Mechanistic Insight into Diosmin-Induced Neuroprotection and Memory Improvement in Intracerebroventricular-Quinolinic Acid Rat Model: Resurrection of Mitochondrial Functions and Antioxidants.

Mian Huang,Ajay Singh Kushwah,Manish Kumar,Ritu Kainth,Mohammad Khalid,Navpreet Singh,Ruchika Garg

doi:10.1155/2022/8584558

Abstract

Neurodegeneration is the final event after a cascade of pathogenic mechanisms in several brain disorders that lead to cognitive and neurological loss. Quinolinic acid (QA) is an excitotoxin derived from the tryptophan metabolism pathway and is implicated in several ailments, such as Alzheimer's, Parkinson's, Huntington's, and psychosis disease. Diosmin (DSM) is a natural flavonoid possessing such properties that may halt the course of neurodegenerative progression. In past studies, free radical scavenging, along with properties, such as antihyperglycemic, anti-inflammatory, and vasoactive properties, of DSM were pragmatic. Hence, in the current experimentations, the neuroprotective activity of DSM was investigated in the QA rat prototype. QA was administered through the intracerebroventricular route (QA-ICV) in rats on day one, and DSM (50 and 100 mg/kg, intraperitoneal route) was given from day 1 to 21. Memory, gait, sensorimotor functions, and biomarkers of oxidative mutilation and mitochondrial functions were evaluated in the whole brain. Results showed significant deterioration of sensorimotor performance, gait, and working- and long-term memory in rats by QA-ICV. These behavioral anomalies were significantly attenuated by DSM (50 and 100 mg/kg) and donepezil (standard drug). QA-ICV-induced decrease in body mass (g), diet, and water ingestion were also attenuated by DSM or donepezil treatments. QA-ICV inhibited mitochondrial complex I and II activities that caused an increase in oxidative and nitrosative stress along with a reduction in endogenous antioxidants in the brain. DSM dose-dependently ameliorated mitochondrial functions and decreased oxidative stress in QA-ICV-treated rats. DSM can be a possible alternative in treating neurodegenerative disorders with underlying mitochondrial dysfunction pathology.

Highlights

Progressive neurodegeneration with concomitant cognitive and neurological deficits are the major manifestations of several brain ailments, such as Alzheimer’s (AD), Parkinson’s (PD), and Huntington’s disease (HD)
Quinolinic acid (QA)-ICV- and DNP-treated rats disclosed a significant escalation in body mass (g), feed, and water intake relative to rats that remained exposed to lone QA was administered through the intracerebroventricular route (QA-ICV)
Quinolinate phosphoribosyltransferase (QPRT) catabolizes QA to NAD+ and carbon dioxide. e activity of quinolinate phosphoribosyltransferase (QPRT) is maximum in the olfactory bulb and lowermost in the cortex, hippocampus, and striatum, where QA may exert neurotoxic action to a great extent in these brain regions. ese brain areas are adversely affected in numerous neurodegenerative disorders, such as AD, PD, HD, and schizophrenia that lead to severe cognitive decline [9, 10]

Summary

Introduction

Progressive neurodegeneration with concomitant cognitive and neurological deficits are the major manifestations of several brain ailments, such as Alzheimer’s (AD), Parkinson’s (PD), and Huntington’s disease (HD). Synaptic waning and impaired long-lasting potentiation because of the decreased expression of neurotrophins (e.g., neurotrophic factors, abrineurin, and neural development factors), neurochemical aberrations (e.g., acetylcholine, glutamate, monoamines, and c-aminobutyric acid), neuropeptides (e.g., oxytocin, substance P, somatostatin, and orexin), and changes in the internal milieu of the brain leads to deterioration of short term and long-term memory [1]. Excessive excitatory drive in the brain culminates in brain atrophy via free radicals, proinflammatory cytokines, and activation of cell death pathways [3, 4]. Quinolinic acid (QA) is a product of the kynurenine pathway of tryptophan metabolism and is an endogenous ligand of NMDARs [5]. QA activates the immune system (microglia and astrocytes), increasing the expression of chemotactic factors (e.g., monocyte chemoattractant protein-1, RANTES) and instigating free radicals. Recent studies revealed that natural products could ameliorate the symptoms of cognitive dysfunction and improve the therapeutic outcome in neurodegenerative disorders [12, 13]

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