Neuroprotective effect of liraglutide and memantine in a rat model of Alzheimer’s disease

Objective:To assess the effect of memantine combined with liraglutide on aluminum chloride(AlCl_(3))and D-galactose(D-GAL)-induced neurotoxicity in rats.Methods:Male Wistar rats were divided into 5 groups of 5 animals each:the positive control,the negative control,the memantine-treated group,the liraglutide-treated group,and the combination group treated with memantine and liraglutide.AlCl_(3)and D-GAL were used to induce neurotoxicity.Behavioral tests,brain beta-amyloid protein,and oxidative stress biomarkers were evaluated.Results:The Morris water maze test indicated an enhanced memory in the combination group.Moreover,the combination treatment of liraglutide and memantine resulted in a remarkable reduction in the beta-amyloid protein level in the brain tissue.Neuronal inflammation and oxidative stress biomarkers were significantly reduced,and the levels of antioxidant parameters were enhanced.Conclusions:The combination of liraglutide and memantine exerts neuroprotective effects and enhances memory and cognitive functions in rats with Alzheimer’s disease.

Memantine对新生大鼠脑缺氧缺血损伤的脑保护效果

围产期窒息所致脑缺氧缺血损伤(HI)为新生儿期危害最大的常见病,常导致新生儿死亡和幸存者严重后遗症。迄今为止,对脑缺氧缺血损伤尚无根本性防治措施。近来报道非竞争性NMDA受体拮抗剂Memantine对脑缺氧缺血损伤具有脑保护作用。本文对一组脑缺氧缺血损伤新生大鼠模型对照应用Memantine,通过比较左右脑半球重量减少百分值,观察Memantine的脑保护效果,现报告如下。

Memantine对缺氧缺血脑保护作用的相关研究

缺氧缺血性脑病是新生儿期严重的临床疾患 ,目前尚无有效的药物治疗方案。大量研究证实 ,非竞争性NMDA受体拮抗剂美金胺 (Memantine)可以有效地减少缺氧缺血所导致的脑损伤。应用膜片钳技术的研究进一步从细胞水平证实了美金胺治疗缺氧缺血性脑病的有效性和安全性 。

Physiopathology of ischemic stroke and its modulation using memantine:evidence from preclinical stroke

Ischemic stroke is the most common type of cerebrovascular disease and is caused by an interruption of blood flow in the brain.In this disease,two different damage areas are identifying:the lesion core,in which cells quickly die;and the penumbra(surrounding the lesion core),in which cells are functionally weakened but may recover and restore their functions.The currently approved treatments for ischemic stroke are the recombinant tissue plasminogen activator and endovascular thrombectomy,but they have a short therapeutic window(4.5 and 6 hours after stroke onset,respectively)and a low percentage of stroke patients actually receive these treatments.Memantine is an approved drug for the treatment of Alzheimer's disease.Memantine is a noncompetitive,low affinity and use-dependent antagonist of N-methyl-D-aspartate glutamate receptor.Memantine has several advantages over developing a new drug to treat focal ischemic stroke,but the most important is that it has sufficient safe probes in preclinical models and humans,and if the preclinical studies provide more evidence about pharmacological actions in tissue protection and repair,this could help to increase the number of clinical trials.The present review summarizes the physiopathology of isquemic stroke and the pharmacological actions in neuroprotection and neuroplasticity of memantine in the post stroke stage of preclinical stroke models,to illustrate their potential to improve functional recovery in human patients.

Memantine combined with environmental enrichment improves spatial memory and alleviates Alzheimer's disease-like pathology in senescence-accelerated prone-8(SAMP8) mice

Memantine is a N-methyl-D-aspartate (NMDA) receptor antagonist approved for the treatment of moderate to severe Alzheimer's disease (AD). Environmental enrichment (EE) has shown significant beneficial effects on func- tional improvement in AD. In this study, we sought to determine whether combining these two distinct therapies would yield greater benefit than either drug used alone. We investigated the effect of memantine combined with EE on spatial learning and memory and AD-like pathology in a widely used AD model, the senescence-accelerated prone mice (SAMP8). The SAMP8 mice were randomly assigned to enriched housing (EH) or standard housing (SH), where either memantine (20 mg/kg) or saline was given by gastric lavage once daily continuously for eight weeks. Our results showed that, when provided separately, memantine and EE significantly improved spatial learning and memory by shortening escape latencies and increasing the frequency of entrance into the target quadrant. When combined, memantine and EE showed additive effect on learning and memory as evidenced by significant shorter escape latencies and higher frequency of target entrance than either drug alone. Consistent with the behavior results, pathological studies showed that both memantine and EE significantly reduced hippocampal CA1 neurofibrilliary tangles (NFTs) as well as amyloid beta precursor protein (APP) levels. Combining both therapies synergistically lessened NFTs and APP expression compared to either drug alone in SAMP8 mice, indicating that the combination of memantine with EE could offer a novel and efficient therapeutic strategy for the treatment of AD.

