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Carnosine as a Possible Drug for Zinc-Induced Neurotoxicity and Vascular Dementia.

ABSTRACT: Increasing evidence suggests that the metal homeostasis is involved in the pathogenesis of various neurodegenerative diseases including senile type of dementia such as Alzheimer's disease, dementia with Lewy bodies, and vascular dementia. In particular, synaptic Zn2+ is known to play critical roles in the pathogenesis of vascular dementia. In this article, we review the molecular pathways of Zn2+-induced neurotoxicity based on our and numerous other findings, and demonstrated the implications of the energy production pathway, the disruption of calcium homeostasis, the production of reactive oxygen species (ROS), the endoplasmic reticulum (ER)-stress pathway, and the stress-activated protein kinases/c-Jun amino-terminal kinases (SAPK/JNK) pathway. Furthermore, we have searched for substances that protect neurons from Zn2+-induced neurotoxicity among various agricultural products and determined carnosine (?-alanyl histidine) as a possible therapeutic agent for vascular dementia.

SUBMITTER: Kawahara M

PROVIDER: S-EPMC7177235 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Carnosine as a Possible Drug for Zinc-Induced Neurotoxicity and Vascular Dementia.

Kawahara Masahiro M Sadakane Yutaka Y Mizuno Keiko K Kato-Negishi Midori M Tanaka Ken-Ichiro KI

International journal of molecular sciences 20200407 7

Increasing evidence suggests that the metal homeostasis is involved in the pathogenesis of various neurodegenerative diseases including senile type of dementia such as Alzheimer's disease, dementia with Lewy bodies, and vascular dementia. In particular, synaptic Zn<sup>2+</sup> is known to play critical roles in the pathogenesis of vascular dementia. In this article, we review the molecular pathways of Zn<sup>2+</sup>-induced neurotoxicity based on our and numerous other findings, and demonstrat ...[more]

PMID: 32272780

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Project description:BackgroundSynaptic damage and glutamate excitotoxicity have been implicated in the pathogenesis of vascular dementia (VD). Clathrin, RAB5B and N-methyl-D-aspartic acid receptor 1 (NMDAR1) proteins play a vital role in endocytosis of synaptic vesicles in neurons and glutamate over accumulation. Previous researches have been confirmed that Shenzhi Jiannao (SZJN) formula has an anti-apoptotic and neuroprotective effect in VD, but the underlying mechanisms are still unclear. In this study, we aimed to explore the effect of SZJN formula on cognitive impairment and glutamate excitotoxicity via clathrin-mediated endocytosis (CME) in vivo and in vitro.MethodsSZJN formula consists of Panax ginseng C.A.Mey., Anemarrhena asphodeloides Bunge, and Paeonia anomala subsp. veitchii (Lynch) D.Y.Hong & K.Y.Pan. All herbs were prepared into granules. Both common carotid arteries were permanent occluded (2-vessel occlusion, 2VO) in male Sprague Dawley (SD) rats to model VD. One day after operation, the rats began daily treatment with SZJN formula for 2 weeks. The neuroprotective effects of SZJN formula was subsequently assessed by the novel object recognition test, Morris water maze, hematoxylin-eosin (HE) staining and Nissl staining. Glutamate cytotoxicity was assessed by detecting cell viability and cell death of PC12 cells. Immunohistochemistry, immunofluorescence, Western blot, and quantitative real-time PCR were used to detect the expression levels of clathrin, RAB5B, and NMDAR1.ResultsAdministration of SZJN formula effectively improved short-term memory and spatial memory. SZJN formula treatment significantly reduced hippocampal neuronal loss, and recovered the arrangement and morphology of neurons and Nissl bodies. Moreover, SZJN formula promoted the proliferation of PC12 cells and inhibited glutamate-induced cell death. The down-regulation of clathrin and RAB5B, as well as the upregulation of NMDAR1 in the brain induced by 2VO or glutamate was also notably reversed by SZJN formula at both the protein and mRNA levels, which may contribute to SZJN formula induced improved neurological function.ConclusionsTaken together, our findings provide evidence that the neuroprotective effects of SZJN formula in experimental VD maybe mediated through promoting the expression of clathrin-mediated endocytosis and reducing NMDARs-associated glutamate excitotoxicity. SZJN formula serves as a promising alternative therapy and may be a useful herbal medicine for preventing progression of VD.

Project description:For patients with a diagnosis of vascular dementia there is evidence that aspirin is widely prescribed - in one study, completed by geriatricians and psychiatrists in the UK, 80% of patients with cognitive impairment (with vascular risk factors) were prescribed aspirin. However, a number of queries remain unanswered: Is there convincing evidence that aspirin benefits patients with vascular dementia? Does aspirin affect cognition or improve prognosis? In addition, does the risk of cerebral or gastric haemorrhage outweigh any benefit?To assess the evidence of effectiveness of the use of aspirin for vascular dementia.Computerized databases were searched independently by two reviewers. In addition, relevant websites were searched and some journals were handsearched. Specialists in the field were approached for unpublished material and any publications found were searched for additional references. The most recent search for trials was carried out in February 2000.All randomized controlled trials investigating the effect of aspirin for vascular dementia are included. Inclusion/exclusion of studies comprised systematic assessment of the quality of study design and the risk of bias.Data were extracted independently by both reviewers, using a previously tested data extraction form and, where required, authors were contacted for data not provided in the papers. The aim is to evaluate data recorded via tools assessing cognitive and behavioural changes along with mortality, morbidity and institutionalization data.No trials are eligible for inclusion in this review.There is no evidence that aspirin is effective in treating patients with a diagnosis of vascular dementia. Further research is needed to assess the effect of aspirin on cognition, and on other outcomes such as behaviour, and quality of life. At present there is no evidence relating to other queries about the use of aspirin for dementia (these are described in the Background section of this review). The most recent search for references to relevant research was carried out in February 2000, but no new evidence was found.

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Carnosine as a Possible Drug for Zinc-Induced Neurotoxicity and Vascular Dementia.

Publications

Carnosine as a Possible Drug for Zinc-Induced Neurotoxicity and Vascular Dementia.

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