Chronic Cerebral Hypoperfusion In Rats Research Articles

(S)-Oxiracetam is the Active Ingredient in Oxiracetam that Alleviates the Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion in Rats

Chronic cerebral hypoperfusion is a pathological state that is associated with the cognitive impairments in vascular dementia. Oxiracetam is a nootropic drug that is commonly used to treat cognitive deficits of cerebrovascular origins. However, oxiracetam is currently used as a racemic mixture whose effective ingredient has not been identified to date. In this study, we first identified that (S)-oxiracetam, but not (R)-oxiracetam, was the effective ingredient that alleviated the impairments of spatial learning and memory by ameliorating neuron damage and white matter lesions, increasing the cerebral blood flow, and inhibiting astrocyte activation in chronic cerebral hypoperfused rats. Furthermore, using MALDI-MSI and LC-MS/MS, we demonstrated that (S)-oxiracetam regulated ATP metabolism, glutamine-glutamate and anti-oxidants in the cortex region of hypoperfused rats. Altogether, our results strongly suggest that (S)-oxiracetam alone could be a nootropic drug for the treatment of cognitive impairments caused by cerebral hypoperfusion.

Chronic Cerebral Hypoperfusion Promotes Amyloid-Beta Pathogenesis via Activating β/γ-Secretases.

Chronic cerebral hypoperfusion (CCH) contributes to the Alzheimer's-like pathogenesis, but the relationship between CCH and the occurrence of Alzheimer's disease (AD) remains obscure. The aim is to elucidate the potential pathophysiological mechanism in the field of amyloid-beta (Aβ) pathology induced by CCH. A rat model of CCH has been developed with permanent bilateral occlusion of common carotid arteries (BCCAO). The cognitive function of rats was tested by the Morris water maze. The levels of Aβ (Aβ40 and Aβ42) and soluble amyloid precursor protein (sAPP: sAPPα and sAPPβ) were determined by enzyme linked immunosorbent assay. The expression of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), presenilin1 (PS1), nicastrin (NCT), anterior pharynx-defective 1alpha (Aph-1α) and presenilin enhancer 2 (Pen-2), sAPPα and sAPPβ were detected by Western blotting. Morris water maze test showed that CCH induced decline in learning and memory related to Aβ levels in the hippocampus. The levels of sAPPα, ADAM10 and ADAM17 in the hippocampus of CCH rats were higher than the control ones (P < 0.05); the levels of sAPPβ, BACE and BACE1 increased more than the control ones (P < 0.05). CCH intervention (1-week or 4-week) markedly increased the expression of PS1, Aph-1α and Pen-2 in the hippocampus of rats, but had no effect on NCT. CCH contributed to cognitive impairment and altered the amyloidogenic and non-amyloidogenic pathway of APP processing by boosting the activity of β-secretase/γ-secretase and α-secretase respectively. The non-amyloidogenic pathway can't overcome the damage role of the amyloidogenic pathway in the process of chronic cerebral hypoperfusion which promotes amyloid-beta pathogenesis.

Cannabinoid receptor agonist WIN55,212-2 and fatty acid amide hydrolase inhibitor URB597 ameliorate neuroinflammatory responses in chronic cerebral hypoperfusion model by blocking NF-κB pathways.

