Therapeutic potential of blocking GAPDH nitrosylation with CGP3466b in experimental autoimmune encephalomyelitis

Godfrey, Wesley H.; Hwang, Soonmyung; Cho, Kaho; Shanmukha, Shruthi; Gharibani, Payam; Abramson, Efrat; Kornberg, Michael D.

doi:10.3389/fneur.2022.979659

Cited by 3 publications

(3 citation statements)

References 52 publications

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“…Mice were euthanized with an overdose of isoflurane and then perfused with ice-cold PBS delivered via a cardiac puncture ( Godfrey et al, 2023 ). Spinal cords were mechanically dissociated, then chemically dissociated with collagenase (200 U/ml) and DNase (100 U/ml) with constant shaking for 10 min, triturated with a pipette, and incubated for an additional 10 min.…”

Section: Methodsmentioning

confidence: 99%

TPPB modulates PKC activity to attenuate neuroinflammation and ameliorate experimental multiple sclerosis

Shanmukha,

Godfrey,

Gharibani

et al. 2024

Front. Cell. Neurosci.

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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.

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Section: Methodsmentioning

confidence: 99%

TPPB modulates PKC activity to attenuate neuroinflammation and ameliorate experimental multiple sclerosis

Shanmukha,

Godfrey,

Gharibani

et al. 2024

Front. Cell. Neurosci.

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“…EAE was induced in 8-12 weeks old female C57BL/6J mice as previously described (17,70). MOG35-55 peptide (amino acid sequence MEVGWYRSPFSRVVHLYRNGK) was prepared by the JH Synthesis and Sequencing Core Facility.…”

Section: Eaementioning

confidence: 99%

PKC modulator bryostatin-1 therapeutically targets CNS innate immunity to attenuate neuroinflammation and promote remyelination

Gharibani,

Abramson,

Shanmukha

et al. 2023

Preprint

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In multiple sclerosis (MS), microglia and macrophages within the central nervous system (CNS) play an important role in determining the balance between myelin repair and demyelination/neurodegeneration. Phagocytic and regenerative functions of these CNS innate immune cells support remyelination, whereas chronic and maladaptive inflammatory activation promotes lesion expansion and disability, particularly in the progressive forms of MS. No currently approved drugs convincingly target microglia and macrophages within the CNS, contributing to the critical lack of therapies promoting remyelination and slowing progression in MS. Here, we found that the protein kinase C (PKC)-modulating drug bryostatin-1 (bryo-1), a CNS-penetrant compound with an established human safety profile, produces a shift in microglia and CNS macrophage transcriptional programs from pro-inflammatory to regenerative phenotypes, both in vitro and in vivo. Treatment of microglia with bryo-1 prevented the activation of neurotoxic astrocytes while stimulating scavenger pathways, phagocytosis, and secretion of factors that promote oligodendrocyte differentiation. In line with these findings, systemic treatment with bryo-1 augmented remyelination following a focal demyelinating injury in vivo. Our results demonstrate the potential of bryo-1 and functionally related PKC modulators as myelin regenerative and neuroprotective agents in MS and other neurologic diseases through therapeutic targeting of microglia and CNS-associated macrophages.One Sentence SummaryPKC modulation in CNS innate immune cells favors the activation of a beneficial phenotype that promotes myelin regeneration and neuroprotection.

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“…We examined the effect of CGP3466B (also known as Omigapil maleate or TCH346) [41], which inhibits glyceraldehyde-3-phosphate dehydrogenase (GAPDH) nitrosylation and has anti-apoptotic and neuroprotective effects. CGP3466B is under clinical investigation for the treatment of congenital muscular dystrophy [42] and has also been suggested for the treatment of multiple sclerosis [43]. CGP3466B provides a neuroprotective effect after traumatic brain injury in rats.…”

Section: Chemical Inhibition Of the Hippo Pathway Promotes Growth Of ...mentioning

confidence: 99%

Genome-Wide Screening in Human Embryonic Stem Cells Highlights the Hippo Signaling Pathway as Granting Synthetic Viability in ATM Deficiency

Viner-Breuer

Golan‐Lev

Benvenisty

et al. 2023

Cells

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ATM depletion is associated with the multisystemic neurodegenerative syndrome ataxia–telangiectasia (A–T). The exact linkage between neurodegeneration and ATM deficiency has not been established yet, and no treatment is currently available. In this study, we aimed to identify synthetic viable genes in ATM deficiency to highlight potential targets for the treatment of neurodegeneration in A–T. We inhibited ATM kinase activity using the background of a genome-wide haploid pluripotent CRISPR/Cas9 loss-of-function library and examined which mutations confer a growth advantage on ATM-deficient cells specifically. Pathway enrichment analysis of the results revealed the Hippo signaling pathway as a major negative regulator of cellular growth upon ATM inhibition. Indeed, genetic perturbation of the Hippo pathway genes SAV1 and NF2, as well as chemical inhibition of this pathway, specifically promoted the growth of ATM-knockout cells. This effect was demonstrated in both human embryonic stem cells and neural progenitor cells. Therefore, we suggest the Hippo pathway as a candidate target for the treatment of the devastating cerebellar atrophy associated with A–T. In addition to the Hippo pathway, our work points out additional genes, such as the apoptotic regulator BAG6, as synthetic viable with ATM-deficiency. These genes may help to develop drugs for the treatment of A–T patients as well as to define biomarkers for resistance to ATM inhibition-based chemotherapies and to gain new insights into the ATM genetic network.

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Therapeutic potential of blocking GAPDH nitrosylation with CGP3466b in experimental autoimmune encephalomyelitis

Cited by 3 publications

References 52 publications

TPPB modulates PKC activity to attenuate neuroinflammation and ameliorate experimental multiple sclerosis

TPPB modulates PKC activity to attenuate neuroinflammation and ameliorate experimental multiple sclerosis

PKC modulator bryostatin-1 therapeutically targets CNS innate immunity to attenuate neuroinflammation and promote remyelination

Genome-Wide Screening in Human Embryonic Stem Cells Highlights the Hippo Signaling Pathway as Granting Synthetic Viability in ATM Deficiency

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