Promising Therapeutic Potential of miR-220-3p Mimic Against Murine Trimethyltin Hippocampal Injury

Trimethyltin (TMT) is an organotin compound known to induce neurotoxicity within the limbic system of the brain, particularly in the hippocampal region, with neurodegenerative changes resembling those of Alzheimer's disease (AD).

This investigation examined the impact of miRNA-220-3p (miR-220-3p) on TMT-induced neurotoxicity and associated behavioral abnormalities, such as spatial learning and memory impairments, and identified the potential molecular mechanisms.

To induce neurotoxicity, TMT was injected (8 mg/kg, i.p. once), and after 1 hour, miR-220-3p was microinjected intraventricularly (ICV route, once) for the possible mitigation of TMT-induced neurotoxicity. Different behavioral assessments were employed to determine spatial learning and memory function. Moreover, hippocampal measurements of brain-derived neurotrophic factor (BDNF) and Sirtuin-1, oxidative stress-, apoptosis-, and neuroinflammation-related factors, and histochemical changes were performed.

The TMT injection led to behavioral abnormalities in the novel object discrimination and Barnes maze tests, heightened oxidative stress [elevating reactive oxygen species (ROS) levels, nitrite, and lipid peroxidation and decreasing the activities of antioxidant enzymes, including catalase (CAT) and superoxide dismutase (SOD)], reduced BDNF and Sirtuin-1 levels, increased neuroinflammation [escalating the secretion of pro-inflammatory mediators, including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)], raised activities of acetylcholinesterase (AChE), myeloperoxidase (MPO), beta-secretase 1 (BACE-1), caspase-1, and caspase-3, accompanied by a reduced number of CA1 pyramidal neurons and higher glial fibrillary acidic protein (GFAP) immunoreactivity. In contrast, microinjection of miR-220-3p reversed most of these alterations.

The findings of this investigation imply that miR-220-3p may mitigate TMT-induced neurotoxicity, which is attributed to the suppression of hippocampal oxidative stress, neuroinflammation, and caspase-dependent apoptosis and pyroptosis, and part of its beneficial effect is associated with the upregulation of BDNF and Sirtuin-1.