The present study explored the protective effects of cannabinoid receptor agonist WIN55,212-2 (WIN) and fatty acid amide hydrolase inhibitor URB597 (URB) against neuroinflammation in rats with chronic cerebral hypoperfusion (CCH). Activated microglia, astrocytes, and nuclear factor kappa B (NF-κB) p65-positive cells were measured by immunofluorescence. Reactive oxygen species (ROS) was assessed by dihydroethidium staining. The protein levels of cluster of differentiation molecule 11b (OX-42), glial fibrillary acidic protein (GFAP), NF-κB p65, inhibitor of kappa B alpha (IκB-a), IκB kinase a/β (IKK a/β), phosphorylated IKK a/β (p-IKK a/β), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-α, and interleukin-1β (IL-1β) were examined by western blotting or enzyme-linked immunosorbent assay. All the protein levels of OX-42, GFAP, TNF-a, IL-1β, COX-2, and iNOS are increased in CCH rats. WIN and URB downregulated the levels of OX-42, GFAP, TNF-α, IL-1β, COX-2 and iNOS and inhibited CCH-induced ROS accumulation in CCH rats, indicating that WIN and URB might exert their neuroprotective effects by inhibiting the neuroinflammatory response. In addition, the NF-κB signaling pathway was activated by CCH in frontal cortex and hippocampus, while the aforementioned changes were reversed by WIN and URB treatment. These findings suggest that WIN and URB treatment ameliorated CCH-induced neuroinflammation through inhibition of the classical pathway of NF-κB activation, resulting in mitigation of chronic ischemic injury.

VEGF-Mediated Cognitive and Synaptic Improvement in Chronic Cerebral Hypoperfusion Rats Involves Autophagy Process.

Chronic cerebral hypoperfusion (CCH) is associated with various neurodegenerative diseases characterized by cognitive impairment. Dozens of studies including ours have indicated that exogenous administration of vascular endothelial growth factor (VEGF) could exert effective cognitive protection during ischemia. Nevertheless, the underlying mechanism has not been well clarified. To address this issue, we explored the synaptic mechanisms in vivo since hippocampal synaptic function is essential to the learning and memory process. Besides, the role of autophagy in cognitive dysfunction under conditions of CCH is still controversial. And abnormal autophagy could threaten normal neurotransmission at synapse where a large amount of protein synthesis and degradation take place. Hence, we further examined whether the altered synaptic function was associated with autophagy. The results showed that CCH impaired spatial cognition as evidenced in Morris water maze. We further found that VEGF mitigated impaired hippocampal synaptic function including basal synaptic transmission, paired-pulse facilitation, short-term, long-term plasticity, depotentiation, and the level of synaptic proteins as assessed by electrophysiological examination and western blot assay. Furthermore, our results demonstrated that CCH could induce excessive autophagy which could be inhibited by VEGF. Thus, we speculated that VEGF could ameliorate impaired synaptic function induced by CCH because of its ability to inhibit excessive autophagy, and eventually improve spatial learning and memory function. Importantly, our findings shed light on potential therapeutic strategies to be exploited in the usage of VEGF.

Dl-3-n-Butylphthalide Treatment Enhances Hemodynamics and Ameliorates Memory Deficits in Rats with Chronic Cerebral Hypoperfusion.

Our previous study has revealed that chronic cerebral hypoperfusion (CCH) activates a compensatory vascular mechanism attempting to maintain an optimal cerebral blood flow (CBF). However, this compensation fails to prevent neuronal death and cognitive impairment because neurons die prior to the restoration of normal CBF. Therefore, pharmacological invention may be critical to enhance the CBF for reducing neurodegeneration and memory deficit. Dl-3-n-butylphthalide (NBP) is a compound isolated from the seeds of Chinese celery and has been proven to be able to prevent neuronal loss, reduce inflammation and ameliorate memory deficits in acute ischemic animal models and stroke patients. In the present study, we used magnetic resonance imaging (MRI) techniques, immunohistochemistry and Morris water maze (MWM) to investigate whether NBP can accelerate CBF recovery, reduce neuronal death and improve cognitive deficits in CCH rats after permanent bilateral common carotid artery occlusion (BCCAO). Rats were intravenously injected with NBP (5 mg/kg) daily for 14 days beginning the first day after BCCAO. The results showed that NBP shortened recovery time of CBF to pre-occlusion levels at 2 weeks following BCCAO, compared to 4 weeks in the vehicle group, and enhanced hemodynamic compensation through dilation of the vertebral arteries (VAs) and increase in angiogenesis. NBP treatment also markedly reduced reactive astrogliosis and cell apoptosis and protected hippocampal neurons against ischemic injury. The escape latency of CCH rats in the MWM was also reduced in response to NBP treatment. These findings demonstrate that NBP can accelerate the recovery of CBF and improve cognitive function in a rat model of CCH, suggesting that NBP is a promising therapy for CCH patients or vascular dementia.

