Inhibition of JNK Alleviates Chronic Hypoperfusion-Related Ischemia Induces Oxidative Stress and Brain Degeneration via Nrf2/HO-1 and NF-κB Signaling.

Abstract

Cerebral ischemia is one of the leading causes of neurological disorders. The exact molecular mechanism related to chronic unilateral cerebral ischemia-induced neurodegeneration and memory deficit has not been precisely elucidated. In this study, we examined the effect of chronic ischemia on the induction of oxidative stress and c-Jun N-terminal kinase-associated detrimental effects and unveiled the inhibitory effect of specific JNK inhibitor (SP600125) on JNK-mediated brain degeneration in adult mice. Our behavioral, biochemical, and immunofluorescence studies revealed that chronic ischemic injuries sustained increased levels of oxidative stress-induced active JNK for a long time, whereas SP600125 significantly reduced the elevated level of active JNK and further regulated Nrf2/HO-1 and NF-κB signaling, which have been confirmed in vivo. Neuroinflammatory mediators and loss of neuronal cells was significantly reduced with the administration of SP600125. Ischemic brain injury caused synaptic dysfunction and memory impairment in mice. However, these were significantly improved with SP600125. On the whole, these findings suggest that elevated ROS-mediated JNK is a key mediator in chronic ischemic conditions and has a crucial role in neuroinflammation, neurodegeneration, and memory dysfunction. Our findings suggest that chronic oxidative stress associated JNK would be a potential target in time-dependent studies of chronic ischemic conditions induced brain degeneration.

• Authors: Muhammad Sohail Khan, Amjad Khan, Sareer Ahmad, Riaz Ahmad, Inayat U R Rehman, Muhammad Ikram, Myeong Ok Kim
• Journal: Oxidative medicine and cellular longevity (Oxid Med Cell Longev) Vol. 2020 Pg. 5291852 ( 2020) ISSN: 1942-0994 [Electronic] United States
• PMID: 32617137 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Muhammad Sohail Khan et al.

Chemical References

• Anthracenes
• NF-E2-Related Factor 2
• NF-kappa B
• pyrazolanthrone
• Heme Oxygenase-1
• JNK Mitogen-Activated Protein Kinases

Topics

• Aging (pathology)
• Animals
• Anthracenes (pharmacology)
• Apoptosis (drug effects)
• Brain Ischemia (complications, pathology, physiopathology)
• Heme Oxygenase-1 (metabolism)
• Hippocampus (pathology)
• JNK Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Male
• Memory Disorders (complications, pathology, physiopathology)
• Mice, Inbred C57BL
• Models, Biological
• NF-E2-Related Factor 2 (metabolism)
• NF-kappa B (metabolism)
• Neurodegenerative Diseases (complications, pathology, physiopathology)
• Neurons (drug effects, metabolism, pathology)
• Oxidative Stress (drug effects)
• Perfusion
• Phosphorylation (drug effects)
• Signal Transduction
• Synapses (drug effects, metabolism)
• Up-Regulation (drug effects)