Polycyclitol derivatives restore long- term memory via cdk5/p25 activation of tau signaling in experimental cerebral malaria

Tau hyperphosphorylation at Ser396/404 and its adverse neurological effects have been evident in animal models of cerebral malaria. As a countermeasure, quest for novel pharmacological therapeutics to reduce tau hyperphosphorylation in neurodegeneration and restore behavioral and cognitive functions with high efficacy has been at the forefront of neurobiological studies. In this study, using an experimental model of cerebral malaria, we administered four different polycyclitol derivatives, SR4 (01–04) as an adjunctive to Artemether along with Artemether monotherapy, and studied cyclin-dependent kinase 5/p25-based tau signaling cascade in association with restoration of long-term memory. Limitations of scyllo -inositol and rationale to synthesize these polycyclitols efficiently have also been captured in the backdrop. Initially, we studied long-term, short-term memory and novelty-based learning by conducting Barnes maze, T-maze, and novel object recognition task in treated animal groups. The cognitive outcomes of SR4-02 ( 15 ) and SR4-04 ( 18 ) treated groups exhibited better learning and memory compared to artemether monotherapy, SR4-01 ( 16 ) and SR4-03 ( 17 ) treated groups. We further evaluated cdk5/p25 signaling and tau phosphorylation status using western blotting, immunohistochemistry, and Golgi-Cox staining to study neuronal arborization pattern. Immunohistochemical analysis of the hippocampal and cortical tissue regions showed reduced phospho tau at Ser396 expression in SR4-02 ( 17 ) and SR4-04 ( 18 ) treated groups compared to cerebral malaria group. Similarly, Golgi-cox images showed increased neuronal arborization in Cornus Ammonis (CA1) and CA3 regions of hippocampus and cortex of SR4-02 ( 15 ) and SR4-04 ( 18 ) treated mice. Overall, based on our findings, SR4-02 and SR4-04 polycyclitol derivatives have the potential to alleviate tau levels and restore cognition in experimental models of cerebral malaria.