Neovascularization and Synaptic Function Regulation with Memantine and Rosuvastatin in a Rat Model of Chronic Cerebral Hypoperfusion

Zhang, Nan; Song, Chenchen; Zhao, Baomin; Xing, Mengya; Luo, Lanlan; Gordon, M.S.; Cheng, Yan

doi:10.1007/s12031-017-0974-1

Cited by 9 publications

(7 citation statements)

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“…Memantine improved stroke outcomes via increasing BDNF, GDNF, and VEGF levels, reducing reactive astrogliosis and enhancing vascular density [24,44]. In a rat model of chronic cerebral hypoperfusion, memantine enhanced neovascularization with increases in BDNF and VEGF expressions [45]. The precise mechanism of how memantine enhances the production of growth factors is not clear.…”

Section: Discussionmentioning

confidence: 99%

Memantine ameliorates motor impairments and pathologies in a mouse model of neuromyelitis optica spectrum disorders

Yick

Tang

Ka-Fai

et al. 2020

J Neuroinflammation

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Background: Neuromyelitis optica spectrum disorders (NMOSD) are central nervous system (CNS) autoimmune inflammatory demyelinating diseases characterized by recurrent episodes of acute optic neuritis and transverse myelitis. Aquaporin-4 immunoglobulin G (AQP4-IgG) autoantibodies, which target the water channel aquaporin-4 (AQP4) on astrocytic membrane, are pathogenic in NMOSD. Glutamate excitotoxicity, which is triggered by internalization of AQP4glutamate transporter complex after AQP4-IgG binding to astrocytes, is involved in early NMOSD pathophysiologies. We studied the effects of memantine, a N-methyl-D-aspartate (NMDA) receptor antagonist, on motor impairments and spinal cord pathologies in mice which received human AQP4-IgG. Methods: Purified IgG from AQP4-IgG-seropositive NMOSD patients were passively transferred to adult C57BL/6 mice with disrupted blood-brain barrier. Memantine was administered by oral gavage. Motor impairments of the mice were assessed by beam walking test. Spinal cords of the mice were assessed by immunofluorescence and ELISA. Results: Oral administration of memantine ameliorated the motor impairments induced by AQP4-IgG, no matter the treatment was initiated before (preventive) or after (therapeutic) disease flare. Memantine profoundly reduced AQP4 and astrocyte loss, and attenuated demyelination and axonal loss in the spinal cord of mice which had received AQP4-IgG. The protective effects of memantine were associated with inhibition of apoptosis and suppression of neuroinflammation, with decrease in microglia activation and neutrophil infiltration and reduction of increase in levels of proinflammatory cytokines including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). In addition, memantine elevated growth factors including brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and vascular endothelial growth factor (VEGF) in the spinal cord. Conclusions: Our findings support that glutamate excitotoxicity and neuroinflammation play important roles in complement-independent pathophysiology during early development of NMOSD lesions, and highlight the potential of oral memantine as a therapeutic agent in NMOSD acute attacks.

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Section: Discussionmentioning

confidence: 99%

Memantine ameliorates motor impairments and pathologies in a mouse model of neuromyelitis optica spectrum disorders

Yick

Tang

Ka-Fai

et al. 2020

J Neuroinflammation

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“…CCH is induced by chronic, moderate and persistent deficit of CBF, increasing evidence from laboratorial and clinical researches has indicated CCH is a robustly common factor in pathogenesis of cerebrovascular diseases and neurodegenerative disorders, results in the development and progression of cognitive impairment, such as VD (Du et al, 2017). But to date, it has been difficult to modulate the complex pathological changes caused by CCH (Zhang N. et al, 2017). Model animals of BCCAO are often used to study VD resulting from hypoperfusion (Du et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Dl-3-n-Butylphthalide Reduces Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion Through GDNF/GFRα1/Ret Signaling Preventing Hippocampal Neuron Apoptosis

Wei

Lin

et al. 2019

Front. Cell. Neurosci.

