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CNS & Neurological Disorders - Drug Targets


ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

Review Article

Neuroprotective Methodologies of Co-Enzyme Q10 Mediated Brain Hemorrhagic Treatment: Clinical and Pre-Clinical Findings

Author(s): Kajal Rajdev and Sidharth Mehan*

Volume 18, Issue 6, 2019

Page: [446 - 465] Pages: 20

DOI: 10.2174/1871527318666190610101144

Price: $65


Cerebral brain hemorrhage is associated with the highest mortality and morbidity despite only constituting approximately 10-15% of all strokes classified into intracerebral and intraventricular hemorrhage where most of the patients suffer from impairment in memory, weakness or paralysis in arms or legs, headache, fatigue, gait abnormality and cognitive dysfunctions. Understanding molecular pathology and finding the worsening cause of hemorrhage will lead to explore the therapeutic interventions that could prevent and cure the disease. Mitochondrial ETC-complexes dysfunction has been found to increase neuroinflammatory cytokines, oxidative free radicals, excitotoxicity, neurotransmitter and energy imbalance that are the key neuropathological hallmarks of cerebral hemorrhage. Coenzyme Q10 (CoQ10), as a part of the mitochondrial respiratory chain can effectively restore these neuronal dysfunctions by preventing the opening of mitochondrial membrane transition pore, thereby counteracting cell death events as well as exerts an anti-inflammatory effect by influencing the expression of NF-kB1 dependent genes thus preventing the neuroinflammation and energy restoration. Due to behavior and biochemical heterogeneity in post cerebral brain hemorrhagic pattern different preclinical autologous blood injection models are required to precisely investigate the forthcoming therapeutic strategies. Despite emerging pre-clinical research and resultant large clinical trials for promising symptomatic treatments, there are very less pharmacological interventions demonstrated to improve post operative condition of patients where intensive care is required. Therefore, in current review, we explore the disease pattern, clinical and pre-clinical interventions under investigation and neuroprotective methodologies of CoQ10 precursors to ameliorate post brain hemorrhagic conditions.

Keywords: Brain hemorrhage, mitochondrial dysfunction, Co-enzyme Q10, cytochrome-C, intracerebral hemorrhage, intraventricular hemorrhage.

Graphical Abstract
Caceres JA, Goldstein JN. Intracranial hemorrhage. Emerg Med Clin North Am 2012; 30(3): 771-94.
Stroke epidemiology and stroke care services in India 2013; 15(3): 128-34.
Marinkovic I, Strbian D, Mattila OS, Abo-Ramadan U, Tatlisumak T. A novel combined model of intracerebral and intraventricular hemorrhage using autologous blood-injection in rats. Neuroscience 2014; 272: 286-94.
Bu Y, Chen M, Gao T, Wang X, Li X, Gao F. Mechanisms of hydrocephalus after intraventricular haemorrhage in adults. Stroke Vasc Neurol 2016; 1(1): 23-7.
Ikram MA, Wieberdink RG, Koudstaal PJ. International epidemiology of intracerebral hemorrhage. Curr Atheroscler Rep 2012; 14(4): 300-6.
Poon MT, Bell SM, Salman RAS. Epidemiology of intracerebral haemorrhage. . In: New Insights in Intracerebral Hemorrhage. Karger Publishers 2016; Vol. 37: pp. 1-12.
Nedergaard M, Klinken L, Paulson OB. Secondary brain stem hemorrhage in stroke. Stroke 1983; 14(4): 501-5.
An SJ, Kim TJ, Yoon BW. Epidemiology, risk factors, and clinical features of intracerebral hemorrhage: An update. J Stroke 2017; 19(1): 3-10.
Vespa PM, O’Phelan K, Shah M, et al. Acute seizures after intracerebral hemorrhage: A factor in progressive midline shift and outcome. Neurology 2003; 60(9): 1441-6.
Wityk RJ, Caplan LR. Hypertensive intracerebral hemorrhage. Epidemiology and clinical pathology. Neurosurg Clin N Am 1992; 3(3): 521-32.
Aguilar MI, Brott TG. Update in intracerebral hemorrhage. Neurohospitalist 2011; 1(3): 148-59.
Wallmark S, Ronne-Engström E, Lundström E. Prevalence of spasticity after aneurysmal subarachnoid haemorrhage. J Rehabil Med 2014; 46(1): 23-7.
Egge A, Waterloo K, Sjøholm H, et al. Outcome 1 year after aneurysmal subarachnoid hemorrhage: Relation between cognitive performance and neuroimaging. Acta Neurol Scand 2005; 112(2): 76-80.
Mayer SA, Kreiter KT, Copeland D, et al. Global and domain-specific cognitive impairment and outcome after subarachnoid hemorrhage. Neurology 2002; 59(11): 1750-8.
Badjatia N, Rosand J. Intracerebral hemorrhage. Neurologist 2005; 11(6): 311-24.
Biffi A, Sonni A, Anderson CD, et al. Variants at APOE influence risk of deep and lobar intracerebral hemorrhage. Ann Neurol 2010; 68(6): 934-43.
Flaherty ML. Anticoagulant-associated intracerebral hemorrhage. Semin Neurol 2010; 30(05): 565-72.
Sweis R, Biller J. Toxicity/substance abusePrimer on cerebrovascular diseases. Academic Press 2017; pp. 614-22.
Hegde A, Nair R, Upadhyaya S. Spontaneous intracerebral hemorrhage in hemophiliacs-A treatment dilemma. Int J Surg Case Rep 2016; 29: 17-9.
