Bryostatin-1 alleviates experimental multiple sclerosis

Abstract

Multiple sclerosis (MS) is an inflammatory disorder targeting the central nervous system (CNS). The relapsing-remitting phase of MS is largely driven by peripheral activation of autoreactive T-helper (Th) 1 and Th17 lymphocytes. In contrast, compartmentalized inflammation within the CNS, including diffuse activation of innate myeloid cells, characterizes the progressive phase of MS, the most debilitating phase that currently lacks satisfactory treatments. Recently, bryostatin-1 (bryo-1), a naturally occurring, CNS-permeable compound with a favorable safety profile in humans, has been shown to act on antigen-presenting cells to promote differentiation of lymphocytes into Th2 cells, an action that might benefit Th1-driven inflammatory conditions such as MS. In the present study, we show that bryo-1 provides marked benefit in mice with experimental autoimmune encephalomyelitis (EAE), an experimental MS animal model. Preventive treatment with bryo-1 abolishes the onset of neurologic deficits in EAE. More strikingly, bryo-1 reverses neurologic deficits after EAE onset, even when treatment is initiated at a late stage of disease when peak adaptive immunity has subsided. Treatment with bryo-1 in vitro promotes an anti-inflammatory phenotype in antigen-presenting dendritic cells, macrophages, and to a lesser extent, lymphocytes. These findings suggest the potential for bryo-1 as a therapeutic agent in MS, particularly given its established clinical safety. Furthermore, the benefit of bryo-1, even in late treatment of EAE, combined with its targeting of innate myeloid cells suggests therapeutic potential in progressive forms of MS.

Unlocking the Drug Potential of the Bryostatin Family: Recent Advances in Product Synthesis and Biomedical Applications

“…Multiple sclerosis (MS) is an inflammation of the CNS, mainly driven by self-activated T-helper (Th) 1a nd peripheral activation of Th17 lymphocytes, while diffuse activation of myeloid cells is ap rogression of MS and currently has no satisfactory treatment. In 2018, the researchers at the John Hopkins University brought the hope for the treatment of MS, they discovered that bryo 1 could preventthe progresso fM S. [41] 2.5 Inhibitory activity of bryostatin 1o nc ell aging Fibroblasts are responsible for the synthesis of structural proteins (e.g.,c ollagen) that support the structural integrity of the skin andp romote wound healing. Bryo 1 facilitated the activation and survival of human dermal fibroblasts under stressful conditions and promoted rejuvenationo fh ealthy skin.…”

Designed PKC-targeting bryostatin analogs modulate innate immunity and neuroinflammation

“…We previously reported that naturally-derived bryo-1 inhibits production of pro-inflammatory cytokines (such as IL-12) by lipopolysaccharide (LPS)-stimulated murine bone marrow-derived dendritic cells (mBMDCs), while augmenting production of regulatory cytokines such as IL-10 ( Kornberg et al, 2018). These actions were associated with the beneficial effects of bryo-1 we observed in autoimmune neuroinflammation.…”

“…We recently reported that natural bryo-1 attenuates neuroinflammation in a mouse model of MS by specifically targeting myeloid cells of the innate immune system, skewing the phenotype of macrophages and DCs from pro-inflammatory to anti-inflammatory/reparative phenotypes (Kornberg et al, 2018). Whether PKC isoforms are the key molecular targets mediating these immunologic actions has remained under investigation, as bryo-1 has also been reported to act directly on toll-like receptor 4 (TLR4) to activate myeloid differentiation primary response 88 (MyD88)-independent signaling through TIR-domain-containing adapter-inducing interferon- (TRIF) (Ariza et al, 2011).…”

Bryostatin‐1 ameliorated experimental colitis in Il‐10−/− Mice by protecting the intestinal barrier and limiting immune dysfunction

“…The final concentration of Bry‐1 was 10 μg/mL. The treatment group received an intraperitoneal (ip) injection of 30 μg/kg Bry‐1 every other day for 4 weeks, and the control groups received an equal volume of vehicle control (20% ethanol and 1% DMSO in PBS) every other day for 4 weeks, as previously described . After 4 weeks, the mice were killed under anaesthesia.…”