Journal of Pharmaceutical Analysis Articles Provide Novel Insights into Previously Unknown Disease Mechanisms

Researchers decode underlying mechanisms of diabetic cardiomyopathy (DCM), hippocampal neurotoxicity, and dysbiosis mediated Alzheimer's disease (AD) progression

XI'AN, China, Feb. 27, 2024 /PRNewswire/ -- DCM is the leading cause of heart failure in patients with chronic diabetes, with unclear mechanisms and limited treatments. Another mystery is the regulation of cytochrome P450 enzymes (CYPs) in the central nervous system. Moreover, the link between the gut microbiome, microbiota-derived metabolites, and the progression of AD remains unknown. In the December issue of Journal of Pharmaceutical Analysis (JPA), three articles explore the interconnected pathologies of DCM, hippocampal neurotoxicity, and AD, offering a comprehensive insight.

In the first study, researchers used mass spectrometry imaging (MSI), a technique combining the specificity of mass spectrometry (MS) with spatial imaging information, to map region-specific metabolites in the rat heart. Their findings, available online on 17 August 2023, were published in Volume 13, Issue 12 of the journal in December 2023. The team developed DCM mouse models to visualize region-specific metabolites, and analyze the ferulic acid's impact. Employing optimized ambient air-flow-assisted desorption electrospray ionization (AFADESI)-MSI and matrix-assisted laser desorption ionization (MALDI)-MSI, they observed heterogeneous metabolic activity and region-specific metabolite distribution in frozen rat heart tissue sections. Blood analyses showed decreased levels of glucose, HbA1c, triglycerides, and alanine aminotransferase following a 20-week high-dose ferulic acid regimen. "Our novel method unveiled metabolic changes in DCM rat hearts and is the first to explore alterations and spatial distribution of endogenous metabolites in the diabetic heart," say corresponding authors Dr. Zeper Abliz and Dr. Zhonghua Wang.

The second study, available online on 25 July 2023, aimed to understand CYP regulation in the hippocampus in response to antiepileptic drug, phenytoin (PHT). PHT causes neuronal damage and cognitive impairment, increasing CYP-mediated testosterone metabolism. The study found that pregnenolone 16α-carbonitrile (PCN), a pregnane X receptor (PXR) agonist, relieved PHT-induced neuronal side effects. Surprisingly, PCN increased hepatic CYP expression but decreased hippocampal CYP3A11 and CYP2B10 expression. The hippocampal CYP suppression by PCN was independent of PXR but linked to glucocorticoid receptor signaling pathway activation. Corresponding authors Hui Wang and Dan Xu conclude, "We propose glucocorticoids as a potential therapeutic strategy for mitigating the neuronal side effects of PHT. Within the coming 5 to 10 years, this research holds the potential to drive substantial progress in the field of PCN, potentially revolutionizing our understanding of PCN's mechanisms within the body." 

The third study, available online on 28 July 2023, attempted to demonstrate the link between gut microbiome and AD progression. It found that gut dysbiosis in transgenic AD mice increased the levels of trimethylamine N-oxide (TMAO), which activated the CDK5/STAT3 pathway in the brain, leading to enhanced cognitive impairment. Fecal microbiota transplantation from non-transgenic mice mitigated neuronal inflammation. "The involving microbiota-gut-brain axis mechanisms underlying AD pathology may afford a new perspective on the novel targets for AD treatment," explain corresponding authors Dr. Yan-Fang Xian and Dr. Zhi-Xiu Lin.

Overall, these studies pave the way for further research and improved treatment strategies.

Reference

Titles of original papers:

1. Integrated mass spectrometry imaging reveals spatial-metabolic alteration in diabetic cardiomyopathy and the intervention effects of ferulic acid
2. Pregnenolone 16α-carbonitrile negatively regulates hippocampal cytochrome P450 enzymes and ameliorates phenytoin-induced hippocampal neurotoxicity
3. Gut dysbiosis aggravates cognitive deficits, amyloid pathology and lipid metabolism dysregulation in a transgenic mouse model of Alzheimer's disease

Journal: Journal of Pharmaceutical Analysis

DOI:

1. https://doi.org/10.1016/j.jpha.2023.08.011 
2. https://doi.org/10.1016/j.jpha.2023.07.013
3. https://doi.org/10.1016/j.jpha.2023.07.014

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SOURCE Journal of Pharmaceutical Analysis