Repurposing antimicrobial agents for neuroprotection: mechanisms, clinical potential, and challenges
This narrative review concludes that antimicrobials such as minocycline, doxycycline, macrolides, and antimalarials show neuroprotective effects in preclinical models, but human clinical evidence is scarce, inconsistent, and insufficient to support therapeutic recommendations.
| Population | Patients with neurological diseases (Alzheimer's, Parkinson's, ALS, stroke, MS, epilepsy, spinal cord injury) or corresponding animal models |
|---|---|
| Intervention | Repurposed antimicrobial agents (minocycline, doxycycline, macrolides, chloroquine, hydroxychloroquine, dapsone, ivermectin, niclosamide) |
| Comparator | Placebo, vehicle, or no treatment (experimental models); in some clinical trials, placebo-controlled |
| Outcome | Functional progression in ALS (ALSFRS-R); Conversion to definite MS in clinically isolated syndrome; Microglial activation and pro-inflammatory cytokines (animal models); Infarct volume and neurological deficit in stroke models; Dopaminergic neuronal loss in Parkinson models; Functional recovery after spinal cord injury (animal models and clinical trials); Clinical adverse events (tolerability of high doses in ALS) |
Summary of findings
| Outcome | Effect | 95% CI | Certainty | Clinical relevance | Notes |
|---|---|---|---|---|---|
| Functional progression in ALS (ALSFRS-R) | MD -1.30 ALSFRS-R points (minocycline vs placebo), 95% CI not reported; n=412, phase III RCT | — | Moderate | — | 1 studies |
| Conversion to definite MS in clinically isolated syndrome | absolute risk difference ~27.1 percentage points (33.9% vs 61.0%), 95% CI not reported; n=44, RCT | — | Low | — | 1 studies |
| Microglial activation and pro-inflammatory cytokines (animal models) | direction consistently favorable across multiple animal models; in the pooled effect size available | — | Very low | — | |
| Infarct volume and neurological deficit in stroke models | direction favorable in animal models (3-45 mg/kg); in the pooled effect size; in the clinical RCT data reported | — | Very low | — | |
| Dopaminergic neuronal loss in Parkinson models | direction favorable in MPTP animal models (30-120 mg/kg); in the clinical RCT data reported | — | Very low | — | |
| Functional recovery after spinal cord injury (animal models and clinical trials) | mixed direction: favorable in some animal models; in the significant improvement in cervical contusion rat model (90 mg/kg x 3d); clinical data insufficient | — | Low | — | |
| Clinical adverse events (tolerability of high doses in ALS) | mean tolerated dose 387 mg/day (target 400 mg/day); increased GI adverse events and elevated BUN/liver enzymes at high doses; n=23 crossover trial | — | Low | — | 2 studies |
Context
Neurological diseases such as Alzheimer's, Parkinson's, ALS, and stroke lack effective disease-modifying treatments. Drug repurposing of agents with known safety profiles represents a faster and less costly development strategy. Antimicrobials with anti-inflammatory and immunomodulatory properties have been investigated in this context.
What the study showed
In animal models, minocycline consistently reduces microglial activation, pro-inflammatory cytokines, infarct volume, and dopaminergic neuronal loss. In human ALS, a phase III RCT (n=412) showed functional worsening in the minocycline group versus placebo (ALSFRS-R: −1.30 additional points, 95% CI not reported in the source text). In clinically isolated syndrome (RCT, n=44), minocycline reduced conversion to definite MS at 2 years: 61.0% in placebo versus 33.9% in the minocycline group (absolute difference of 27.1 percentage points; RR not specified by the study). Most clinical data derive from small, pilot, or phase II studies without statistical power for definitive outcomes.
How it was done
Non-systematic narrative review synthesizing preclinical evidence (in vitro and in vivo rodent models) and clinical evidence (phase I–III trials, pilot studies, case series) on multiple antimicrobials across various neurological diseases. No registered protocol, explicit inclusion/exclusion criteria, reported systematic search, or formal risk-of-bias assessment of included studies. Duration of individual studies ranges from weeks to years.
Effect magnitude
The only clinical magnitude data with a clear unfavorable direction is the ALS RCT (n=412): minocycline accelerated functional decline by −1.30 points on the ALSFRS-R versus placebo. For MS (n=44), the absolute reduction in conversion was 27.1 percentage points in favor of minocycline, but the 95% CI was not provided in the source text.
Risk of bias
This is a narrative review without systematic methodology and without applied risk-of-bias tools (no RoB 2, ROBINS-I, or AMSTAR-2). Most neuroprotective data derive from animal models with unestablished translational validity. Cited clinical trials are heterogeneous in population, dose, duration, and outcome, precluding quantitative synthesis. Implicit publication bias exists due to narrative study selection.
What this study does NOT prove
This review does not prove clinical efficacy of any antimicrobial as a neuroprotective agent in humans; preclinical data do not automatically translate into clinical benefit. Results are not generalizable to pediatric, elderly with comorbidities, or underrepresented ethnic populations in cited studies.
In clinical practice
No reviewed antimicrobial agent has sufficient clinical evidence to be recommended as a neuroprotective agent outside clinical trials. Clinicians should treat preclinical data as hypotheses, not as a basis for prescribing. Off-label use of minocycline in ALS is contraindicated by phase III RCT data.
Limitations
This is a narrative review without systematic methodology and without applied risk-of-bias tools (no RoB 2, ROBINS-I, or AMSTAR-2). Most neuroprotective data derive from animal models with unestablished translational validity. Cited clinical trials are heterogeneous in population, dose, duration, and outcome, precluding quantitative synthesis. Implicit publication bias exists due to narrative study selection.
What is still missing
Adequately powered phase III RCTs with standardized clinical outcomes and well-defined populations are needed for each specific neurological indication. Studies evaluating biological sex differences and optimized dosing regimens are absent.
Technical appendix
Version history
- 1.0 · 2026-09-15 — Auto-generated under Evidence Standard v1.0