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Protein kinase C (PKC) plays a key role in modulating the activities of the innate immune cells of the central nervous system (CNS). A delicate balance between pro-inflammatory and regenerative activities by microglia and CNS-associated macrophages is necessary for the proper functioning of the CNS. Thus, a maladaptive activation of these CNS innate immune cells results in neurodegeneration and demyelination associated with various neurologic disorders, such as multiple sclerosis (MS) and Alzheimer's disease. Prior studies have demonstrated that modulation of PKC activity by bryostatin-1 (bryo-1) and its analogs (bryologs) attenuates the pro-inflammatory processes by microglia/CNS macrophages and alleviates the neurologic symptoms in experimental autoimmune encephalomyelitis (EAE), an MS animal model. Here, we demonstrate that (2S,5S)-(E,E)-8-(5-(4-(trifluoromethyl)phenyl)-2,4-pentadienoylamino)benzolactam (TPPB), a structurally distinct PKC modulator, has a similar effect to bryo-1 on CNS innate immune cells both in vitro and in vivo , attenuating neuroinflammation and resulting in CNS regeneration and repair. This study identifies a new structural class of PKC modulators, which can therapeutically target CNS innate immunity as a strategy to treat neuroinflammatory and neurodegenerative disorders., Competing Interests: The Johns Hopkins University has filed a patent for the application of PKC modulator bryo-1 and related technology, and PK and MK are co-inventors on the patent. MK has received consulting fees from Biogen, Genentech, Novartis, TG Therapeutics, and OptumRx. Stanford University has filed patents on bryostatin and other PKC modulators which have been licensed by Neurotrope BioScience for the treatment of neurological disorders and by Bryologyx Inc. for use in HIV/AIDS eradication and cancer immunotherapy. PW is an advisor to both companies and a cofounder of the latter. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Shanmukha, Godfrey, Gharibani, Lee, Guo, Deng, Wender, Kornberg and Kim.)

Multiple sclerosis (MS) is a neuroinflammatory disease of the central nervous system (CNS). Although classically considered a demyelinating disease, neuroaxonal injury occurs in both the acute and chronic phases and represents a pathologic substrate of disability not targeted by current therapies. Nitric oxide (NO) generated by CNS macrophages and microglia contributes to neuroaxonal injury in all phases of MS, but candidate therapies that prevent NO-mediated injury have not been identified. Here, we demonstrate that the multifunctional protein glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is robustly nitrosylated in the CNS in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. GAPDH nitrosylation is blocked in vivo with daily administration of CGP3466b, a CNS-penetrant compound with an established safety profile in humans. Consistent with the known role of nitrosylated GAPDH (SNO-GAPDH) in neuronal cell death, blockade of SNO-GAPDH with CGP3466b attenuates neurologic disability and reduces axonal injury in EAE independent of effects on the immune system. Our findings suggest that SNO-GAPDH contributes to neuroaxonal injury during neuroinflammation and identify CGP3466b as a candidate neuroprotective therapy in MS., Competing Interests: MK has received consulting fees from Biogen Idec, Genentech, Janssen Pharmaceuticals, Novartis, OptumRx, and TG Therapeutics on topics unrelated to this manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Godfrey, Hwang, Cho, Shanmukha, Gharibani, Abramson and Kornberg.)