Effect of Captopril and BQ123 Endothelin-1 Antagonist on Experimentally Induced Hyperlipidemic Nephropathy in Rats.

BACKGROUND: Kidney disease is a universal public health problem, and epidemiological studies demonstrated that the incidences of chronic kidney disease are increasing day by day. However, the efficiency of currently available drugs on the progression of nephropathy is limited. Therefore, the current research was designed to evaluate the therapeutic efficacy of captopril and BQ123 against hyperlipidemia-induced nephropathy in rats. OBJECTIVE: The objective of this study was to examine the implication of Endothelin-1 in experimentally induced hyperlipidemic nephropathy in rats. METHODS: Animals were divided into various groups, and the administration of a high-fat diet for six weeks induced hyperlipidemia. After confirmation of hyperlipidemia, treatment was started for the next 14 days. At the end of the experimental period, the animals were sacrificed, and various biochemical parameters and histopathological studies were performed. RESULTS: Treatment of both the agents in combination effectively decreased BUN levels, serum creatinine, serum nitrite, and proinflammatory markers and ameliorated the pathological injuries to kidneys. CONCLUSION: Furthermore, both treatments also inhibited oxidative stress and restored the hyperlipidemia-induced reduction in the level of antioxidant enzymes.

5-N-ethyl Carboxamidoadenosine Stimulates Adenosine-2b Receptor-Mediated Mitogen-Activated Protein Kinase Pathway to Improve Brain Mitochondrial Function in Amyloid Beta-Induced Cognitive Deficit Mice.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with loss in memory as one of the cardinal features. 5-N-ethyl carboxamidoadenosine (NECA), an agonist of adenosine-2b receptor, exerts neuroprotective activity against several experimental conditions. Further, NECA activates mitogen-activated protein kinase (MAPK) and also attenuates mitochondrial toxicity in mammalian tissues other than brain. Moreover, there is no report on the role of A2b/MAPK-mediated signaling pathway in Aß-induced mitochondrial toxicity in the brain of the experimental animals. Therefore, the present study evaluated the neuroprotective activity of NECA with or without MAPK inhibitor against Aß-induced cognitive deficit and mitochondrial toxicity in the experimental rodents. Further, the effect of NECA with or without MAPK inhibitor was evaluated on Aß-induced mitochondrial toxicity in the memory-sensitive mice brain regions. Intracerebroventricular (ICV) injection of Aß 1-42 was injected to healthy male mice through Hamilton syringe via polyethylene tube to induce AD-like behavioral manifestations. NECA attenuated Aß-induced cognitive impairments in the rodents. In addition, NECA ameliorated Aß-induced Aß accumulation and cholinergic dysfunction in the selected memory-sensitive mouse HIP, PFC, and AMY. Further, NECA significantly attenuated Aß-induced mitochondrial toxicity in terms of decrease in the mitochondrial function, integrity, and bioenergetics in the brain regions of these animals. However, MAPKI diminished the therapeutic effects of NECA on behavioral, biochemical, and molecular observations in AD-like animals. Therefore, it can be speculated that NECA exhibits neuroprotective activity perhaps through MAPK activation in AD-like rodents. Moreover, A2b-mediated MAPK activation could be a promising target in the management of AD.

Amyloid beta (1-42) downregulates adenosine-2b receptors in addition to mitochondrial impairment and cholinergic dysfunction in memory-sensitive mouse brain regions.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory impairment. Adenosinergic receptors are considered as a potential alternative in the management of several neurodegenerative disorders. However, there is no information available on the role of A2b receptor in the pathophysiology of AD. Therefore, the effect of Aß on the level of expression of A2b receptor was investigated in discrete memory-sensitive mouse brain regions. Aß (1-42) was injected intracerebroventricularly to healthy male mouse to induce AD-like behavioral manifestations on Day-1 (D-1) of the experimental protocol. The animals were subjected to the Morris water maze (MWM) test on D-14 to D-18. On D-18, the animals were subjected to the Y-maze test after 30 min lag to the MWM paradigm. Aß significantly attenuated the spatial working memory in MWM and Y-maze tests. In addition, Aß significantly increased cholinergic dysfunction in terms of decrease in the activity of ChAT and ACh level and increase in the AChE activity in the hippocampus, pre-frontal cortex and amygdala of AD-like animals. Further, there was a significant increase in the extent of apoptosis in the selected mouse brain regions. Moreover, Aß caused a substantial reduction in the mitochondrial function, integrity and bioenergetics in all the mouse brain regions. Furthermore, there was a significant decrease in the level of expression of A2b receptors in the selected brain regions of the rodents. Hence, it can be assumed that A2b receptor downregulation could be another therapeutic target in the management of AD.