Chronic pre-treatment with memantine prevents amyloid-beta protein-mediated long-term potentiation disruption

Previous studies indicate that memantine, a low-affinity N-methyI-D-aspartate receptor antagonist exerted acute protective effects against amyloid-β protein-induced neurotoxicity. In the present study, the chronic effects and mechanisms of memantine were investigated further using electrophysiological methods. The results showed that 7-day intraperitoneal application of memantine, at doses of 5 mg/kg or 20 mg/kg, did not alter hippocampal long-term potentiation induction in rats, while 40 mg/kg memantine presented potent long-term potentiation inhibition. Then further in vitro studys were carried out in 5 mg/kg and 20 mg/kg memantine treated rats. We found that 20 mg/kg memantine attenuated the potent long-term potentiation inhibition caused by exposure to amyloid-β protein in the dentate gyrus in vitro. These findings are the first to demonstrate the antagonizing effect of long-term systematic treatment of memantine against amyloid-β protein triggered long-term potentiation inhibition to improve synaptic plasticity.

Morinda citrifolia L. (noni) and memantine attenuate periventricular tissue injury of the fourth ventricle in hydrocephalic rabbits

This study was designed to evaluate the neuroprotective effects of Morinda citrifofia L. （Rubiaceae） commonly known as noni, and memantine （a N-methy-D-aspartate receptor inhibitor） on hydrocephalus-induced neurodegenerative disorders. Kaolin was injected into the cistern magna of male adult New Zealand rabbits to establish a hydrocephalus animal model. Memantine （20 mg/kg, intraperitoneally; memantine-treated group） or noni （5 mL/kg, intragastrically; noni-treated group） was administered daily for 2 weeks. Microtubule-associated protein-2 and caspase-3 immunohistochemistry were performed to detect neuronal degeneration and apoptosis in the periventricular tissue of the fourth ventricle of rabbits. Microtubule-associated protein-2 staining density was significantly decreased in the hydrocephalic group, while the staining density was significantly increased in the memantine- and noni-treated groups, especially in the noni-treated group. Noni treatment decreased the number of caspase-3-positive cells in rabbits with hydrocephalus, while memantine had no effect. These findings suggest that noni exhibits more obvious inhibitory effects on hydrocephalus-induced neurodegenerative disorders than memantine in periventricular tissue of the fourth ventricle.

Memantine: New prospective in bipolar disorder treatment

We review preclinical and clinical evidences strongly suggesting that memantine, an old drug currently approved for Alzheimer's dementia, is an effective treatment for acute mania and for the prevention of manic/hypomanic and depressive recurrences of manicdepressive illness. Lithium remains the first line for the treatment and prophylaxis of bipolar disorders, but currently available treatment alternatives for lithium resistant patients are of limited and/or questionable efficacy. Thus, research and development of more effective mood stabilizer drugs is a leading challenge for modern psychopharmacology. We have demonstrated that 21 d administration of imipramine causes a behavioural syndrome similar to a cycle of bipolar disorder, i.e., a mania followed by a depression, in rats. Indeed, such treatment causes a behavioural supersensitivity to dopamine D2 receptor agonists associated with an increase sexual activity and aggressivity(mania). The dopamine receptor sensitization is followed, after imipramine discontinuation, by an opposite phenomenon(dopamine receptor desensitization) and an increased immobility time(depression) in the forced swimming test of depression. Memantine blocks the development of the supersensitivity and the ensuing desensitization associated with the depressive like behavior. On the basis of these observations we have suggested the use of memantine in the treatment of mania and in the prophylaxis of bipolar disorders. To test this hypothesis we performed several naturalistic studies that showed an acute antimanic effect and a long-lasting and progressive mood-stabilizing action(at least 3 years), without clinically relevant side effects. To confirm the observations of our naturalistic trials we are now performing a randomized controlled clinical trial. Finally we described the studies reporting the efficacy of memantine in maniclike symptoms occurring in psychiatric disorders other than bipolar. Limitations: A randomized controlled clinical trial is needed to confirm our naturalistic observations.Conclusion: We believe that this review presents enough pharmacological and clinical information to consider the administration of memantine in the treatment of bipolar disorders that no respond to standard mood stabilizers.