Chronic Cerebral Hypoperfusion Induced Synaptic Proteome Changes in the rat Cerebral Cortex.

Chronic cerebral hypoperfusion (CCH) evokes mild cognitive impairment (MCI) and contributes to the progression of vascular dementia and Alzheimer's disease (AD). How CCH induces these neurodegenerative processes that may spread along the synaptic network and whether they are detectable at the synaptic proteome level of the cerebral cortex remains to be established. In the present study, we report the synaptic protein changes in the cerebral cortex after stepwise bilateral common carotid artery occlusion (BCCAO) induced CCH in the rat. The occlusions were confirmed with magnetic resonance angiography 5weeks after the surgery. Synaptosome fractions were prepared using sucrose gradient centrifugation from cerebral cortex dissected 7weeks after the occlusion. The synaptic protein differences between the sham operated and CCH groups were analyzed with label-free nanoUHPLC-MS/MS. We identified 46 proteins showing altered abundance due to CCH. In particular, synaptic protein and lipid metabolism, as well as GABA shunt-related proteins showed increased while neurotransmission and synaptic assembly-related proteins showed decreased protein level changes in CCH rats. Protein network analysis of CCH-induced protein alterations suggested the importance of increased synaptic apolipoprotein E (APOE) level as a consequence of CCH. Therefore, the change in APOE level was confirmed with Western blotting. The identified synaptic protein changes would precede the onset of dementia-like symptoms in the CCH model, suggesting their importance in the development of vascular dementia.

Oral administration of grape seed polyphenol extract restores memory deficits in chronic cerebral hypoperfusion rats.

Chronic cerebral hypoperfusion (CCH) has been recognized as an important cause of both vascular dementia and Alzheimer's disease (AD), the two most prominent neurodegenerative diseases causing memory impairment in the elderly. However, an effective therapy for CCH-induced memory impairment has not yet been established. Grape seed polyphenol extract (GSPE) has powerful antioxidant properties and protects neurons and glia during ischemic injury, but its potential use in the prevention of CCH-induced memory impairment has not yet been investigated. Here, CCH-related memory impairment was modeled in rats using permanent bilateral occlusion of the common carotid artery. A Morris water maze task was used to evaluate memory, the levels of acetylcholinesterase, choline acetyltransferase, acetylcholine were used to evaluate cholinergic function, and oxidative stress was assessed by measuring the enzyme activity of superoxide dismutase, glutathione peroxidase, malonic dialdehyde, and catalase. We found that oral administration of GSPE for 1 month can rescue memory deficits. We also found that GSPE restores cholinergic neuronal function and represses oxidative damage in the hippocampus of CCH rats. We propose that GSPE protects memory in CCH rats by reducing ischemia-induced oxidative stress and cholinergic dysfunction. These findings provide a novel application of GSPE in CCH-related memory impairments.

Neuroprotective and axonal outgrowth-promoting effects of tetramethylpyrazine nitrone in chronic cerebral hypoperfusion rats and primary hippocampal neurons exposed to hypoxia