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Hippocampal neuron death is a key factor in vascular dementia (VD) induced by chronic cerebral hypoperfusion (CCH). Dl-3-n-butylphthalide (NBP) is a multiple-effects drug. Therefore, the potential molecular mechanisms underlying CCH and its feasible treatment should be investigated. This study had two main purposes: first, to identify a potential biomarker in a rat model of CCH induced VD using antibody microarrays; and second, to explore the neuroprotective role of NBP at targeting the potential biomarker. Glial cell line-derived neurotrophic factor (GDNF)/GDNF family receptor alpha-1 (GFRα1)/receptor tyrosine kinase (Ret) signaling is altered in the hippocampus of CCH rats; however, NBP treatment improved cognitive function, protected against hippocampal neuron apoptosis via regulation of GDNF/GFRα1/Ret, and activated the phosphorylation AKT (p-AKT) and ERK1/2 (p-ERK1/2) signaling. We also found that 1 h oxygen-glucose deprivation (OGD) followed by 48 h reperfusion (R) in cultured hippocampal neurons led to downregulation of GDNF/GFRα1/Ret. NBP upregulated the signaling and increased neuronal survival. Ret inhibitor (NVP-AST487) inhibits Ret and downstream effectors, including p-AKT and p-ERK1/2. Additionally, both GDNF and GFRα1 expression are markedly inhibited in hippocampal neurons by coincubation with NVP-AST487, particularly under conditions of OGD/R. GDNF/GFRα1/Ret signaling and neuronal viability can be maintained by NBP, which activates p-AKT and p-ERK1/2, increases expression of Bcl-2, and decreases expression of Bax and cleaved caspase-3. The current study showed that GDNF/GFRα1/Ret signaling plays an essential role in the CCH induced VD. NBP was protective against hippocampal neuron apoptosis, and this was associated with regulation of GDNF/GFRα1/Ret and AKT/ERK1/2 signaling pathways, thus reducing cognitive impairment.

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“…Memantine has also showed effects to reverse the CBF decline and spatial memory impairment induced by 2-VO surgery. , Memantine is an uncompetitive NMDA receptor antagonist, which might enhance cognitive functions in a variety of animal models. Many reports have revealed that degeneration of neurons in brain might subsequently cause cognitive function impairment. , Excessive Ca 2+ influx has been closely associated with neurotoxins such as glutamate or β-amyloid that might overstimulate NMDA receptors.…”

Section: Resultsmentioning

confidence: 99%

“…Many reports have revealed that degeneration of neurons in brain might subsequently cause cognitive function impairment. , Excessive Ca 2+ influx has been closely associated with neurotoxins such as glutamate or β-amyloid that might overstimulate NMDA receptors. Memantine blocks the overstimulation of NMDA receptor in pathological conditions but not physiological conditions, which is important to minimize adverse effects . Moreover, memantine has been reported to restore brain-derived neurotrophic factor (BDNF) levels, which might improve learning and memory in the chronic cerebral hypoperfusion model .…”

Section: Resultsmentioning

confidence: 99%

Pharmacological Characterizations of anti-Dementia Memantine Nitrate via Neuroprotection and Vasodilation in Vitro and in Vivo

Mak

Liu

et al. 2020

ACS Chem. Neurosci.

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We have previously designed and synthesized a series of novel memantine nitrates, and some of them have shown neuroprotective effects; however, the detailed mechanisms remain unknown. In this study, we demonstrated that MN-12, one of the memantine nitrates, concentration-dependently protected against glutamate-induced neurotoxicity in rat primary cultured cerebellar granule neurons (CGNs). Western blotting assays revealed that MN-12 might possess neuroprotective effects through the inhibition of ERK pathway and activation of PI3K/Akt pathway concurrently. Moreover, MN-12 concentration-dependently dilated precontracted rat middle cerebral artery through activation of NO−cGMP pathway ex vivo. In the 2-vessel occlusion (2VO) rat model, MN-12 alleviated the impairments of spatial memory and motor dysfunction possibly via neuroprotection and improvement of the cerebral blood flow. Furthermore, the results of preliminary pharmacokinetic studies showed that MN-12 might quickly distribute to the major organs including the brain, indicating that MN-12 could penetrate the blood−brain barrier. Taken together, MN-12 might provide multifunctional therapeutic benefits for dementia associated with Alzheimer's disease, vascular dementia, and ischemic stroke, via neuroprotection and vessel dilation to improve the cerebral blood flow.

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Neovascularization and Synaptic Function Regulation with Memantine and Rosuvastatin in a Rat Model of Chronic Cerebral Hypoperfusion

Cited by 9 publications

References 50 publications

Memantine ameliorates motor impairments and pathologies in a mouse model of neuromyelitis optica spectrum disorders

Memantine ameliorates motor impairments and pathologies in a mouse model of neuromyelitis optica spectrum disorders

Dl-3-n-Butylphthalide Reduces Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion Through GDNF/GFRα1/Ret Signaling Preventing Hippocampal Neuron Apoptosis

Pharmacological Characterizations of anti-Dementia Memantine Nitrate via Neuroprotection and Vasodilation in Vitro and in Vivo

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