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

Abstract

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.

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

“…The number of differentiating OL (Olig2 + CC1 + ) represented as a percentage of total Olig2 + also showed a similar trend of increased OL differentiation in the TPPB-treated group (Figure 5D). This result suggests a potential enhancement of remyelination by TPPB, similar to bryo-1 (Gharibani et al, 2023).…”

“…We found that SUW014 interestingly did not ameliorate the neurologic symptoms of EAE, while TPPB was able to improve EAE phenotype like bryo-1 and bryologs. We recently established that bryo-1 is able to activate phagocytosis in macrophages and microglia (which is critical during remyelination as myelin debris inhibits myelin formation) and enhance remyelination in LPC-induced demyelination model (Gharibani et al ., 2023). Here, we also demonstrated that TPPB stimulates phagocytosis by macrophages and increases remyelination in focal LPC-induced demyelination animal model.…”

“…We recently demonstrated that modulation of PKC activity hinders pro-inflammatory responses from microglia and macrophages, while activating anti-inflammatory and regenerative responses from these cells (Kornberg et al ., 2018; Abramson et al ., 2021; Gharibani et al ., 2023). In experimental autoimmune encephalomyelitis (EAE), an MS animal model, modulation of PKC activity prevented the development of neurologic symptoms, and therapeutic treatment of EAE mice with a PKC modulator significantly improved the symptoms of EAE.…”

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

“…Focal demyelination was induced in 8–12-week-old C57BL/6 J mice by injecting 1% LPC (Sigma) in PBS into the ventral funiculus as described previously ( Gharibani et al, 2023 ). Briefly, mice were anesthetized with ketamine (100 mg/kg) and xylazine (10 mg/kg) injected IP.…”

“…We recently demonstrated that modulation of PKC activity hinders pro-inflammatory responses from microglia and macrophages, while activating anti-inflammatory and regenerative responses from these cells ( Kornberg et al, 2018 ; Abramson et al, 2021 ; Gharibani et al, 2023 ). In experimental autoimmune encephalomyelitis (EAE), an MS animal model, modulation of PKC activity prevented the development of neurologic symptoms, and therapeutic treatment of EAE mice with a PKC modulator significantly improved the symptoms of EAE.…”