Failure of memantine to “reverse” quinpirole-induced hypomotility

AIM: To evaluate antidepressant-like effect of memantine in a rat model.METHODS: Male Wistar rats were treated intraperitoneally with either vehicle, memantine(10 mg/kg) or imipramine(20 mg/kg), for 3 wk. Twenty-four hour after the last treatment animals were challenged with quinpirole(0.3 mg/kg s.c.) and tested for motor activity. After 1 h habituation to the motility cages, the motor response was recorded for the following 45-min and the data were collected in 5-min time bins. RESULTS: As expected, chronic treatment with imipramine potentiated the locomotor stimulant effect of quinpirole. On the contrary, chronic memantine administration failed to induce the behavioral supersensitivity to the dopamine agonist. CONCLUSION: The results show that memantine, at variance with antidepressant treatments, fails to induce dopaminergic behavioral supersensitivity. This observation is consistent with the results of preclinical and clinical studies suggesting that memantine does not have an acute antidepressant action but does have an antimanic and mood-stabilizing effect.

Effect of Artesunate vs Memantine in Aluminum Chloride Induced Model of Neurotoxicity in Rats

Alzheimer disease is one of the commonest neurological diseases which is characterized by amyloid plaques accumulation in multiple brain regions. This study investigated the potential neuroprotective effect of artesunate on aluminum induced neurotoxicity vs memantine in rats. 40 male albino Wistar rats were divided randomly into 4 groups as follow: Group 1 negative control, group 2 positive control group induced by ammonium chloride, group 3 rats treated by NH4Cl + artesunate solution, group 4 rats treated by NH4Cl + memantine S.C. spatial Memory and Learning were evaluated using Morris Water Maze (MWM) test. Malondialdehyde (MDA) and reduced glutathione (GSH) levels were measured in cerebral cortex tissue homogenate. Tumor necrosis factor-α (TNFα) and interleukin-1 beta (IL-1β) concentrations were measured in rat cerebral cortex tissue homogenate using rat enzyme linked immunosorbent assay (ELISA) kits. Real-time quantitative reverse transcription-polymerase chain reaction (Real-time qRT-PCR) for Caspase-3, Bcl-2 and iNOS gene expression was measured in rat cerebral cortex. Slices from cerebral cortex were studied by histopathological examination. Artesunate significantly decreased MDA level and inhibited iNOS, caspase and upregulated Bcl-2 gene expression in cerebral cortex. ART increased significantly antioxidant level GSH, and decreased significantly TNF-alpha and IL-B levels. It reduced significantly 1ry retention latency, 2ry retention latency and initial acquisition latency. It also improved brain histopathology and decreased amyloid plaque deposition. ART exerted neuroprotective effect through oxidative stress correction and enhancement of antiapoptotic markers in neuronal cells of the cerebral cortex.

The regulatory effect of memantine on expression and synthesis of heat shock protein 70 gene in neonatal rat models with cerebral hypoxic ischemia

To evaluate the neuroprotective effect of memantine, a non-competitive antagonist at the N-methyl-D-aspartate receptor, against hypoxic ischemia (HI) by exploring its regulation on the expression and synthesis of heat shock protein 70 (HSP70) gene in neonatal rat models with cerebral HI Methods Memantine was intraperitoneally injected at a dose of 20 mg/kg in neonatal rat models either before (PRE group) or after (POST group) induction of HI The expression and synthesis of the HSP70 gene and its corresponding product were determined by rapid competitive PCR and immunohistochemistry, respectively Results There was an increase in the expression of HSP70 mRNA two hours after induction of HI, which reached its peak at 48 hours, then decreased gradually The same expression occurred at relatively low levels in the control group Also, HSP70 synthesis was detected as early as 2h after HI, reached its peak between 48 and 72 hours, then declined over time After memantine administration, the expression of the gene and its synthesis of the corresponding product decreased significantly during the time intervals 24-72 h for the gene and 48-72 h for the product compared to the HI group Conclusion It was shown that HI is very sensitive to the expression of the HSP70 gene and synthesis of its corresponding product, which could be regulated by memantine The latter may have the ability to reduce brain damage; thus decreased HSP70 mRNA expression could be a marker for HI It is suggested that memantine can be a promising agent for neuroprotection against HI, although an overall and abstract assessment of memantine is required to see if it can be used on neonates clinically later on

