Extended Cognitive Recovery in Down Syndrome Mice via Sustained Release of Am404 From Microplates
Abstract
Abstract Neurodevelopmental disorders (NDDs) are often characterized by cognitive deficits associated with hippocampal dysfunction and microglial activation. In the in the Dp(16) and Ts65Dn mouse models of Down syndrome (DS), paracetamol (PRC) has been shown to modulate microglia-mediated neuroinflammation and rescue memory tasks. However, the high doses of PRC typically required limit its long-term use due to dose-related toxicity, including reported hepatotoxicity and cardiotoxicity. Here, we employed polymeric microPLates (µPL) made of poly(lactic-co-glycolic acid) (PLGA) to sustain delivery of AM404 (AM404-µPL), the primary PRC metabolite with glia-directed anti-inflammatory activity. Using a top-down fabrication approach, AM404 was loaded into square-shaped µPL and evaluated for activity in vitro and in vivo . Free AM404 enhanced microglial metabolism and exerted anti-inflammatory effects comparable to paracetamol in activated microglia from Dp(16) mice. In vivo , low-dose free AM404 (1 mg/kg for three days) improved cognitive deficits in DS mice without affecting control mice; whereas higher doses (10 mg/kg) impaired cognition in healthy mice and had no effect on DS mice. In contrast, a single injection of AM404-µPL improved DS mice cognition for two weeks without harming healthy mice. Notably, after one week, cognitive abilities in DS mice matched those achieved with repeated low-dose of free AM404. These findings support AM404 sustained delivery as a strategy to…
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