Roob G, Lechner A, Schmidt R, Flooh E, Hartung HP, Fazekas F. Frequency and location of microbleeds in patients with primary intracerebral hemorrhage. Stroke 2000; 31(11): 2665-9.
Broderick JP, Adams HP Jr, Barsan W, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: A statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 1999; 30(4): 905-15.
Neil L. Brain hemorrhage: Causes, symptoms, treatments. WebMD Medical Reference 2016.
Sutherland GR, Auer RN. Primary intracerebral hemorrhage. J Clin Neurosci 2006; 13(5): 511-7.
Qureshi AI, Suarez JI, Parekh PD, et al. Risk factors for multiple intracranial aneurysms. Neurosurgery 1998; 43(1): 22-6.
Nolte KB, Brass LM, Fletterick CF. Intracranial hemorrhage associated with cocaine abuse: A prospective autopsy study. Neurology 1996; 46(5): 1291-6.
Charidimou A, Boulouis G, Gurol ME, et al. Emerging concepts in sporadic cerebral amyloid angiopathy. Brain 2017; 140(7): 1829-50.
Itoh Y, Yamada M, Hayakawa M, Otomo E, Miyatake T. Cerebral amyloid angiopathy: A significant cause of cerebellar as well as lobar cerebral hemorrhage in the elderly. J Neurol Sci 1993; 116(2): 135-41.
Findlay JM. Intraventricular Hemorrhage. In: James C. Grotta, Joseph P. Broderick, Eng H. Lo, Ralph L. Sacco, Gregory W. Albers, Scott E. Kasner, A. David Mendelow, Lawrence K.S. Wong, Eds; Stroke (Sixth Edition). Elsevier: Amsterdam, Netherlands 2016.
Stapf C, Mast H, Sciacca RR, et al. Predictors of hemorrhage in patients with untreated brain arteriovenous malformation. Neurology 2006; 66(9): 1350-5.
Singleton TC, Keane M. Diagnostic and therapeutic challenges of intracranial hemorrhage in neonates with congenital hemophilia: A case report and review. Ochsner J 2012; 12(3): 249-53.
Aronowski J, Zhao X. Molecular pathophysiology of cerebral hemorrhage: Secondary brain injury. Stroke 2011; 42(6): 1781-6.
Aronowski J, Hall CE. New horizons for primary intracerebral hemorrhage treatment: Experience from preclinical studies. Neurol Res 2005; 27(3): 268-79.
Li L, Wang P, Zhao H, Luo Y. Noncoding RNAs and intracerebral hemorrhage. CNS Neurol Disord Drug Targets 2019; 18(3): 205-11.
Chakrabarty A. Pathology of intracerebral haemorrhage. Neuropathology Article 2008.
Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorrhage. Lancet 2009; 373(9675): 1632-44.
Gutteridge JMC, Smith A. Antioxidant protection by haemopexin of haem-stimulated lipid peroxidation. Biochem J 1988; 256(3): 861-5.
Wan J, Ren H, Wang J. Iron toxicity, lipid peroxidation and ferroptosis after intracerebral haemorrhage. Stroke Vasc Neurol 2019; 4(2): 93-5.
Garton T, Keep RF, Hua Y, Xi G. Brain iron overload following intracranial haemorrhage. Stroke Vasc Neurol 2016; 1(4): 172-84.
Zhao F, Hua Y, He Y, Keep RF, Xi G. Minocycline-induced attenuation of iron overload and brain injury after experimental intracerebral hemorrhage. Stroke 2011; 42(12): 3587-93.
Ward RJ, Zucca FA, Duyn JH, Crichton RR, Zecca L. The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol 2014; 13(10): 1045-60.
Whyte E, Skidmore E, Aizenstein H, Ricker J, Butters M. Cognitive impairment in acquired brain injury: A predictor of rehabilitation outcomes and an opportunity for novel interventions. PM R 2011; 3(6)(Suppl. 1): S45-51.
Biffi A, Bailey D, Anderson CD, et al. Risk factors associated with early vs delayed dementia after intracerebral hemorrhage. JAMA Neurol 2016; 73(8): 969-76.
Gottesman RF. Dementia after intracerebral hemorrhage. JAMA Neurol 2016; 73(8): 916-7.
Frey U, Huang YY, Kandel ER. Effects of cAMP simulate a late stage of LTP in hippocampal CA1 neurons. Science 1993; 260(5114): 1661-4.
Cammarota M, Bevilaqua LR, Rossato JI, Ramirez M, Medina JH, Izquierdo I. Relationship between short- and long-term memory and short- and long-term extinction. Neurobiol Learn Mem 2005; 84(1): 25-32.
Colucci L, Bosco M, Rosario Ziello A, Rea R, Amenta F, Fasanaro AM. Effectiveness of nootropic drugs with cholinergic activity in treatment of cognitive deficit: A review. J Exp Pharmacol 2012; 4: 163-72.
Ferreira-Vieira TH, Guimaraes IM, Silva FR, Ribeiro FM. Alzheimer’s disease: Targeting the cholinergic system. Curr Neuropharmacol 2016; 14(1): 101-15.
Cikankova T, Sigitova E, Zverova M, et al. Mitochondrial dysfunctions in bipolar disorder: Effect of the disease and pharmacotherapy. CNS Neurol Disord Drug Targets 2017; 16(2): 176-86.