Chronic cerebral hypoperfusion is an important risk factor for vascular dementia and other brain dysfunctions, for which there are currently no effective medications available. We investigated the neuroprotective and axonal outgrowth promoting effects of tetramethylpyrazine nitrone (TBN) in a permanent bilateral occlusion of the common carotid arteries (2VO) rat model and in primary hippocampal neurons exposed to oxygen glucose deprivation (OGD). At 6th week after 2VO, TBN increased the time spent in novel arms in the Y-maze test and improved the discrimination ratio in object reorganization task. TBN attenuated axonal damage, and reduced oxidative DNA injury and lipid peroxidation in white matter. TBN also attenuated the neuronal apoptosis and ameliorated accumulation of astrocytes in parietal cortex and CA1 region of hippocampus. Western blot analyses indicated that TBN increased Bcl-2 expression, decreased Bax and Caspase 3 expressions, and upregulated the phosphorylation levels of high-molecular weight neurofilament (p-NFH), Akt (p-Akt) and glycogen synthase kinase-3β (p-GSK3β) in hippocampus at 6th week after chronic hypoperfusion. In vitro, TBN rescued hippocampal neuronal viability and axonal elongation from OGD damage. The p-Akt and p-GSK3β upregulation by TBN was abolished by a specific phosphoinositide 3-kinase (PI3K) inhibitor LY294002, resulting in suppression of axonal outgrowth. Collectively, the results showed that TBN alleviated white matter lesion and impairment of cortex and hippocampus, attenuated oxidative damage and enhanced axonal outgrowth through the regulation of PI3K/Akt/GSK3β signaling pathway, leading to improved cognitive deficit in a rat chronic hypoperfusion model.

Erratum to: the Role of Autophagy in the Correlation Between Neuron Damage and Cognitive Impairment in Rat Chronic Cerebral Hypoperfusion.

Pathological changes and cognitive impairment caused by chronic cerebral hypoperfusion (CCH) have been previously reported. However, how these changes progress remains unclear. Additionally, there are few studies regarding the mechanism underlying the involvement of autophagy in these processes. Two-step bilateral common carotid artery occlusion (BCCAO) was performed to replicate CCH in Sprague Dawley rats. The animals were divided into seven groups, including a sham group and 2-, 4-, 8-, 12-, 16-, and 20-week BCCAO groups (n = 7 per group). Five additional rats were used to monitor cerebral blood fluid (CBF) changes via laser speckle contrast imaging (LSCI). We tested for cognitive changes and pathological changes, including neuronal injury, white matter lesions, and β-Amyloid (Aβ) deposition, via acknowledged methods. Autophagy was analyzed via western blotting and immunohistochemistry. Cognitive impairment appeared beginning at 8 weeks after BCCAO despite improvement in CBF. Neuronal damage began at 8 weeks in the hippocampal CA1 region and at 4 weeks in the cortex. White matter injury was detected in all BCCAO groups. Intracellular Aβ accumulation occurred earlier than extracellular plaque formation. The levels of autophagy-related proteins (Beclin-1, light chain 3B, and P62) increased beginning at 2 weeks in the cortex and at 4 weeks in the hippocampus and remained elevated throughout the remainder of the study period. Despite recovery of CBF, autophagy dysfunction occurred early after CCH and played an important role in neuronal deterioration, cognitive decline, and intracellular Aβ aggregation.

The Role of Autophagy in the Correlation Between Neuron Damage and Cognitive Impairment in Rat Chronic Cerebral Hypoperfusion.

Pathological changes and cognitive impairment caused by chronic cerebral hypoperfusion (CCH) have been previously reported. However, how these changes progress remains unclear. Additionally, there are few studies regarding the mechanism underlying the involvement of autophagy in these processes. Two-step bilateral common carotid artery occlusion (BCCAO) was performed to replicate CCH in Sprague Dawley rats. The animals were divided into seven groups, including a sham group and 2-, 4-, 8-, 12-, 16-, and 20-week BCCAO groups (n=7 per group). Five additional rats were used to monitor cerebral blood fluid (CBF) changes via laser speckle contrast imaging (LSCI). We tested for cognitive changes and pathological changes, including neuronal injury, white matter lesions, and β-Amyloid (Aβ) deposition, via acknowledged methods. Autophagy was analyzed via western blotting and immunohistochemistry. Cognitive impairment appeared beginning at 8weeks after BCCAO despite improvement in CBF. Neuronal damage began at 8weeks in the hippocampal CA1 region and at 4weeks in the cortex. White matter injury was detected in all BCCAO groups. Intracellular Aβ accumulation occurred earlier than extracellular plaque formation. The levels of autophagy-related proteins (Beclin-1, light chain 3B, and P62) increased beginning at 2weeks in the cortex and at 4weeks in the hippocampus and remained elevated throughout the remainder of the study period. Despite recovery of CBF, autophagy dysfunction occurred early after CCH and played an important role in neuronal deterioration, cognitive decline, and intracellular Aβ aggregation.

