The Neuroprotective Potentials of Dual GIP/GLP1-RA (Tirzepatide): From Preclinical Experiments to Clinical Trials: A...

Tirzepatide (TZP), the first approved dual glucagon-like peptide 1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) agonist, has shown neuroprotective effects in preclinical models and early observational studies. This review maps and appraises current preclinical and clinical evidence on TZP's potential neuroprotective effects in neurodegenerative diseases (Alzheimer's and Parkinson's disease), neuroinflammation, cerebrovascular outcomes, neurovestibular disorders, brain tumor response, and idiopathic intracranial hypertension.

PubMed, Scopus, Web of Science, Embase, and Elton B. Stephens Company (EBSCO) were searched through September 30, 2025. Eligible sources included original preclinical or clinical studies reporting neurological or neuroprotective effects of TZP. Quality was assessed using SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) and Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADE) for in vivo studies, toxicological data reliability assessment tool (ToxRTool) for in vitro, Newcastle-Ottawa scale (NOS) for cohorts, and Joanna Briggs Institute (JBI) for case reports.

Twenty-two studies met inclusion criteria as follows: 11 preclinical investigations, 3 retrospective cohorts, and 8 case reports. Preclinical studies demonstrated mitochondrial stabilization (adenosine triphosphate [ATP] restoration; PINK1/Parkin), anti-oxidative and anti-inflammatory signaling, synaptic support (PSD-95/synaptophysin), and blood-brain barrier reinforcement (claudin-1), alongside behavioral improvements. Retrospective cohorts reported reduced cerebrovascular and neurodegenerative disease incidence, papilledema, and headaches, though one cohort identified higher risk of central vertigo and vestibular neuronitis. Case reports documented compression neuropathies, autoimmune encephalitis, hypoglycemia-related seizures, psychiatric reactions, and rhabdomyolysis, most resolving with dose adjustment or discontinuation. Risk-of-bias appraisal revealed frequent "unclear" ratings in animal studies, "reliable with restrictions" in vitro, and high NOS scores for cohorts.

TZP exhibits biologically plausible neuroprotective mechanisms preclinically. Prospective trials with standardized neurological endpoints, active-comparator designs, and structured safety monitoring are warranted.