Shin SS, Dixon CE. Alterations in cholinergic pathways and therapeutic strategies targeting cholinergic system after traumatic brain injury. J Neurotrauma 2015; 32(19): 1429-40.
Reilly PL. Brain injury: The pathophysiology of the first hours.‘Talk and Die revisited’. J Clin Neurosci 2001; 8(5): 398-403.
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.
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.
Schinder AF, Olson EC, Spitzer NC, Montal M. Mitochondrial dysfunction is a primary event in glutamate neurotoxicity. J Neurosci 1996; 16(19): 6125-33.
Webster KA. Mitochondrial membrane permeabilization and cell death during myocardial infarction: Roles of calcium and reactive oxygen species. Future Cardiol 2012; 8(6): 863-84.
Celsi F, Pizzo P, Brini M, et al. Mitochondria, calcium and cell death: A deadly triad in neurodegeneration. Biochimica et Biophysica Acta (BBA)-. Bioenergetics 2009; 1787(5): 335-44.
Rothman SM, Olney JW. Glutamate and the pathophysiology of hypoxic--ischemic brain damage. Ann Neurol 1986; 19(2): 105-11.
Dávalos A, Shuaib A, Wahlgren NG. Neurotransmitters and pathophysiology of stroke: Evidence for the release of glutamate and other transmitters/mediators in animals and humans. J Stroke Cerebrovasc Dis 2000; 9(6 Pt 2): 2-8.
Kumar A, Dhawan A, Kadam A, Shinde A. Autophagy and mitochondria: Targets in neurodegenerative disorders. CNS Neurol Disord Drug Targets 2018; 17(9): 696-705.
Kim-Han JS, Kopp SJ, Dugan LL, Diringer MN. Perihematomal mitochondrial dysfunction after intracerebral hemorrhage. Stroke 2006; 37(10): 2457-62.
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. []. [PMID: 11435792].
Grote E, Hassler W. The critical first minutes after subarachnoid hemorrhage. Neurosurgery 1988; 22(4): 654-61.
Bederson JB, Levy AL, Ding WH, et al. Acute vasoconstriction after subarachnoid hemorrhage. Neurosurgery 1998; 42(2): 352-60.
Bergeron M, Yu AY, Solway KE, Semenza GL, Sharp FR. Induction of Hypoxia-Inducible Factor-1 (HIF-1) and its target genes following focal ischaemia in rat brain. Eur J Neurosci 1999; 11(12): 4159-70.
Hishikawa T, Ono S, Nishiguchi M, et al. MRNA and protein expression of hypoxia inducible factor-1 in the rat subarachnoid hemorrhage model. Surg Cereb Stroke 2003; 31(Suppl.): 43-6.
Ostrowski RP, Colohan ART, Zhang JH. (2007) Molecular Mecha nisms for Early Brain Injury After Subarachnoid Hemorrhage.Handbook of Neurochemistry and Molecular Neurobiology;. pp 235-253.
Shevtsova EF, Vinogradova DV, Neganova ME, et al. Mitochondrial permeability transition pore as a suitable target for neuroprotective agents against Alzheimer’s disease. CNS Neurol Disord Drug Targets 2017; 16(6): 677-85.
Büki A, Okonkwo DO, Wang KK, Povlishock JT. Cytochrome c release and caspase activation in traumatic axonal injury. J Neurosci 2000; 20(8): 2825-34.
Tweedie D, Milman A, Holloway HW, et al. Apoptotic and behavioral sequelae of mild brain trauma in mice. J Neurosci Res 2007; 85(4): 805-15.
Kim S, Han SC, Gallan AJ, Hayes JP. Neurometabolic indicators of mitochondrial dysfunction in repetitive mild traumatic brain injury. Concussion 2017; 2(3): CNC45.
Denicourt C, Dowdy SF. Medicine. Targeting apoptotic pathways in cancer cells. Science 2004; 305(5689): 1411-3.
Xi G, Keep RF, Hoff JT. Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol 2006; 5(1): 53-63.
Janzer RC, Raff MC. Astrocytes induce blood-brain barrier properties in endothelial cells. Nature 1987; 325(6101): 253-7.
Takano T, Tian GF, Peng W, et al. Astrocyte-mediated control of cerebral blood flow. Nat Neurosci 2006; 9(2): 260-7.
Anderson CM, Swanson RA. Astrocyte glutamate transport: Review of properties, regulation, and physiological functions. Glia 2000; 32(1): 1-14.
Scimemi A. Astrocytes and the warning signs of intracerebral hemorrhagic stroke. Neural Plast 2018; 2018: 1-11.
Liu Z, Chopp M. Astrocytes, therapeutic targets for neuroprotection and neurorestoration in ischemic stroke. Prog Neurobiol 2016; 144: 103-20.
Simard M, Nedergaard M. The neurobiology of glia in the context of water and ion homeostasis. Neuroscience 2004; 129(4): 877-96.
Xi G, Reiser G, Keep RF. The role of thrombin and thrombin receptors in ischemic, hemorrhagic and traumatic brain injury: deleterious or protective? J Neurochem 2003; 84(1): 3-9.
Coughlin SR. Thrombin signalling and protease-activated receptors. Nature 2000; 407(6801): 258-64.
Shavit E, Michaelson DM, Chapman J. Anatomical localization of protease-activated receptor-1 and protease-mediated neuroglial crosstalk on peri-synaptic astrocytic endfeet. J Neurochem 2011; 119(3): 460-73.