The ameliorative effects of exercise on cognitive impairment and white matter injury from blood-brain barrier disruption induced by chronic cerebral hypoperfusion in adolescent rats

Vascular dementia is the progressive change in blood vessels that leads to neuronal injuries in vulnerable areas induced by chronic cerebral hypoperfusion (CCH). CCH induces disruption of blood-brain barrier (BBB), and this BBB disruption can initiate the cognitive impairment and white matter injury. In the present study, we evaluated the effect of treadmill exercise on the cognitive impairment, white matter injury, and BBB disruption induced by CCH. Vascular dementia was induced by permanent bilateral common carotid arteries occlusion (BCCAO) in rats. The rats in the exercise group were made to run on a treadmill for 30min once a day for 14 weeks, starting 4 weeks after birth. Our results revealed that treadmill exercise group was alleviated the cognitive impairment and myelin degradation induced by CCH. The disruption of BBB after CCH indicates degradation of occludin, zonula occluden-1 (ZO-1), and up-regulation of matrix metalloproteinases (MMPs). Treadmill exercise may provide protective effects on BBB disruption from degradation of occludin, ZO-1, and overexpression of MMP-9 after CCH. These findings suggest that treadmill exercise ameliorates cognitive impairment and white matter injury from BBB disruption induced by CCH in rats. The present study will be valuable for means of prophylactic and therapeutic intervention for patients with CCH.

MicroRNA-181c Ameliorates Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion in Rats.

Chronic cerebral hypoperfusion (CCH) characterized by global cerebral ischemia is an important risk factor contributing to the development of dementia. MicroRNAs (miRNAs) play important roles in the cellular adaptation to long-term ischemia/hypoxia by turning off or on the expression of target genes. MiR-181c is widely expressed in the nervous system, and tripartite motif 2 (TRIM2) is one of its target genes. In this work, we had identified that progressive spatial memory deficiency was induced in the bilateral common carotid artery occlusion (2-VO) rat models. Meanwhile, inhibition of miR-181c expression and upregulation of TRIM2 in the hippocampus of 2-VO rats were found accompanying with reduction in the dendritic branching and dendrite spine density of the hippocampal neurons. Viral vector-mediated miR-181c delivery might improve the cognitive deficiency via TRIM2 on neurofilament light (NF-L) ubiquitination resulting in remodeling of the hippocampal neurons as well as increase in N-methyl-D-aspartate receptor 1 (NR1) subunit cell surface expression. Meanwhile, miR-181c might rescue the cellular activity from ischemia/hypoxia. These results indicated a novel miRNA-mediated mechanism involving miR-181c and TRIM2 in the cognitive impairment induced by CCH and provided a rationale for the development of miRNA-based strategies for prevention of dementia.

Oxiracetam can improve cognitive impairment after chronic cerebral hypoperfusion in rats

Chronic cerebral hypoperfusion (CCH) induces cognitive deficits. Although CCH can be improved, cognitive impairment is not improved accordingly. To date, many studies have focused on investigating the pathophysiological mechanisms of CCH; however, the treatment of the induced cognitive impairment remains ineffective. Thus, the mechanisms underlying cognitive impairment after CCH and potential agents for treating this impairment need to be explored further. Oxiracetam is a nootropic drug that improves clinical outcomes for some central nervous system (CNS) disorders. Whether it can improve cognitive impairment after CCH is unknown. In this study, we used behavioural methods, electrophysiology, biochemistry, histopathological staining and transmission electron microscope to investigate rat's cognitive impairment by CCH, and found that Oxiracetam could improve CCH-induced cognitive impairment and prevent deficits of neural plasticity, white matter lesions, and synaptic ultrastructure. These results suggest that Oxiracetam may be effective as a potential agent against CCH-induced cognitive impairment.

