Elamipretide (SS-31) and NMN Combination Therapy Targets TREM2 to Mitigate Post-Ischemic Brain Injury in Mice

Ischemic stroke is a devastating cerebrovascular disorder leading to high mortality and long-term disability, largely due to uncontrolled neuroinflammation and apoptosis. Current reperfusion therapies have narrow windows, leaving many patients without effective treatment. Developing novel neuroprotective strategies is crucial. Elamipretide (SS-31), a mitochondrial-targeted peptide, and nicotinamide mononucleotide (NMN), an NAD+ precursor, are known neuroprotective agents. This study explores their combined efficacy and the role of triggering receptor expressed on myeloid cells 2 (TREM2) in mitigating post-ischemic injury.

Researchers established a middle cerebral artery occlusion/reperfusion (MCAO/R) model in male mice. Animals received SS-31, NMN, or a combination of both. Therapeutic outcomes were assessed via neurobehavioral scoring, histopathological staining, transcriptomic sequencing, and protein expression analyses. To elucidate specific molecular mechanisms, TREM2 overexpression experiments and pharmacological inhibition of the NF-κB pathway were also conducted. The abstract did not specify the exact doses, routes, or frequency of administration for either compound, nor the total number of animals (n) used.

Co-administration of SS-31 and NMN significantly attenuated post-ischemic brain damage and ameliorated neurological deficits (P < 0.0001), demonstrating effects markedly superior to either monotherapy. Transcriptomic profiling revealed that the combination therapy specifically modulated innate immune and apoptotic pathways. This was concomitant with a significant downregulation of TREM2 expression. Mechanistically, the combination therapy effectively inhibited NF-κB (p65) activation, which in turn contributed to the downregulation of TREM2. Overexpression of TREM2 partially reversed the neuroprotective effects, confirming its role. The synergistic action of the combination therapy appears to target multiple facets of stroke pathology. > The combination of Elamipretide and NMN significantly reduced post-ischemic brain damage and improved neurological function by targeting TREM2 and inhibiting NF-κB activation.