Neuroprotective effect of chlorogenic acid in global cerebral ischemia-reperfusion rat model.

Abstract

The ischemic cascade is initiated in the hypoperfused region of the brain that leads to neuronal cell death. Identification of multi-target inhibitor against prominent molecular mediators of ischemic cascade might be a suitable strategy to combat cerebral ischemic stroke. The present study is designed to evaluate the neuroprotective efficacy of chlorogenic acid (CGA) in the global cerebral ischemic rat model. The effective dose of CGA was evaluated on the basis of reduction in cerebral infarction area percentage, Evans blue extravasation, and restoration of brain water content. The expression of tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), and caspase-3 was evaluated by immunohistochemistry and morphological and cellular alterations in the cortex were observed by brain histology. The level of glutamate, calcium, and nitrate in different regions of the brain, as well as cerebrospinal fluid (CSF), was evaluated. The level of calcium and nitrate was compared with ifenprodil-an antagonist of N-methyl-D-aspartate receptor (NMDAR) and 7-nitroindazole-an inhibitor of neuronal nitric oxide synthase (nNOS) respectively. Further, molecular docking was performed to compare the inhibition potential of CGA against NMDAR and nNOS with their inhibitors. Dose optimization results revealed that intranasal administration of CGA (10 mg/kg b.w.) significantly reduced the cerebral infarction area, Evans blue extravasation and restored the brain water content compared with ischemia group. It also significantly reduced the calcium, nitrate, and glutamate levels compared with ischemia group in the cortex, hippocampus cerebellum, and CSF. Immunohistochemical analysis revealed that CGA significantly reduced the expression of TNF-α, iNOS, and caspase-3 as compared with the ischemia group. In molecular docking study, CGA displayed similar binding interaction as that of Ifenprodil and 7-nitroindazole with NMDAR and nNOS respectively. The current findings suggest that the treatment with CGA confers neuroprotection in global ischemic insult by inhibiting and downregulating the different molecular markers of cerebral ischemia.

• Authors: Gaurav Kumar, Sumedha Mukherjee, Pankaj Paliwal, Saumitra Sen Singh, Hareram Birla, Surya Pratap Singh, Sairam Krishnamurthy, Ranjana Patnaik
• Journal: Naunyn-Schmiedeberg's archives of pharmacology (Naunyn Schmiedebergs Arch Pharmacol) Vol. 392 Issue 10 Pg. 1293-1309 (10 2019) ISSN: 1432-1912 [Electronic] Germany
• PMID: 31190087 (Publication Type: Journal Article)

Chemical References

• Neuroprotective Agents
• Chlorogenic Acid
• Nitric Oxide Synthase Type I
• Nitric Oxide Synthase Type II
• Nos1 protein, rat
• Nos2 protein, rat

Topics

• Animals
• Brain Ischemia (pathology, prevention & control)
• Cerebral Infarction (drug therapy, pathology)
• Chlorogenic Acid (administration & dosage, pharmacology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Male
• Molecular Docking Simulation
• Neuroprotective Agents (administration & dosage, pharmacology)
• Nitric Oxide Synthase Type I (metabolism)
• Nitric Oxide Synthase Type II (metabolism)
• Rats
• Rats, Inbred Strains
• Stroke (pathology, prevention & control)