Memantine对缺氧缺血新生大鼠脑细胞钙超载的影响

目的探讨Memantine对缺氧缺血性脑损伤的防治作用。方法40只7d龄Wistar大鼠随机分为假手术组10只、缺氧缺血组10只、Memantine前治疗组10只、Memantine后治疗组10只。分别于左脑缺氧缺血前、后腹腔注射Memantine和生理盐水,24h后,用荧光指示剂Fura-2/AM检测左侧大脑细胞悬液的[Ca2+]i。结果缺氧缺血组[Ca2+]i明显高于假手术组(P<0·01);Memantine前、后治疗组[Ca2+]i明显低于缺氧缺血组(P<0·01),Memantine前、后治疗组之间则差异无显著意义(P>0·05)。结论缺氧缺血性脑损伤可以引起神经细胞内钙超载,Memantine可有效阻止钙内流,防治缺氧缺血性脑损伤。

Are memantine, methylphenidate and donepezil effective in sparing cognitive functioning after brain irradiation?

One strategy to reduce neurocognitive deterioration in patients after brain irradiation is the use of neuroprotective medication.To generate up-to date knowledge regarding neuroprotective agents we performed a systematic review on the clinical effectiveness of three agents that were reported to have neuroprotective characteristics:memantine,methylphenidate and donepezil.The use of memantine after brain irradiation showed a delay in cognitive deterioration,although at 24 weeks this did not reach significance(P=0.059).Lack of significance is likely to be the result of the limited statistical power of 35%and memantine did show significant differences in secondary outcomes.The study on methylphenidate was not conclusive.Donepezil revealed significant differences in a few cognitive tests however no difference in global cognition was found.In addition,larger effects were observed in individuals with greater cognitive dysfunction prior to treatment.

Incorporation of Dihydroartemisinin into Memantine Through a Propriate Spacer to Make Hybrid with Enhanced Effects to Protect PC12 Cells from Corticosterone-caused Impairments

Ten memantine（Mema）-dihydroartemisinin（DHA） ligands were designed and synthesized. Three types of isomers including α, β, and a defined y isomer were found in each intermediates（1a--1e）. Type γ isomer was firstly reported here and confirmed as a less stable eclipsed conformation. The bonding of Mema with DHA through different carbon chains generally makes the new entities more cytotoxic than either Mema or artemisinm（Arte）. The β Mema/DHA ligands are a little bit more cytotoxic than a ligands. By applying corticosterone（Cort）-impaired PC12 cells models, it was found that Mema and those ligands with more than 3 carbon chains showed weak or no neuroprotective activities against the insults. However, two ligands, 2a（β） and 2b（β） showed better effects than either Arte or their combination（Mema/Arte in 1：1 molar ratio） at a dose of 5 μmol/L. Furthermore, ligands 2a（β）, 2b（β） and 2c（β） were confn-med as mild N-methyl-D-aspartate（NMDA） antagonists, and their corresponding α isomers are weak NMDA antagonists. All the data indicate that the bonding of Mema/DHA in compacted β conformation mode results in enhanced effects against Cort-induced insults in PC12 ceils and might reverse memantine as an anti-depression NMDA antagonist.

Progress in mechanisms of acetylcholinesterase inhibitors and memantine for the treatment of Alzheimer’s disease

Alzheimer’s disease(AD)is the most common causes of dementia in the elderly.Currently,only two classes of drugs,acetylcholinesterase inhibitors(AChEIs)and memantine are approved.AChEIs ameliorate cognitive and psychiatric symptoms in AD patients through activation of acetylcholine(ACh)receptors by increased synaptic ACh levels and also have protective effects against glutamate neurotoxicity and inflammation,whereas memantine appears to mainly protect against excitotoxicity and neurodegeneration.Herein,we review the pharmacologic properties of the available AChEIs and memantine,and focus on recent progress in the mechanisms of AD in relation to acetylcholinergic and glutamatergic involvement.

