Inhibitors of Src Family Kinases, Inducible Nitric Oxide Synthase, and NADPH Oxidase as Potential CNS Drug Targets for Neurological Diseases

Abstract

Neurological diseases share common neuroinflammatory and oxidative stress pathways. Both phenotypic and molecular changes in microglia, astrocytes, and neurons contribute to the progression of disease and present potential targets for disease modification. Src family kinases (SFKs) are present in both neurons and glial cells and are upregulated following neurological insults in both human and animal models. In neurons, SFKs interact with post-synaptic protein domains to mediate hyperexcitability and neurotoxicity. SFKs are upstream of signaling cascades that lead to the modulation of neurotransmitter receptors and the transcription of pro-inflammatory cytokines as well as producers of free radicals through the activation of glia. Inducible nitric oxide synthase (iNOS/NOS-II) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), the major mediators of reactive nitrogen/oxygen species (RNS/ROS) production in the brain, are also upregulated along with the pro-inflammatory cytokines following neurological insult and contribute to disease progression. Persistent neuronal hyperexcitability, RNS/ROS, and cytokines can exacerbate neurodegeneration, a common pathognomonic feature of the most prevalent neurological disorders such as Alzheimer's disease, Parkinson's disease, and epilepsy. Using a wide variety of preclinical disease models, inhibitors of the SFK-iNOS-NOX2 signaling axis have been tested to cure or modify disease progression. In this review, we discuss the SFK-iNOS-NOX2 signaling pathway and their inhibitors as potential CNS targets for major neurological diseases.

Trial registration: ClinicalTrials.gov NCT00992667 NCT04327089.

Fig. 1:

A brief and general overview of the Fyn-iNOS-NOX2 mediated mechanisms in a neurological disease. Following an insult, Fyn kinase phosphorylates PKCδ which then leads to NFκB mediated transcription of proinflammatory cytokines, iNOS and gp91^phox in microglia. Fyn also phosphorylated p130cas which recruits Pyk2/paxillin complex to mediate microglial migration, often to the site of neuronal injury and interact via the appropriate receptors expressed by neurons in response to an insult. In neurons, phosphorylated Fyn and tau interact and move to the postsynaptic site to engage with PSD95 and can also phosphorylate glutamatergic receptors. This can lead to excessive calcium influx and activation of nNOS to produce RNS/ROS leading to hyperexcitability and neurotoxicity. AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; Ca, calcium; IkB, inhibitor of nuclear factor kappa B; iNOS, inducible nitric oxide synthase; NADPH, nicotinamide adenine dinucleotide phosphate; NFkB, nuclear factor kappa light chain enhancer; NMDAR, N-Methyl-D-aspartic acid or N-Methyl-D-aspartate receptor; ; nNOS, neuronal nitric oxide synthase; NOX2, NADPH oxidase 2; PKCδ, protein kinase C delta; PSD, post synaptic density; RNS, reactive nitrogen species; ROS, reactive oxygen species; *Yellow stars indicate phosphorylation.

Fig. 2

Major protein domains of Src family kinases. SH, Src homology

Fig. 3

Major protein domains of iNOS (inducible nitric oxide synthase) and NOX (NADPH oxidase). CaM, calmodulin binding domain; FAD, Flavin adenine dinucleotide; FE III, Iron III; FMN, Flavin mononucleotide; NADPH, nicotinamide adenine dinucleotide phosphate