Kinesins are the motor proteins that transport excitatory receptors to the synaptic membrane by forming a complex with receptor cargo leading to central sensitization causing neuropathic pain. Many regulatory proteins govern the transit of receptors by activating kinesin, and Aurora kinases are one of them. In this study, we have performed in silico molecular dynamics simulation to delineate the dynamic interaction of Aurora kinase A with its pharmacological inhibitor, tozasertib. The results from the molecular dynamics study shows that tozasertib-Aurora kinase A complex is stabilized through hydrogen bonding, polar interactions, and water bridges. Findings from the in vitro studies suggest that tozasertib treatment significantly attenuates lipopolysaccharide (LPS)-induced increase in oxidonitrosative stress and kif11 overexpression in C6 glial cell lines. Further, we investigated the regulation of kif11 and its modulation by tozasertib in an animal model of neuropathic pain. Two weeks post-CCI surgery we observed a significant increase in pain hypersensitivity and kif11 overexpression in DRG and spinal cord of nerve-injured rats. Tozasertib treatment significantly attenuates enhanced pain hypersensitivity along with the restoration of kif11 expression in DRG and spinal cord and oxidonitrosative stress in the sciatic nerve of injured rats. Our findings demonstrate the potential role of tozasertib for the management of neuropathic pain.
Keywords: Aurora kinase; Kif11; chronic constriction injury; molecular dynamics simulation; neuropathic pain; tozasertib.