Bhardwaj M, Kumar A. Neuroprotective mechanism of Coenzyme Q10 (CoQ10) against PTZ induced kindling and associated cognitive dysfunction: Possible role of microglia inhibition. Pharmacol Rep 2016; 68(6): 1301-11.
Taylor RA, Sansing LH. Microglial responses after ischemic stroke and intracerebral hemorrhage. Clin Dev Immunol 2013 2013.
Wang J, Doré S. Inflammation after intracerebral hemorrhage. J Cereb Blood Flow Metab 2007; 27(5): 894-908.
Hanley DF. Intraventricular hemorrhage: Severity factor and treatment target in spontaneous intracerebral hemorrhage. Stroke 2009; 40(4): 1533-8.
Mendelow AD, Gregson BA, Rowan EN, Murray GD, Gholkar A, Mitchell PM. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): A randomised trial. Lancet 2013; 382(9890): 397-408.
Lei B, Sheng H, Wang H, et al. Intrastriatal injection of autologous blood or clostridial collagenase as murine models of intracerebral hemorrhage. J Vis Exp 2014; (89): 89.
Sansing LH, Kasner SE, McCullough L, Agarwal P, Welsh FA, Kariko K. Autologous blood injection to model spontaneous intracerebral hemorrhage in mice. J Vis Exp 2011; (54): 54.
Krafft PR, Rolland WB, Duris K, et al. Modeling intracerebral hemorrhage in mice: injection of autologous blood or bacterial collagenase. J Vis Exp 2012; (67): e4289
Belayev L, Saul I, Curbelo K, et al. Experimental intracerebral hemorrhage in the mouse: Histological, behavioral, and hemodynamic characterization of a double-injection model. Stroke 2003; 34(9): 2221-7.
Nakamura T, Xi G, Hua Y, Schallert T, Hoff JT, Keep RF. Intracerebral hemorrhage in mice: Model characterization and application for genetically modified mice. J Cereb Blood Flow Metab 2004; 24(5): 487-94.
Xi G, Hua Y, Keep RF, Younger JG, Hoff JT. Systemic complement depletion diminishes perihematomal brain edema in rats. Stroke 2001; 32(1): 162-7.
Deinsberger W, Vogel J, Kuschinsky W, Auer LM, Böker DK. Experimental intracerebral hemorrhage: Description of a double injection model in rats. Neurol Res 1996; 18(5): 475-7.
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.
Hickenbottom SL, Grotta JC, Strong R, Denner LA, Aronowski J. Nuclear factor-kappaB and cell death after experimental intracerebral hemorrhage in rats. Stroke 1999; 30(11): 2472-7.
Felberg RA, Grotta JC, Shirzadi AL, et al. Cell death in experimental intracerebral hemorrhage: The “black hole” model of hemorrhagic damage. Ann Neurol 2002; 51(4): 517-24.
Xue M, Del Bigio MR. Intracerebral injection of autologous whole blood in rats: Time course of inflammation and cell death. Neurosci Lett 2000; 283(3): 230-2.
Chen Z, Gao C, Hua Y, Keep RF, Muraszko K, Xi G. Role of iron in brain injury after intraventricular hemorrhage. Stroke 2011; 42(2): 465-70.
Xue M, Balasubramaniam J, Buist RJ, Peeling J, Del Bigio MR. Periventricular/intraventricular hemorrhage in neonatal mouse cerebrum. J Neuropathol Exp Neurol 2003; 62(11): 1154-65.
Lodhia KR, Shakui P, Keep RF. Hydrocephalus in a rat model of intraventricular hemorrhage. Acta Neurochir Suppl 2006; 96: 207-11.
Gao F, Liu F, Chen Z, Hua Y, Keep RF, Xi G. Hydrocephalus after intraventricular hemorrhage: The role of thrombin. J Cereb Blood Flow Metab 2014; 34(3): 489-94.
Belayev L, Saul I, Curbelo K, et al. Experimental intracerebral hemorrhage in the mouse: Histological, behavioral, and hemodynamic characterization of a double-injection model. Stroke 2003; 34(9): 2221-7.
Nakamura T, Xi G, Hua Y, Schallert T, Hoff JT, Keep RF. Intracerebral hemorrhage in mice: Model characterization and application for genetically modified mice. J Cereb Blood Flow Metab 2004; 24(5): 487-94.
Liu L, Wang S, Xu R, et al. Experimental intracerebral haemorrhage: description of a semi-coagulated autologous blood model in rats. Neurol Res 2015; 37(10): 874-9.
Tao C, Zhang R, Hu X, et al. A novel brainstem hemorrhage model by autologous blood infusion in rat: White matter injury, magnetic resonance imaging, and neurobehavioral features. J Stroke Cerebrovasc Dis 2016; 25(5): 1102-9.
Deinsberger W, Vogel J, Kuschinsky W, Auer LM, Böker DK. Experimental intracerebral hemorrhage: Description of a double injection model in rats. Neurol Res 1996; 18(5): 475-7.
Zhu W, Gao Y, Chang CF, Wan JR, Zhu SS, Wang J. Mouse models of intracerebral hemorrhage in ventricle, cortex, and hippocampus by injections of autologous blood or collagenase. PLoS One 2014; 9(5)e97423
MacLellan CL, Silasi G, Poon CC, et al. Intracerebral hemorrhage models in rat: Comparing collagenase to blood infusion. J Cereb Blood Flow Metab 2008; 28(3): 516-25.
Santos GCD, Antunes LMG, Santos ACD, Bianchi MDLP. Coenzyme Q10 and its effects in the treatment of neurodegenerative diseases. Braz J Pharm Sci 2009; 45(4): 607-18.