Selective Modulator of Cannabinoid Receptor Type 2 Reduces Memory Impairment and Infarct Size During Cerebral Hypoperfusion and Vascular Dementia.

Vascular dementia is the highly devastating neurodegenerative disorder after Alzheimer's disease (AD) and mainly found in aged people but the effectual therapeutic target is still not there. Chronic cerebral hypoperfusion (CCH) has been broadly found in vascular dementia (VaD) patients. CCH is thought to link with neurodegenerative disorders and their subsequent cognitive deteriorate on. This study has been framed to examine the role of a selective agonist of cannabinoid receptor type 2(CB2); 1-phenylisatin in CCH induced VaD. Permanent bilateral common carotid arteries ligation or two vessels occlusion (2VO) technique was used to induce CCH in rats. 2VO animals have shown significant impairment in learning-memory (Morris water maze) and in executive functioning (Attentional set-shifting test). These animals have shown a considerable reduction in brain oxidative stress (thiobarbituric reactive acid substance-TBARS; glutathione-GSH; catalase-CAT and superoxide dismutase-SOD), mitochondrial dysfunction (complexes I, II, IV) with a significant enhancement in cholinergic activity- AChE and brain infarct size2,3,5-triphenylterazolium chloride staining (TTC staining). Animals treated with 2VO have also demonstrated a considerable augmentation in brain edema (water content). Oral administration of 1-phenylisatin has significantly recuperated 2VO induced impairment in learning-memory, an increase in TBARS, GSH, CAT, SOD, mitochondrial activity with a significant reduction in AChE activity and brain damage. Administration of 1- phenylisatin has also reported recovering brain edema in these animals. These results indicate that 2VO induced CCH in rats, which was attenuated with the treatment of 1-phenylisatin. Hence, it may be suggested that modulation of cannabinoid receptor may provide benefits in CCH as cognitive impairment and VaD. Therefore, selective agonists of CB2 receptors may be a potential research target for the alleviation of VaD.

Selective modulator of cannabinoid receptor type 2 (CB2) against biochemical alterations and brain damage in chronic cerebral hypoperfusion induced vascular dementia

Vascular dementia is the second most common cause of cognitive decline in aged people but the effectual therapeutic target is still missing. Chronic cerebral hypoperfusion (CCH) has been widely found in vascular dementia (VaD) patients. CCH is thought to link with neurodegenerative disorders and their subsequent cognitive impairment. The present study has been framed to investigate the role of selective agonist of CB2 receptor (1-phenylisatin) in CCH induced VaD. Permanent bilateral common carotid arteries ligation or two vessels occlusion (2VO) technique was used to induce CCH in rats. 2VO animals have shown significant impairment in learning-memory (Morris water maze) and in executive functioning (Attentional set shifting test). These animals have shown a considerable reduction in brain oxidative stress (thiobarbituric reactive acid substance-TBARS; glutathione-GSH; catalase-CAT and superoxide dismutase-SOD), mitochondrial complex activity (complexes I, II, IV) with the enhancement in cholinergic activity- AChE and brain infarct size (TTC staining). These animals have also shown a considerable increase in brain edema (water content). Oral administration of 1-phenylisatin has significantly recuperated 2VO induced impairment in learning-memory, increase in TBARS, GSH, CAT, SOD, mitochondrial activity with a significant reduction in AChE activity and brain damage. Administration of 1-phenylisatin has also been reported to recover brain edema in these animals. These results indicate that 2VO induced CCH in rats, which was attenuated with the treatment of 1-phenylisatin. Hence, it may be suggested that modulation in cannabinoid receptor may provide benefits in CCH as cognitive impairment and VaD. Therefore, pharmacological positive modulation of CB2 receptors may be a potential research target for alleviation of VaD.

