Work

Effects of Lovastatin on Autism-Like Behavioral, Metabolic, and Neuroinflammatory Alterations in Male BTBR T+ Tf/J Mice

Year: 2026

Type: article

Abstract: Introduction: Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, thereby reducing cellular cholesterol and isoprenoid biosynthesis. In addition to lowering serum cholesterol, statins exert pleiotropic neuroprotective effects, including anti-inflammatory, antioxidant, and immunomodulatory actions mediated through the mevalonate pathway. Statins are increasingly being explored for drug repurposing in neuropsychiatric and neurodevelopmental disorders. This study evaluated the therapeutic potential of lovastatin in the BTBR T+ tf/J mouse model of autism spectrum disorder (ASD), a well-established idiopathic model exhibiting core behavioral deficits and dysregulated cholesterol homeostasis characterized by elevated serum cholesterol and reduced brain cholesterol, consistent with reports of altered cholesterol metabolism in ASD. Methods: BTBR mice received lovastatin (10, 20, and 40 mg/kg, i.p. for 21 days) and were assessed for repetitive behaviour, cognitive performance and social interaction. Cholesterol-related markers, HMG-CoA reductase levels and neuroinflammatory markers were also examined. Results: BTBR mice exhibited increased marble-burying behaviour, reduced spontaneous alternation and social interaction, elevated HMG-CoA reductase levels, decreased brain free cholesterol, increased serum cholesterol, and heightened brain levels of TNF-α and IL-6 compared with C57BL/6J controls. Lovastatin was associated with improvements across the evaluated autism related behavioral outcomes. The 40 mg/kg dose of Lovastatin showed the largest observed behavioral effects overall. Following 21 days of treatment, lovastatin reduced brain HMG-CoA reductase levels at all tested doses and reduced elevated serum cholesterol levels. Exploratory neuroinflammatory analyses showed that lovastatin at 40 mg/kg significantly lowered brain TNF-α and IL-6 levels in BTBR mice. Conclusion: Lovastatin was associated with improvements in autism related behavioral outcomes in male BTBR mice, while modulating systemic cholesterol dysregulation and neuroinflammatory responses. These findings provide preclinical evidence supporting further investigation of lovastatin in ASD-related phenotypes.

Source: Drug Design Development and Therapy

DOI: 10.2147/dddt.s630326