Villalba JM, Parrado C, Santos-Gonzalez M, Alcain FJ. Therapeutic use of coenzyme Q10 and coenzyme Q10-related compounds and formulations. Expert Opin Investig Drugs 2010; 19(4): 535-54.
Saini R. Coenzyme Q10: The essential nutrient. J Pharm Bioallied Sci 2011; 3(3): 466-7.
Ferrante RJ, Andreassen OA, Dedeoglu A, et al. Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington’s disease. J Neurosci 2002; 22(5): 1592-9.
Müller T, Büttner T, Gholipour AF, Kuhn W. Coenzyme Q10 supplementation provides mild symptomatic benefit in patients with Parkinson’s disease. Neurosci Lett 2003; 341(3): 201-4.
Salama M, Murillo-Rodríguez E, et al. Co-enzyme Q10 to treat neurological disorders: Basic mechanisms, clinical outcomes, and future research direction. CNS Neurol Disord Drug Targets 2013; 12(5): 641-64.
Tawfik MK. Coenzyme Q10 enhances the anticonvulsant effect of phenytoin in pilocarpine-induced seizures in rats and ameliorates phenytoin-induced cognitive impairment and oxidative stress. Epilepsy Behav 2011; 22(4): 671-7.
Ely JT, Fudenberg HH, Bliznakov EG, Branch JD. Hemorrhagic stroke in human pretreated with coenzyme Q10: Exceptional recovery as seen in animal models. J Orthomol Med 1998; 13(2): 105-9.
Langsjoen PH. Introduction to Coenzyme Q10 1995.Available from: .
Hernández-Camacho JD, Bernier M, López-Lluch G, Navas P. Coenzyme Q10 supplementation in aging and disease. Front Physiol 2018; 9: 44.
Fotino AD, Thompson-Paul AM, Bazzano LA. Effect of coenzyme Q10 supplementation on heart failure: A meta-analysis. Am J Clin Nutr 2013; 97(2): 268-75.
Mortensen SA, Rosenfeldt F, Kumar A, et al. The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: Results from Q-SYMBIO: A randomized double-blind trial. JACC Heart Fail 2014; 2(6): 641-9.
Bonakdar RA, Guarneri E. Coenzyme Q10. Am Fam Physician 2005; 72(6): 1065-70.
López-Lluch G, Del Pozo-Cruz J, Sánchez-Cuesta A, Cortés-Rodríguez AB, Navas P. Bioavailability of coenzyme Q10 supplements depends on carrier lipids and solubilization. Nutrition 2019; 57: 133-40.
Bonakdar RA, Guarneri E. Coenzyme Q10. Am Fam Physician 2005; 72(6): 1065-70.
Coenzyme Q10. Med Lett Drugs Ther 2006; 48(1229): 19-20.
Sanoobar M, Eghtesadi S, Azimi A, Khalili M, Jazayeri S, Reza GM. Coenzyme Q10 supplementation reduces oxidative stress and increases antioxidant enzyme activity in patients with relapsing-remitting multiple sclerosis. Int J Neurosci 2013; 123(11): 776-82.
Lee D, Shim MS, Kim KY, et al. Coenzyme Q10 inhibits glutamate excitotoxicity and oxidative stress-mediated mitochondrial alteration in a mouse model of glaucoma. Invest Ophthalmol Vis Sci 2014; 55(2): 993-1005.
Doll DN, Hu H, Sun J, Lewis SE, Simpkins JW, Ren X. Mitochondrial crisis in cerebrovascular endothelial cells opens the blood-brain barrier. Stroke 2015; 46(6): 1681-9.
Rose J, Brian C, Woods J, et al. Mitochondrial dysfunction in glial cells: Implications for neuronal homeostasis and survival. Toxicology 2017; 391: 109-15.
Singh A, Kumar A. Microglial inhibitory mechanism of coenzyme Q10 against Aβ (1-42) induced cognitive dysfunctions: Possible behavioral, biochemical, cellular, and histopathological alterations. Front Pharmacol 2015; 6: 268.
Hawking ZL. Alzheimer's disease: The role of mitochondrial dysfunction and potential new therapies. Biosci Horiz: Int J Stud Res 2016; 9
Shults CW, Beal MF, Fontaine D, Nakano K, Haas RH. Absorption, tolerability, and effects on mitochondrial activity of oral coenzyme Q10 in parkinsonian patients. Neurology 1998; 50(3): 793-5.
Mehan S, Monga V, Rani M, Dudi R, Ghimire K. Neuroprotective effect of solanesol against 3-nitropropionic acid-induced Huntington’s disease-like behavioral, biochemical, and cellular alterations: Restoration of coenzyme-Q10-mediated mitochondrial dysfunction. Indian J Pharmacol 2018; 50(6): 309-19.
Ferrante RJ, Andreassen OA, Dedeoglu A, et al. Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington’s disease. J Neurosci 2002; 22(5): 1592-9.
Abdin AA, Hamouda HE. Mechanism of the neuroprotective role of coenzyme Q10 with or without L-dopa in rotenone-induced parkinsonism. Neuropharmacology 2008; 55(8): 1340-6.
Sharma S, Kheradpezhou M, Shavali S, et al. Neuroprotective actions of coenzyme Q10 in Parkinson’s disease. Methods Enzymol 2004; 382: 488-509.
Facecchia K. Pre-clinical evaluation of water-soluble coenzyme q10 for therapeutic treatment of Parkinson’s disease. Thesis: University of Windsor 2012.
