Optimizing Fingolimod Dosing in STZ-Induced Cognitive Impairment: Divergent Behavioral and Histopathological Responses Reveal a Narrow Neuroprotective Window

Background/Objective: Fingolimod, an S1P receptor modulator, is neuroprotective and anti-inflammatory in animal models of neurodegenerative disorders; its optimal dosage regimen for cognitive dysfunction is yet to be defined. The impact of fingolimod on cognitive function, neuroinflammation, oxidative levels, as well as hippocampal morphology, was evaluated in the streptozotocin-induced model of memory dysfunction in rats. Methods: Male Sprague-Dawley rats were injected intracerebroventricularly with STZ (3 mg/kg) followed by daily i.p. fingolimod administration at 0.25, 0.5, or 1 mg/kg for 10 days. Behavioral function was evaluated using open-field tests, Morris water maze, and passive avoidance tasks. The hippocampal tissue was examined for cytokine and neurotrophic factor gene expression using qRT-PCR. malondialdehyde (MDA) levels, as a measure of lipid peroxidation, and stereological parameters, including CA1 neuronal counts and volumes, were evaluated. Results: The STZ produced significant impairments in memory, increased pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), elevated MDA levels, and CA1 neuronal loss and atrophy. Fingolimod at a dose of 0.25 mg/kg significantly ameliorated spatial and fear/memories, in addition to reducing neuroinflammation and oxidative stress. On the other hand, the dose of 0.5 mg/kg significantly restored both the number and volume of the CA1. The 1 mg/kg dose produced severe behavioral distress and was excluded. Conclusion: Fingolimod has dose-dependent, domain-specific neuroprotective actions, promoting functional recovery at low doses and structural repair at middle to higher doses. These findings highlight a narrow therapeutic window as a key issue in the translation of S1P modulator therapies from cognitive impairment to Alzheimer’s disease.