigates experimental autoimmune myocarditis by regulating inflammatory response, NF-κB and PI3K/Akt signaling pathway in mice. Eur Rev Med Pharmacol Sci  2017; 21(8): 1850-9.
[PMID:  28485793] 
[218] 
Guo YP, Jiang HK, Jiang H, Tian HY, Li L. Lipoxin A4 may attenuate the progression of obesity-related glomerulopathy by inhibiting NF-κB and ERK/p38 MAPK-dependent inflammation. Life Sci  2018; 198: 112-8.
[http://dx.doi.org/10.1016/j.lfs.2018.02.039] [PMID:  29499280] 
[219] 
Machado FS, Johndrow JE, Esper L, et al. Anti-inflammatory actions of lipoxin A4 and aspirin-triggered lipoxin are SOCS-2 dependent. Nat Med  2006; 12(3): 330-4.
[http://dx.doi.org/10.1038/nm1355] [PMID:  16415877] 
[220] 
Luo C-L, Li Q-Q, Chen X-P, et al. Lipoxin A4 attenuates brain damage and downregulates the production of pro-inflammatory cytokines and phosphorylated mitogen-activated protein kinases in a mouse model of traumatic brain injury. Brain Res  2013; 1502: 1-10.
[http://dx.doi.org/10.1016/j.brainres.2013.01.037] [PMID:  23370001] 
[221] 
Song Y, Yang Y, Cui Y, Gao J, Wang K, Cui J. Lipoxin A4 methyl ester reduces early brain injury by inhibition of the nuclear factor kappa B (NF-κb)-dependent matrix metallopeptidase 9 (MMP-9) pathway in a rat model of intracerebral hemorrhage. Med Sci Monit  2019; 25: 1838-47.
[http://dx.doi.org/10.12659/MSM.915119] [PMID:  30855024] 
[222] 
Wu J, Ding DH, Li QQ, Wang XY, Sun YY, Li LJ. Lipoxin A4 Regulates Lipopolysaccharide-Induced BV2 Microglial Activation and Differentiation via the Notch Signaling Pathway. Front Cell Neurosci  2019; 13: 19.
[http://dx.doi.org/10.3389/fncel.2019.00019] [PMID:  30778288] 
[223] 
Hawkins KE, DeMars KM, Alexander JC, et al. Targeting resolution of neuroinflammation after ischemic stroke with a lipoxin A4 analog: Protective mechanisms and long-term effects on neurological recovery. Brain Behav  2017; 7(5): e00688.
[http://dx.doi.org/10.1002/brb3.688] [PMID:  28523230] 
[224] 
Sinn D-I, Lee S-T, Chu K, et al. Combined neuroprotective effects of celecoxib and memantine in experimental intracerebral hemorrhage. Neurosci Lett  2007; 411(3): 238-42.
[http://dx.doi.org/10.1016/j.neulet.2006.10.050] [PMID:  17123715] 
[225] 
Chu K, Jeong SW, Jung KH, et al. Celecoxib induces functional recovery after intracerebral hemorrhage with reduction of brain edema and perihematomal cell death. J Cereb Blood Flow Metab  2004; 24(8): 926-33.
[http://dx.doi.org/10.1097/01.WCB.0000130866.25040.7D] [PMID:  15362723] 
[226] 
Jendrossek V, Handrick R, Belka C. Celecoxib activates a novel mitochondrial apoptosis signaling pathway. FASEB J  2003; 17(11): 1547-9.
[http://dx.doi.org/10.1096/fj.02-0947fje] [PMID:  12824303] 
[227] 
Rajdev K, Mehan S. Neuroprotective methodologies of co-enzyme Q10 mediated brain hemorrhagic treatment: Clinical and pre-clinical findings. CNS Neurol Disord Drug Targets  2019; 18(6): 446-65.
[228] 
Rajdev K, Siddiqui EM, Jadaun KS, Mehan S. Neuroprotective potential of solanesol in a combined model of intracerebral and intraventricular hemorrhage in rats. IBRO Rep  2020; 8: 101-14.
[http://dx.doi.org/10.1016/j.ibror.2020.03.001] [PMID:  32368686] 
[229] 
Hostettler IC, Seiffge DJ, Werring DJ. Intracerebral hemorrhage: an update on diagnosis and treatment. Expert Rev Neurother  2019; 19(7): 679-94.
[http://dx.doi.org/10.1080/14737175.2019.1623671] [PMID:  31188036] 
[230] 
Park H-K, Lee S-H, Chu K, Roh J-K. Effects of celecoxib on volumes of hematoma and edema in patients with primary intracerebral hemorrhage. J Neurol Sci  2009; 279(1-2): 43-6.
[http://dx.doi.org/10.1016/j.jns.2008.12.020] [PMID:  19168192] 
[231] 
Kaizaki A, Tien LT, Pang Y, et al. Celecoxib reduces brain dopaminergic neuronaldysfunction, and improves sensorimotor behavioral performance in neonatal rats exposed to systemic lipopolysaccharide. J Neuroinflammation  2013; 10(1): 45.
[http://dx.doi.org/10.1186/1742-2094-10-45] [PMID:  23561827] 
[232] 
Sánchez-Alegría K, Flores-León M, Avila-Muñoz E, Rodríguez-Corona N, Arias C. PI3K signaling in neurons: A central node for the control of multiple functions. Int J Mol Sci  2018; 19(12): 3725.
[http://dx.doi.org/10.3390/ijms19123725] [PMID:  30477115] 
[233] 
Wang J-P, Zhang M-Y. Role for target of Rapamycin (mTOR) signal pathway in regulating neuronal injury after intracerebral hemorrhage. Cell Physiol Biochem  2017; 41(1): 145-53.
[http://dx.doi.org/10.1159/000455983] [PMID:  28214828] 
[234] 
Xu F, Na L, Li Y, Chen L. Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours. Cell Biosci  2020; 10(1): 54.
[http://dx.doi.org/10.1186/s13578-020-00416-0] [PMID:  32266056] 
Rights & Permissions Print Cite
Article Metrics
60
1
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/1574884716666210726110021	Print ISSN 2772-4328
Publisher Name Bentham Science Publisher	Online ISSN 2772-4336
Current Reviews in Clinical and Experimental Pharmacology

Targeting Abnormal PI3K/AKT/mTOR Signaling in Intracerebral Hemorrhage: A Systematic Review on Potential Drug Targets and Influences of Signaling Modulators on Other Neurological Disorders

Abstract

Graphical Abstract

Related Journals

Related Books

Related Articles