Attia HN, Maklad YA. Neuroprotective effects of coenzyme Q10 on paraquat-induced Parkinson’s disease in experimental animals. Behav Pharmacol 2018; 29(1): 79-86.
Janzade A, Jameie SB, Choobchian S, Nasirinezhad F. Neuroprotective effect of coenzyme Q10 in chronic constriction injury-induced neuropathic pain in rats. Thrita 2014; 3(1)
Kandhare AD, Ghosh P, Ghule AE, Bodhankar SL. Elucidation of molecular mechanism involved in neuroprotective effect of Coenzyme Q10 in alcohol-induced neuropathic pain. Fundam Clin Pharmacol 2013; 27(6): 603-22.
Sakhaie MH, Soleimani M, Pirhajati V, Soleimani Asl S, Madjd Z, Mehdizadeh M. Coenzyme Q10 ameliorates trimethyltin chloride neurotoxicity in experimental model of injury in dentate gyrus of hippocampus: A histopathological and behavioral study. Iran Red Crescent Med J 2016; 18(8)e30297
Yang X, Yang Y, Li G, Wang J, Yang ES. Coenzyme Q10 attenuates β-amyloid pathology in the aged transgenic mice with Alzheimer presenilin 1 mutation. J Mol Neurosci 2008; 34(2): 165-71.
Yang X, Dai G, Li G, Yang ES. Coenzyme Q10 reduces β-amyloid plaque in an APP/PS1 transgenic mouse model of Alzheimer’s disease. J Mol Neurosci 2010; 41(1): 110-3.
Kalayci M, Unal MM, Gul S, et al. Effect of coenzyme Q10 on ischemia and neuronal damage in an experimental traumatic brain-injury model in rats. BMC Neurosci 2011; 12(1): 75.
Shults CW, Beal MF, Fontaine D, Nakano K, Haas RH. Absorption, tolerability, and effects on mitochondrial activity of oral coenzyme Q10 in parkinsonian patients. Neurology 1998; 50(3): 793-5.
Shults CW, Oakes D, Kieburtz K, et al. Effects of coenzyme Q10 in early Parkinson disease: Evidence of slowing of the functional decline. Arch Neurol 2002; 59(10): 1541-50.
Negida A, Menshawy A, et al. Coenzyme Q10 for patients with parkinson’s disease: A systematic review and meta-analysis. CNS Neurol Disord Drug Targets 2016; 15(1): 45-53.
Horstink MW, van Engelen BG. The effect of coenzyme Q10 therapy in Parkinson disease could be symptomatic. Arch Neurol 2003; 60(8): 1170-2.
Zhu ZG, Sun MX, Zhang WL, Wang WW, Jin YM, Xie CL. The efficacy and safety of coenzyme Q10 in Parkinson’s disease: A meta-analysis of randomized controlled trials. Neurol Sci 2017; 38(2): 215-24.
Li Z, Wang P, Yu Z, et al. The effect of creatine and coenzyme q10 combination therapy on mild cognitive impairment in Parkinson’s disease. Eur Neurol 2015; 73(3-4): 205-11.
A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease. Neurology 2001; 57(3): 397-404.
Ferrante KL, Shefner J, Zhang H, et al. Tolerance of high-dose (3,000 mg/day) coenzyme Q10 in ALS. Neurology 2005; 65(11): 1834-6.
Kaufmann P, Thompson JLP, Levy G, et al. Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III. Ann Neurol 2009; 66(2): 235-44.
Saulle MF, Schambra HM. Recovery and rehabilitation after intracerebral hemorrhage. Semin Neurol 2016; 36(3): 306-12.
Diringer MN, Edwards DF. Admission to a neurologic/ neurosurgical intensive care unit is associated with reduced mortality rate after intracerebral hemorrhage. Crit Care Med 2001; 29(3): 635-40.
Dastur CK, Yu W. Current management of spontaneous intracerebral haemorrhage. Stroke Vasc Neurol 2017; 2(1): 21-9.
Liu-Deryke X, Janisse J, Coplin WM, Parker D Jr, Norris G, Rhoney DH. A comparison of nicardipine and labetalol for acute hypertension management following stroke. Neurocrit Care 2008; 9(2): 167-76.
Yaghi S, Eisenberger A, Willey JZ. Symptomatic intracerebral hemorrhage in acute ischemic stroke after thrombolysis with intravenous recombinant tissue plasminogen activator: A review of natural history and treatment. JAMA Neurol 2014; 71(9): 1181-5.
Sahni R, Weinberger J. Management of intracerebral hemorrhage. Vasc Health Risk Manag 2007; 3(5): 701-9.
Wrotek SE, Kozak WE, Hess DC, Fagan SC. Treatment of fever after stroke: Conflicting evidence. Pharmacotherapy 2011; 31(11): 1085-91.
Yerram S, Katyal N, Premkumar K, Nattanmai P, Newey CR. Seizure prophylaxis in the neuroscience intensive care unit. J Intensive Care 2018; 6(1): 17.
van Breda EJ, van der Worp HB, van Gemert HMA, et al. PAIS: Paracetamol (acetaminophen) in stroke; protocol for a randomized, double blind clinical trial. [ISCRTN 74418480]. BMC Cardiovasc Disord 2005; 5(1): 24.
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.
Sinn DI, Lee ST, Chu K, et al. Combined neuroprotective effects of celecoxib and memantine in experimental intracerebral hemorrhage. Neurosci Lett 2007; 411(3): 238-42.
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.
