Multi-targeted anti-inflammatory drugs for the treatment of neurological disorders.

Inflammation and kinase pathophysiology in neurological disorders: Inflammation is one of the common features of various acute and degenerative neurological disorders, such as stroke, traumatic brain injury (TBI), Alzheimer's disease (AD), Parkinson's disease (PD), and others. The inflammatory responses are manifested as the synthesis of inflammation mediators, recruitment of leukocytes, and other secondary injuries. Compelling evidence shows that a large number of inflammation mediators (e.g., thrombin, reactive oxygen species, cytokines, chemokines, and other molecules) are implicated in the pathophysiological processes in neurological disorders (Liu and Ander, 2012) (Figure 1). These increased inflammation mediators stimulate their downstream transmembrane receptors (e.g., protease-activated receptors, cytokine receptors, and others), and further activate the intracellular downstream effector kinases, such as Src family kinase, Rho-associated protein kinase, Jun N-terminal kinase, extracellular signal-regulated kinase, cyclin-dependent kinase (CDK), and others (Liu and Ander, 2012) (Figure 1). Aside from overlapping in different neurological disorders, numerous inflammatory molecules and multiple kinase-involved signaling pathways can be linked to a single neurological disorder such as AD (Heneka et al., 2015). Because of their pivot roles in the process of inflammation, kinases have been regarded as anti-inflammatory targets to improve outcomes of neurological disorders.