人工神经元网络法提高毛细管电泳药物控制分析准确度的研究

研究了人工神经元网络法在毛细管电泳定量测定memantine中提高测定准确度的可行性 .在毛细管电泳法定量测定memantine的过程中 ,其浓度与峰高或峰面积以及与二者和内标的比值均没有良好的线性关系 .人工神经元网络具有很强的非线性校正能力 ,其最大优点是无须对分离体系及组分的迁移行为预先予以了解 .人工神经元网络的输入为memantine的峰高和峰面积 ,输出为memantine的浓度 .通过实验确定的网络结构为 2∶2∶1型 .由于人工神经元网络的通用性 。

Comparative efficacy and safety of cognitive enhancers for treating vascular cognitive impairment: systematic review and Bayesian network meta-analysis

Objective: To assess and compare the clinical efficacy and safety of cognitive enhancers(donepezil, galantamine, rivastigmine, and memantine) on cognition, behavior, function, and global status in patients with vascular cognitive impairment.Data sources: The initial literature search was performed with PubMed, EMBASE, the Cochrane Methodology Register, the Cochrane Central Register of Controlled Trials, and Cumulative Index to Nursing & Allied Health(CINAHL) from inception to January 2018 for studies regarding donepezil, galantamine, rivastigmine, and memantine for treatment of vascular cognitive impairment.Data selection: Randomized controlled trials on donepezil, galantamine, rivastigmine, and memantine as monotherapy in the treatment of vascular cognitive impairment were included. A Bayesian network meta-analysis was conducted. Outcome measures: Efficacy was assessed by changes in scores of the Alzheimer's Disease Assessment Scale, cognitive subscale, Mini-Mental State Examination, Neuropsychiatric Inventory scores and Clinician's Interview-Based Impression of Change Scale Plus Caregiver's Input, Activities of Daily Living, the Clinical Dementia Rating scale. Safety was evaluated by mortality, total adverse events(TAEs), serious adverse events(SAEs), nausea, vomiting. diarrhea, or cerebrovascular accidents(CVAs). Results: After screening 1717 citations, 12 randomized controlled trials were included. Donepezil and rivastigmine(mean difference(e) = –0.77, 95% confidence interval(CI): 0.25–1.32; MD = 1.05, 95% CI: 0.18–1.79) were significantly more effective than placebo in reducing Mini-Mental State Examination scores. Donepezil, galantamine, and memantine(MD = –1.30, 95% CI: –2.27 to –0.42; MD = –1.67, 95% CI: –3.36 to –0.06; MD = –2.27, 95% CI: –3.91 to –0.53) showed superior benefits on the Alzheimer's Disease Assessment Scale–cognitive scores compared with placebo. Memantine(MD = 2.71, 95% CI: 1.05–7.29) improved global status(Clinician's Interview-Based Impression of Change Scale Plus Caregiver's Input) more than the placebo. Safety results revealed that donepezil 10 mg(odds ratio(OR) = 3.04, 95% CI: 1.86–5.41) contributed to higer risk of adverse events than placebo. Galantamine(OR = 5.64, 95% CI: 1.31–26.71) increased the risk of nausea. Rivastigmine(OR = 16.80, 95% CI: 1.78–319.26) increased the risk of vomiting. No agents displayed a significant risk of serious adverse events, mortality, cerebrovascular accidents, or diarrhea.Conclusion: We found significant efficacy of donepezil, galantamine, and memantine on cognition. Memantine can provide significant efficacy in global status. They are all safe and well tolerated.

Differentiation renders susceptibility to excitotoxicity in HT22 neurons

HT22 is an immortalized mouse hippocampal neuronal cell line that does not express cholinergic and glutamate receptors like mature hippocampal neurons in vivo. This in part prevents its use as a model for mature hippocampal neurons in memory-related studies. We now report that HT22 cells were appropriately induced to differentiate and possess properties similar to those of mature hippocampal neurons in vivo, such as becoming more glutamate-receptive and excitatory. Results showed that sensitivity of HT22 cells to glutamate-induced toxicity changed dramatically when comparing undifferentiated with differentiated cells, with the half-effective concentration for differentiated cells reducing approximately two orders of magnitude. Moreover, glutamate-induced toxicity in differentiated cells, but not undifferentiated cells, was inhibited by the N-methyi-D- aspartate receptor antagonists MK-801 and memantine. Evidently, differentiated HT22 cells expressed N-methyI-D-aspartate receptors, while undifferentiated cells did not. Our experimental findings indicated that differentiation is important for immortalized cell lines to render post-mitotic neuronal properties, and that differentiated HT22 neurons represent a better model of hippocampal neurons than undifferentiated cells.