Adrianto Y, Susilo H. Comparison of functional improvement scale (Nihss) degree between acute intracerebral hemorrhage stroke patients receiving standard treatment and those receiving standard treatment plus celecoxib. Folia MedicaIndonesiana 2014; 50(4): 234.
Park HK, Lee SH, Chu K, Roh JK. Effects of celecoxib on volumes of hematoma and edema in patients with primary intracerebral hemorrhage. J Neurol Sci 2009; 279(1-2): 43-6.
Lee SH, Park HK, Ryu WS, et al. Effects of celecoxib on hematoma and edema volumes in primary intracerebral hemorrhage: A multicenter randomized controlled trial. Eur J Neurol 2013; 20(8): 1161-9.
Song Y, Jun JH, Shin EJ, Kwak YL, Shin JS, Shim JK. Effect of pregabalin administration upon reperfusion in a rat model of hyperglycemic stroke: Mechanistic insights associated with high-mobility group box 1. PLoS One 2017; 12(2)e0171147
Calikoglu C, Aytekin H, Akgül O, et al. Effect of pregabalin in preventing secondary damage in traumatic brain injury: An experimental study. Med Sci Monit 2015; 21: 813-20.
Aşcı S, Demirci S, Aşcı H, Doğuç DK, Onaran İ. Neuroprotective effects of pregabalin on cerebral ischemia and reperfusion. Balkan Med J 2016; 33(2): 221-7.
Freynhagen R, Strojek K, Griesing T, Whalen E, Balkenohl M. Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible- and fixed-dose regimens. Pain 2005; 115(3): 254-63.
Rahajeng B, Ikawati Z, Andayani TM, Dwiprahasto I. The effect of pregabalin on the quality of life in patients with central post-stroke pain. J Young Pharmacists 2018; 10(2): 222.
Lee ST, Chu K, Jung KH, et al. Memantine reduces hematoma expansion in experimental intracerebral hemorrhage, resulting in functional improvement. J Cereb Blood Flow Metab 2006; 26(4): 536-44.
López-Valdés HE, Clarkson AN, Ao Y, et al. Memantine enhances recovery from stroke. Stroke 2014; 45(7): 2093-100.
Montagne A, Hébert M, Jullienne A, et al. Memantine improves safety of thrombolysis for stroke. Stroke 2012; 43(10): 2774-81.
Kafi H, Salamzadeh J, Beladimoghadam N, Sistanizad M, Kouchek M. Study of the neuroprotective effects of memantine in patients with mild to moderate ischemic stroke. Iran J Pharm Res 2014; 13(2): 591-8.
Bakhshayesh-Eghbali B, Hajinnori M, Seyed-Saadat SM, Seyed-Saadat SN, Kazemnezhad-Leili E, Rouhi-Rad M. Comparing the effect of memantine and placebo on clinical outcome of intracranial hemorrhage: A randomized double blind clinical trial. Caspian J Neurol Sci 2015; 1(3): 11-8.
Orgogozo JM, Rigaud AS, Stöffler A, Möbius HJ, Forette F. Efficacy and safety of memantine in patients with mild to moderate vascular dementia: A randomized, placebo-controlled trial (MMM 300). Stroke 2002; 33(7): 1834-9.
Barrett KM, Brott TG, Brown RD Jr, et al. Enhancing recovery after acute ischemic stroke with donepezil as an adjuvant therapy to standard medical care: Results of a phase IIA clinical trial. J Stroke Cerebrovasc Dis 2011; 20(3): 177-82.
Taverni JP, Seliger G, Lichtman SW. Donepezil medicated memory improvement in traumatic brain injury during post acute rehabilitation. Brain Inj 1998; 12(1): 77-80.
Zhang L, Plotkin RC, Wang G, Sandel ME, Lee S. Cholinergic augmentation with donepezil enhances recovery in short-term memory and sustained attention after traumatic brain injury. Arch Phys Med Rehabil 2004; 85(7): 1050-5.
Mayuex R, Chun M. Acquired and hereditary dementia’s Merritt’ s Textbook of Neurology. 9th ed. Baltimore: Williams and Wilkins 1995.
Wang BF, Cui ZW, Zhong ZH, et al. Curcumin attenuates brain edema in mice with intracerebral hemorrhage through inhibition of AQP4 and AQP9 expression. Acta Pharmacol Sin 2015; 36(8): 939-48.
Cai J, Xu D, Bai X, et al. Curcumin mitigates cerebral vasospasm and early brain injury following subarachnoid hemorrhage via inhibiting cerebral inflammation. Brain Behav 2017; 7(9)e00790
Kuo CP, Lu CH, Wen LL, et al. Neuroprotective effect of curcumin in an experimental rat model of subarachnoid hemorrhage. Anesthesiology 2011; 115(6): 1229-38.
Porter AG, Jänicke RU. Emerging roles of caspase-3 in apoptosis. Cell Death Differ 1999; 6(2): 99-104.
Bartels AL, Leenders KL. Cyclooxygenase and neuroinflammation in Parkinson’s disease neurodegeneration. Curr Neuropharmacol 2010; 8(1): 62-8.
De Simone R, Ajmone-Cat MA, Minghetti L. Atypical anti-inflammatory activation of microglia induced by apoptotic neurons: Possible role of phosphatidylserine-phosphatidylserine receptor interaction. Mol Neurobiol 2004; 29(2): 197-212.
Joshi I, Taylor CP. Pregabalin action at a model synapse: Binding to presynaptic calcium channel alpha (2)-delta subunit reduces neurotransmission in mice. Eur J Pharmacol 2006; 553: 82-8.
