Biology subjects

Malekizadeh, Y.

Publications and source records attributed to Malekizadeh, Y..

2 recordsLinked to original sources

bioRxiv2020

Whole transcriptome in-silico screening implicates cardiovascular and infectious disease in the mechanism of action underlying atypical antipsychotic side-effects

INTRODUCTIONStroke/thromboembolic events, infections and death are all significantly increased by antipsychotics in dementia but little is known about why they can be harmful. Using a novel application of a drug repurposing paradigm, we aimed to identify potential mechanisms underlying adverse events. METHODWhole transcriptome signatures were generated for SH-SY5Y cells treated with amisulpride, risperidone and volinanserin using RNA-sequencing. Bioinformatic analysis was performed which scored the association between antipsychotic signatures and expression data from 415,252 samples in the NCBI GEO repository. RESULTSAtherosclerosis, venous thromboembolism and influenza NCBI GEO-derived samples scored positively against antipsychotic signatures. Pathways enriched in antipsychotic signatures were linked to the cardiovascular and immune systems (e.g. BDNF, PDGFR-beta, TNF, TGF-beta, selenoamino acid metabolism and influenza infection). CONCLUSIONThese findings for the first time mechanistically link antipsychotics to specific cardiovascular and infectious diseases which are known side effects of their use in dementia, providing new information to explain related adverse events. COMPETING INTERESTSCB has received grants and personal fees from ACADIA Pharmaceuticals and Lundbeck, and personal fees from Heptares, Roche, Lilly, Otsuka, Orion, GlaxoSmithKline and Pfizer. DAC is an employee of Eli Lilly and Company Ltd.

bioinformatics↗

bioRxiv2019

Brain permeable AMPK activator R481 raises glycemia by autonomic nervous system activation and amplifies the counterregulatory response to hypoglycemia in rats

AMP-activated protein kinase (AMPK) is a critical cellular and whole body energy sensor activated by energy stress, including hypoglycemia, which is frequently experienced by people with diabetes. Previous studies using direct delivery of an AMPK activator to the ventromedial hypothalamus (VMH) in rodents increased hepatic glucose production. Moreover, recurrent glucoprivation in the hypothalamus leads to blunted AMPK activation and defective hormonal responses to subsequent hypoglycemia. These data suggest that amplifying AMPK activation may prevent or reduce frequency hypoglycemia in diabetes. We used a novel brain-permeable AMPK activator, R481, which potently increased AMPK phosphorylation in vitro. R481 significantly increased peak glucose levels during glucose tolerance tests in rats, which were attenuated by treatment with AMPK inhibitor SBI-0206965 and completely abolished by blockade of the autonomic nervous system. This occurred without altering insulin sensitivity measured by hyperinsulinemic-euglycemic clamps. Endogenous insulin secretion was not altered by R481 treatment. During hyperinsulinemic-hypoglycemic clamp studies, R481 treatment reduced exogenous glucose requirements and amplified peak glucagon levels during hypoglycemia. These data demonstrate that peripheral administration of the brain permeable AMPK activator R481 amplifies the counterregulatory response to hypoglycemia in rats, which could have clinical relevance for prevention of hypoglycemia.

neuroscience↗