Bcl-2 as a Double-edged Sword for the Treatment of Multiple Sclerosis: A Systematic Review

Multiple sclerosis (MS) is a chronic immune-mediated neurodegenerative disease that involves inflammation, demyelination, and neuronal loss. The B-cell lymphoma 2 (Bcl-2) protein family regulates intrinsic apoptotic pathways and may impact disease progression via effects on immune cell survival and neuroprotection.

To review current evidence on the role of Bcl-2 and its modulators in MS. Englishlanguage, clinical and preclinical studies (1998-October 2025) were retrieved from PubMed, Google Scholar, and other databases.

Clinical studies show that peripheral B lymphocytes and autoreactive T cells in relapsingremitting MS often exhibit increased Bcl-2 expression, leading to enhanced resistance to apoptosis and persistence of inflammatory immune responses. Factors such as leptin can further increase Bcl-2 levels in autoreactive T cells. In experimental studies, several interventions, including interferon-β1a, solanesol, green tea and pumpkin oils, β-hydroxybutyrate, cannabidiol, galantamine, melatonin, rifampicin, and rapamycin, were shown to modulate apoptotic pathways by increasing Bcl-2 expression or reducing the Bax/Bcl-2 ratio and caspase-3 activation in neurons. These changes were often accompanied by reduced inflammatory cytokines, decreased oxidative stress, improved neuronal survival, and attenuation of demyelination in MS models.

Overall, the collected evidence suggests that modulation of the Bcl-2 balance represents an important mechanism underlying both immune regulation and neuroprotection in MS.

While modulating Bcl-2 pathways can be effective in MS, future research should aim to provide greater clarification and to design precision-based drugs capable of neuroprotective effects.