Thomas SJ, Grossberg GT. Memantine: A review of studies into its safety and efficacy in treating Alzheimer’s disease and other dementias. Clin Interv Aging 2009; 4: 367-77.
Lapchak PA, Araujo DM. Advances in hemorrhagic stroke therapy: Conventional and novel approaches. Expert Opin Emerg Drugs 2007; 12(3): 389-406.
Berthier ML, Green C, Lara JP, et al. Memantine and constraint-induced aphasia therapy in chronic poststroke aphasia. Ann Neurol 2009; 65(5): 577-85.
Xu GQ, Lan Y, Ding MH, Chen SZ, Ding JX, Mao YR. Effects of memantine on cognitive impairment of patients with stroke: A randomized, placebo-controlled trial. Chinese J New Drugs Clin Rem 2010; p. 5.
Babu R, Bagley JH, Di C, Friedman AH, Adamson C. Thrombin and hemin as central factors in the mechanisms of intracerebral hemorrhage-induced secondary brain injury and as potential targets for intervention. Neurosurg Focus 2012; 32(4)E8
Kalia LV, Kalia SK, Salter MW. NMDA receptors in clinical neurology: excitatory times ahead. Lancet Neurol 2008; 7(8): 742-55.
Lipton SA. Failures and successes of NMDA receptor antagonists: molecular basis for the use of open-channel blockers like memantine in the treatment of acute and chronic neurologic insults. NeuroRx 2004; 1(1): 101-10.
Shin CY, Kundel M, Wells DG. Rapid, activity-induced increase in tissue plasminogen activator is mediated by metabotropic glutamate receptor-dependent mRNA translation. J Neurosci 2004; 24(42): 9425-33.
Wityk RJ, Caplan LR. Hypertensive intracerebral hemorrhage. Epidemiology and clinical pathology. Neurosurg Clin N Am 1992; 3(3): 521-32.
Mayer SA, Kreiter KT, Copeland D, et al. Global and domain-specific cognitive impairment and outcome after subarachnoid hemorrhage. Neurology 2002; 59(11): 1750-8.
Wallmark S, Ronne-Engström E, Lundström E. Prevalence of spasticity after aneurysmal subarachnoid haemorrhage. J Rehabil Med 2014; 46(1): 23-7.
Nicole O, Docagne F, Ali C, et al. The proteolytic activity of tissue-plasminogen activator enhances NMDA receptor-mediated signaling. Nat Med 2001; 7(1): 59-64.
Wang X, Lee SR, Arai K, et al. Lipoprotein receptor-mediated induction of matrix metalloproteinase by tissue plasminogen activator. Nat Med 2003; 9(10): 1313-7.
Wilcock GK. Memantine for the treatment of dementia. Lancet Neurol 2003; 2(8): 503-5.
Nadeau SE, Behrman AL, Davis SE, et al. Donepezil as an adjuvant to constraint-induced therapy for upper-limb dysfunction after stroke: An exploratory randomized clinical trial. J Rehabil Res Dev 2004; 41(4)
Pratt RD, Perdomo CA. Donepezil-treated patients with probable vascular dementia demonstrate cognitive benefits. Ann N Y Acad Sci 2002; 977(1): 513-22.
Esatbeyoglu T, Huebbe P, Ernst IM, Chin D, Wagner AE, Rimbach G. Curcumin--from molecule to biological function. Angew Chem Int Ed Engl 2012; 51(22): 5308-32.
Shishodia S. Molecular mechanisms of curcumin action: Gene expression. Biofactors 2013; 39(1): 37-55.
Jiang TF, Zhang YJ, Zhou HY, et al. Curcumin ameliorates the neurodegenerative pathology in A53T alpha-synuclein cell model of Parkinson’s disease through the downregulation of mTOR/p70S6K signaling and the recovery of macroautophagy. J Neuroimmune Pharmacol 2013; 8: 356-69.
Laird MD, Sukumari-Ramesh S, Swift AE, Meiler SE, Vender JR, Dhandapani KM. Curcumin attenuates cerebral edema following traumatic brain injury in mice: A possible role for aquaporin-4? J Neurochem 2010; 113(3): 637-48.
Dong HJ, Shang CZ, Peng DW, et al. Curcumin attenuates ischemia-like injury induced IL-1β elevation in brain microvascular endothelial cells via inhibiting MAPK pathways and nuclear factor-κB activation. Neurol Sci 2014; 35(9): 1387-92.
Kuo CP, Lu CH, Wen LL, et al. Neuroprotective effect of curcumin in an experimental rat model of subarachnoid hemorrhage. Anesthesiology 2011; 115(6): 1229-38.
Badaut J, Ashwal S, Obenaus A. Aquaporins in cerebrovascular disease: A target for treatment of brain edema? Cerebrovasc Dis 2011; 31(6): 521-31.
Tang Y, Wu P, Su J, Xiang J, Cai D, Dong Q. Effects of aquaporin-4 on edema formation following intracerebral hemorrhage. Exp Neurol 2010; 223(2): 485-95.
Zhao X, Zhang Y, Strong R, Zhang J, Grotta JC, Aronowski J. Distinct patterns of intracerebral hemorrhage-induced alterations in NF-kappaB subunit, iNOS, and COX-2 expression. J Neurochem 2007; 101(3): 652-63.
Singh S, Aggarwal BB. Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane). J Biol Chem 1995; 270(42): 24995-5000.

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