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

In a mouse model of ischemic stroke, combining SS-31 with NMN reduced brain damage and improved neurological function more effectively than either drug alone, and this protection depended on suppressing an inflammatory signaling pathway involving TREM2. The combination calmed microglial inflammation and shifted cell-death signals toward survival. The study identifies a new multi-target strategy for stroke neuroprotection.

Journal article — Preclinical mouse model study. Population: Male mice with middle cerebral artery occlusion/reperfusion (MCAO/R) ischemic stroke model. Interventions: SS-31 (elamipretide); NMN (nicotinamide mononucleotide); SS-31 plus NMN combination.

Co-administration of SS-31 and NMN significantly attenuated post-ischemic brain damage and ameliorated neurological deficits (P < 0.0001), showing effects markedly superior to either monotherapy. Transcriptomic profiling linked the combination to modulation of innate immune and apoptotic pathways, with significant TREM2 downregulation. The combination inhibited NF-κB (p65) activation, reduced microglial activation and pro-inflammatory cytokines (IL-1β, TNF-α, IL-6), and rebalanced the Bcl-2/Bax axis. TREM2 overexpression entirely reversed these neuroprotective effects.

This paper is relevant to SS-31 research because it shows that combining SS-31 with NMN produces stronger neuroprotection than SS-31 alone in an ischemic stroke model and links that benefit to NF-κB/TREM2 signaling. It does not establish dosing, safety, or efficacy in humans, nor does it show benefit in other conditions or in females.

Key findings

• Combination SS-31 plus NMN significantly reduced post-ischemic brain damage and improved neurological deficits (P < 0.0001), with effects markedly superior to either monotherapy.
• Transcriptomic profiling showed the combination specifically modulated innate immune and apoptotic pathways and significantly downregulated TREM2.
• Combination treatment inhibited NF-κB (p65) activation, reduced microglial activation, and decreased IL-1β, TNF-α, and IL-6.
• Combination therapy rebalanced the Bcl-2/Bax apoptotic axis.
• TREM2 overexpression entirely reversed the neuroprotective benefits of the combination therapy.

Limitations

• Murine model only; findings may not translate to human ischemic stroke.
• Only male mice were studied, so sex-specific effects were not assessed.
• The abstract does not report doses, treatment timing, or sample sizes, limiting interpretation of clinical applicability.
• No limitations were stated by the authors in the abstract.

The record

• Journal: Neurochemical research 51(4): 216
• Published: 2026-07-14
• PMID: 42443448 — DOI: 10.1007/s11064-026-04846-z
• MeSH terms: Animals, Mice, Inbred C57BL, Mice, Brain Injuries, Brain Ischemia, Oligopeptides, Membrane Glycoproteins, Receptors, Immunologic, Neuroprotective Agents, Drug Therapy, Combination, Apoptosis, Male
• Funding: National Natural Science Foundation of China; Scientific and Technological Research Program of Chongqing Municipal Education Commission; Sichuan Medical and Health Care Promotion Institute Scientific Research Project; Graduate Innovation Project of the First Affiliated Hospital of Chongqing Medical University
• Author countries: China

Peptide profiles: SS-31.

All indexed evidence: SS-31 trials & papers.

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