Induction of Genes Expressed in Endothelial Cells of the Corpus Callosum in the Chronic Cerebral Hypoperfusion Rat Model

Background: Cerebrovascular white matter lesions (WMLs) are associated with cognitive impairment in patients with subcortical vascular dementia. We performed a comprehensive gene expression analysis to elucidate genes associated with WML development in a chronic cerebral hypoperfusion rat model. Methods: Brains of rats with bilateral carotid ligation (2VO, n = 10) and sham-operated rats (n = 5-10/group) were removed on days 1, 7, or 28 after surgery. Total RNA isolated from the corpus callosum was evaluated by microarray analysis and quantitative reverse transcription-polymerase chain reaction. Results: On days 7 and 28, WMLs exhibited histologic changes. On day 7, 16 genes were differentially expressed between groups. mRNA levels of Ptprb, Kcnj8, Crispld2, Bcl6b, and Gja5 were differentially expressed in 2VO rats on day 7, but then returned to normal, whereas mRNA levels of Vwf and Trappc6a were upregulated after day 7. Immunohistochemistry showed that GJA5 and vWF were detected in endothelial cells, KCNJ8 in endothelial cells and astrocytes, CRISPLD2 in neurons and astrocytes, and TRAPPC6A in neurons. Conclusion: Our findings indicate novel genes that may be associated with WML development in the chronic cerebral hypoperfusion rat model, and suggest an important role of neurovascular dysfunction in the pathophysiology.

Neurorestorative effects of epigallocatechin-3-Gallate on cognitive function in a chronic cerebral hypoperfusion rat model.

This study investigated whether (-)-epigallocatechin-3-gallate (EGCG) can enhance cognition by a neurorestorative effect in a rat model of bilateral common carotid artery occlusion (BCCAO). Forty-eight male, 8-week-old Sprague-Dawley rats were randomly allocated to four groups 6 weeks after BCCAO or sham operation: EGCG-single intravenous injection (25 mg/kg/day; SIV group), EGCG-multiple intraperitoneal injection (50 mg/kg/day for 5 days; MIP group), untreated BCCAO group (untreated group), and sham-operated group (sham group). Escape latency was significantly shorter in the SIV and MIP groups than in the untreated group. SIV and MIP groups were significantly different from the untreated group in the activity of superoxide dismutase and the content of malondialdehyde (p < 0.05). Protein expression level of brain-derived neurotrophic factor was not significantly different between groups (p > 0.05), while protein expression of vascular endothelial growth factor was significantly lower in the SIV group than in the untreated group (p < 0.05). Protein expression of N-methyl-D-aspartate receptor subunits NR1 and NR2B was significantly higher in the MIP group than in the untreated group (p < 0.05). EGCG administration at 6 weeks after BCCAO is neurorestorative via an anti-oxidant effect and synaptogenesis, except for angiogenesis.

(-)-SCR1693 Protects against Memory Impairment and Hippocampal Damage in a Chronic Cerebral Hypoperfusion Rat Model.

Chronic cerebral hypoperfusion (CCH) is one of the most common causes of vascular dementia (VaD) and is recognised as an etiological factor in the development of Alzheimer’s disease (AD). CCH can induce severe cognitive deficits, as assessed by the water maze task, along with neuronal loss in the hippocampus. However, there are currently no effective, approved pharmacological treatments available for VaD. In the present study, we created a rat model of CCH using bilateral common carotid artery occlusion and found that (-)-SCR1693, a novel compound, prevented rats from developing memory deficits and neuronal damage in the hippocampus by rectifying cholinergic dysfunction and decreasing the accumulation of the phospho-tau protein. These results strongly suggest that (-)-SCR1693 has therapeutic potential for the treatment of CCH-induced VaD.

Effects of melatonin on cognitive impairment and hippocampal neuronal damage in a rat model of chronic cerebral hypoperfusion.

