Diversity of neurodegenerative processes in the model of brain cortex tissue ischemia

Lobysheva, N. V.; Tonshin, Anton A.; Selin, A.A.; Yaguzhinsky, L. S.; Nartsissov, Yaroslav R.

doi:10.1016/j.neuint.2008.12.015

Cited by 18 publications

(10 citation statements)

References 47 publications

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“…Studies to assess 'pools' of 'relocating Oatp1a4 transporter' in the context of H/R stress are currently being undertaken in our laboratory. In terms of pharmacotherapy, we have previously shown in vivo that Oatp1a4 can mediate blood-tobrain drug transport and therefore be a critical determinant of CNS accumulation of the opioid peptide, [D-penicillamine 2,5 ]-enkephalin. 19 Here, we expand on these critical findings by showing that Oatp1a4 is a key determinant of atorvastatin delivery to the brain, both in normoxic animals and after H/R stress.…”

Section: Discussionmentioning

confidence: 99%

“…1 It is directly associated with neuronal apoptosis, a proteolytic cascade characterized by cytochrome c release, caspase-3 activation, and internucleosomal DNA fragmentation. 2 As neuronal cell damage transpires during H/R, neuroinflammation and apoptosis become more prevalent and dramatically affect brain tissue viability. 1 Such pathophysiologic processes include activation of poly (ADP-ribose) polymerase (PARP), a family of nuclear enzymes involved in DNA repair, programmed cell death, and necrotic tissue damage.…”

Section: Introductionmentioning

confidence: 99%

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Hypoxia/Reoxygenation Stress Signals an Increase in Organic Anion Transporting polypeptide 1a4 (Oatp1a4) at the Blood–Brain Barrier: Relevance to CNS Drug Delivery

Thompson

Sanchez-Covarrubias

Slosky

et al. 2014

J Cereb Blood Flow Metab

121

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Cerebral hypoxia and subsequent reoxygenation stress (H/R) is a component of several diseases. One approach that may enable neural tissue rescue after H/R is central nervous system (CNS) delivery of drugs with brain protective effects such as 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (i.e., statins). Our present in vivo data show that atorvastatin, a commonly prescribed statin, attenuates poly (ADP-ribose) polymerase (PARP) cleavage in the brain after H/R, suggesting neuroprotective efficacy. However, atorvastatin use as a CNS therapeutic is limited by poor blood-brain barrier (BBB) penetration. Therefore, we examined regulation and functional expression of the known statin transporter organic anion transporting polypeptide 1a4 (Oatp1a4) at the BBB under H/R conditions. In rat brain microvessels, H/R (6% O 2 , 60 minutes followed by 21% O 2 , 10 minutes) increased Oatp1a4 expression. Brain uptake of taurocholate (i.e., Oap1a4 probe substrate) and atorvastatin were reduced by Oatp inhibitors (i.e., estrone-3-sulfate and fexofenadine), suggesting involvement of Oatp1a4 in brain drug delivery. Pharmacological inhibition of transforming growth factor-b (TGF-b)/activin receptor-like kinase 5 (ALK5) signaling with the selective inhibitor SB431542 increased Oatp1a4 functional expression, suggesting a role for TGF-b/ALK5 signaling in Oatp1a4 regulation. Taken together, our novel data show that targeting an endogenous BBB drug uptake transporter (i.e., Oatp1a4) may be a viable approach for optimizing CNS drug delivery for treatment of diseases with an H/R component.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hypoxia/Reoxygenation Stress Signals an Increase in Organic Anion Transporting polypeptide 1a4 (Oatp1a4) at the Blood–Brain Barrier: Relevance to CNS Drug Delivery

Thompson

Sanchez-Covarrubias

Slosky

et al. 2014

J Cereb Blood Flow Metab

121

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“…Тем не менее реперфузия может иметь некоторые пагубные последствия, поскольку оксидантный стресс может быстро сменяться реоксигенацией [4][5][6][7][8]. Несмотря на то что результаты исследований моделей ишемии головного мозга на животных указывают на важ-ную роль оксидантного стресса при реперфузион-ном повреждении, доказательства реперфузионного повреждения при инсульте у человека ограниченны.…”

Section: Study Limitationsunclassified

“…Кроме того, у пациентов с более низким содержанием МДА через 1 и 2 часа после введения ТАП чаще наблюдали полное восстановление или более выраженное улучше-ние по шкале NIH (снижение на 8 баллов) через 24 часа (0,99 мкмоль/л по сравнению с 1,10 мкмоль/л, р=0,058 для содержания МДА через 1 час; 1,02 и 1,14 мкмоль/л для содержания МДА через 2 часа, р=0,032). 1,16±0,36 116,9 (81,08-163,25) 23,9 (8,53-45,95) ≥74 лет 1,11±0,29 102,25 (77,94-137,82) 20,37 (8,48-37,5) Пол: 0,26 0,028 0,004 мужской 1,16±0.33 117,4 (84,86-117,4) 27,7 (13,58-51,14) женский 1,10±0,31 92,36 (74-128,1) 12,82 (6,5) АГ: 0,44 0,83 0,48 да 1,12±0,35 104,9 (77,32-148) 19.55 (8,5) нет 1.15±0.29 111 (79,9-153,3) 22,71 (9,(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)6) Сахарный диабет: 0,014 0,16 0,13 да 1,27±0,34 125,35 (80,4-198,4) 25,5 (10,58-59,5) нет 1,10±0,31 107,9 (78,1-140,52) 20,37 (8,23-36,6) Гиперлипидемия: 0,043 0,33 0,78 06±0,32 114,9 (78,05-165) 22,5 (8,6-43,96) нет 1,17±0,32 107,6 (79,9-140,6) 20,73 (8,30-44,6) Курение: 0,89 0,032 0,035 14±0,36 120,9 (97,5-217,1) 35,6 (12,23-61,9) нет 1,12±0,31 104,5 (75,58-142,5) 19,01 (8,(27)(28)(29)(30)(31)(32)(33)…”

