JAK2/STAT3 as a new potential target to manage neurodegenerative diseases: An interactive review

Abstract

Neurodegenerative diseases (NDDs) are a collection of incapacitating disorders in which neuroinflammation and neuronal apoptosis are major pathological consequences due to oxidative stress. Neuroinflammation manifests in the impacted cerebral areas as a result of pro-inflammatory cytokines stimulating the Janus Kinase2 (JAK2)/Signal Transducers and Activators of Transcription3 (STAT3) pathway via neuronal cells. The pro-inflammatory cytokines bind to their respective receptor in the neuronal cells and allow activation of JAK2. Activated JAK2 phosphorylates tyrosines on the intracellular domains of the receptor which recruit the STAT3 transcription factor. The neuroinflammation issues are exacerbated by the active JAK2/STAT3 signaling pathway in conjunction with additional transcription factors like nuclear factor kappa B (NF-κB), and the mammalian target of rapamycin (mTOR). Neuronal apoptosis is a natural process made worse by persistent neuroinflammation and immunological responses via caspase-3 activation. The dysregulation of micro-RNA (miR) expression has been observed in the consequences of neuroinflammation and neuronal apoptosis. Neuroinflammation and neuronal apoptosis-associated gene amplification may be caused by dysregulated miR-mediated aberrant phosphorylation of JAK2/STAT3 signaling pathway components. Therefore, JAK2/STAT3 is an attractive therapeutic target for NDDs. Numerous synthetic and natural small molecules as JAK2/STAT3 inhibitors have therapeutic advances against a wide range of diseases, and many are now in human clinical studies. This review explored the interactive role of the JAK2/STAT3 signaling system with key pathological factors during the reinforcement of NDDs. Also, the clinical trial data provides reasoning evidence about the possible use of JAK2/STAT3 inhibitors to abate neuroinflammation and neuronal apoptosis in NDDs.

Keywords: Clinical trial; JAK2/STAT3; Neuroinflammation; Neuronal apoptosis; Therapeutic advances; miRs.