Chronic cerebral hypoperfusion (CCH), which induces oxidative stress and inflammation in the brain, has previously been associated with cognitive impairment and neuronal cell damage. Melatonin is a well-known free radical scavenger and antioxidant; therefore, the present study investigated the protective effects of melatonin against CCH-induced cognitive impairment and neuronal cell death in a CCH rat model, which was generated via permanent bilateral common carotid artery occlusion (2VO). The rats in the 2VO group exhibited markedly increased escape latencies in a Morris water maze test, as compared with the rats in the sham group. In addition, increased neuronal cell damage was detected in the hippocampal CA1 region of the 2VO rats, as compared with the rats in the sham group. Treatment of the 2VO rats with melatonin significantly reduced the escape latency and neuronal cell damage, and was associated with reduced levels of malondialdehyde, microglial activation, and tumor necrosis factor-α and interleukin-1β in the ischemic hippocampus. The results of the present study suggest that melatonin may attenuate CCH-induced cognitive impairment and hippocampal neuronal cell damage by decreasing oxidative stress, microglial activation and the production of pro-inflammatory cytokines in the ischemic hippocampus.

MK801 improves hippocampal long-term potentiation impairment induced by chronic cerebral hypoperfusion in rat

Event Abstract Back to Event MK801 improves hippocampal long-term potentiation impairment induced by chronic cerebral hypoperfusion in rat Nor F. Azam1 and Zurina Hassan1* 1 Universiti Sains Malaysia, Centre for Drug Research, Malaysia Disorders related to cerebral circulation has become the main reason for any neurological diseases. Blood flow disturbances in the brain may lead to stroke and continuous decrease in blood flow compromises memory. The latter will lead to confusion and progression of dementia. In addition, N-methyl-D-aspartate (NMDA) receptor system in the brain has been implicated in neuronal plasticity, neurotoxicity, learning and memory. The present study aims to evaluate the role of NMDA-receptor system particularly glutamate-mediated long term potentiation (LTP) in the processes of learning and memory formation in chronic cerebral hypoperfusion rats. Cerebral hypoperfusion was developed via permanent ligation of the common carotid arteries to decrease blood flow to the brain. Common carotid arteries of the male Sprague-Dawley rats (250-300g) were permanently ligated (2VO) and sham operated-group were undergone the same surgery without ligation. LTP was recorded on day 28 after surgery in urethane-anesthesized rats. The field excitatory postsynaptic potential (fEPSP) was found to be improved in rats treated with NMDA receptor antagonist, MK801 (0.25mg/kg, intraperitoneal injection) compared to non-treated rats recorded in the hippocampus CA1. The findings confirm the important role of the NMDA-receptor system in reversing the cognitive function of chronic cerebral hypoperfusion rats. Acknowledgements Financial support was received from Ministry of Higher Education (MOHE) Malaysia and Universiti Sains Malaysia special funding for the project of Fundamental Neuroscience-Neurobehaviour (304/CDADAH/652201/K134). Keywords: Hippocampus, LTP, NMDA, in vivo, cerebral hypoperfusion Conference: 14th Meeting of the Asian-Pacific Society for Neurochemistry, Kuala Lumpur, Malaysia, 27 Aug - 30 Aug, 2016. Presentation Type: Poster Presentation Session Topic: 14th Meeting of the Asian-Pacific Society for Neurochemistry Citation: Azam NF and Hassan Z (2016). MK801 improves hippocampal long-term potentiation impairment induced by chronic cerebral hypoperfusion in rat. Conference Abstract: 14th Meeting of the Asian-Pacific Society for Neurochemistry. doi: 10.3389/conf.fncel.2016.36.00160 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 04 Aug 2016; Published Online: 11 Aug 2016. * Correspondence: Dr. Zurina Hassan, Universiti Sains Malaysia, Centre for Drug Research, Minden, Penang, Malaysia, zurina_hassan@hotmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Nor F Azam Zurina Hassan Google Nor F Azam Zurina Hassan Google Scholar Nor F Azam Zurina Hassan PubMed Nor F Azam Zurina Hassan Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.