Section: маркеры оксидантного стресса и течение заболеванияunclassified

“…Примечательно, что поскольку существует про-странственное распределение внешних условий и уровня метаболитов вокруг ишемического очага [8], различные вмешательства, корректирующие метабо-лизм нейронов, должны быть разнесены во времени в зависимости от предполагаемой зоны воздействия. Тем не менее применение метаболической терапии может быть наиболее эффективным именно на ран-них стадиях ишемии [9,10].…”

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Oxidative Stress After Thrombolysis-Induced Reperfusion in Human Stroke

Domı́nguez

Delgado

Vilches

et al. 2010

Stroke

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Background and Purpose-Animal models of transient ischemia suggest that oxygen-derived free radicals produced on reperfusion of ischemic brain could constitute the main cause of reperfusion injury. We aimed to determine the presence and role of lipid peroxidation and protein oxidation-related molecules after tissue plasminogen activator-induced recanalization in human stroke. Methods-A total of 160 patients with strokes involving the middle cerebral artery and treated with tissue plasminogen activator and 60 healthy controls were included. Blood samples, transcranial Doppler recordings, and National Institutes of Health Stroke Scale scores were obtained at baseline (pretreatment), 1 hour and 2 hours after tissue plasminogen activator bolus, and 12 hours and 24 hours after stroke onset. The main lipid peroxidation end-product malondialdehyde, advanced oxidation protein products, and plasma concentrations of myeloperoxidase were assessed. Results-At baseline, all oxidative stress biomarkers were higher than in control subjects (PϽ0.01 for all comparisons).Malondialdehyde remained high compared with controls during the study period, whereas myeloperoxidase concentrations were significantly raised at baseline, 1 hour after tissue plasminogen activator administration, and 12 hours after stroke onset. Malondialdehyde concentrations correlated with stroke severity and were associated with outcome and with hemorrhagic complications. Regarding recanalization, among those patients with middle cerebral artery recanalization by the end of tissue plasminogen activator infusion (44%) or anytime thereafter, no peaking of any of the studied molecules could be identified. Conclusions-Our study showed that systemic oxidative damage to lipids and proteins had already occurred at baseline in stroke. In contrast to animal studies, a relationship between free radical-mediated oxidative damage to lipids or proteins and reperfusion injury after arterial recanalization could not be established. (Stroke. 2010;41:653-660.)Key Words: stroke Ⅲ thrombolysis Ⅲ oxidative stress Ⅲ MDA Ⅲ AOPPs Ⅲ MPO O xidative stress, resulting from an imbalance in redox state in which pro-oxidants overwhelm antioxidant capacity, has emerged as a potential mechanism implicated in the pathogenesis and disease progression of many unrelated pathological processes, including cardiovascular diseases, cancer, and diabetes, and may therefore contribute significantly to disease mechanisms; 1 however, increased oxidative stress may also result from pathological processes. 2 Reactive oxygen species (ROS) are continuously generated in the body as a consequence of aerobic metabolism or as part of the body's defense against microorganisms. ROS are highly reactive to any or all molecular targets: lipids, proteins, nucleic acids, or carbohydrates, 1 modifying their chemical structure and generating oxidation-derived products, markers of biomolecular oxidative damage. 3 Increased ROS production has been demonstrated in ischemic stroke, both during ischemia and reperfusion, o...

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Voltage-Gated Potassium Channels at the Crossroads of Neuronal Function, Ischemic Tolerance, and Neurodegeneration

Shah

Aizenman

2013

Transl. Stroke Res.

122

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Voltage-gated potassium (Kv) channels are widely expressed in the central and peripheral nervous system, and are crucial mediators of neuronal excitability. Importantly, these channels also actively participate in cellular and molecular signaling pathways that regulate the life and death of neurons. Injury-mediated increased K+ efflux through Kv2.1 channels promotes neuronal apoptosis, contributing to widespread neuronal loss in neurodegenerative disorders such as Alzheimer’s disease and stroke. In contrast, some forms of neuronal activity can dramatically alter Kv2.1 channel phosphorylation levels and influence their localization. These changes are normally accompanied by modifications in channel voltage-dependence, which may be neuroprotective within the context of ischemic injury. Kv1 and Kv7 channel dysfunction leads to neuronal hyperexcitability that critically contributes to the pathophysiology of human clinical disorders such as episodic ataxia and epilepsy. This review summarizes the neurotoxic, neuroprotective, and neuroregulatory roles of Kv channels, and highlights the consequences of Kv channel dysfunction on neuronal physiology. The studies described in this review thus underscore the importance of normal Kv channel function in neurons, and emphasize the therapeutic potential of targeting Kv channels in the treatment of a wide range of neurological diseases.

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Diversity of neurodegenerative processes in the model of brain cortex tissue ischemia

Cited by 18 publications

References 47 publications

Hypoxia/Reoxygenation Stress Signals an Increase in Organic Anion Transporting polypeptide 1a4 (Oatp1a4) at the Blood–Brain Barrier: Relevance to CNS Drug Delivery

Hypoxia/Reoxygenation Stress Signals an Increase in Organic Anion Transporting polypeptide 1a4 (Oatp1a4) at the Blood–Brain Barrier: Relevance to CNS Drug Delivery

Oxidative Stress After Thrombolysis-Induced Reperfusion in Human Stroke

Voltage-Gated Potassium Channels at the Crossroads of Neuronal Function, Ischemic Tolerance, and Neurodegeneration

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