Polycyclitol derivatives restore long-term memory by regulating cdk5/p25
based tau signaling in experimental cerebral malaria
Abstract
Tau hyperphosphorylation at Ser396/404 and its adverse neurological
effects have been evident in animal models of cerebral malaria (CM). As
a counter measure, quest for novel pharmacological therapeutics to
ameliorate tau hyperphosphorylation in neurodegeneration and restore
behavioural and cognitive functions with high efficacy in CM has been at
the forefront of neurobiological studies. In this study, using
experimental model of cerebral malaria (ECM), we administered four
different polycyclitol derivatives, SR4 (01-04) as an adjunctive to ARM
therapy resulting in alleviation of cdk5/p25 based tau signaling cascade
and restoration of long-term memory. Limitations of scyllo-inositol and
rational to synthesize these polycyclitols efficiently has 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 SR4-01 (16) and SR4-03 (17) groups. We
further evaluated cdk5/p25 and tau phosphorylation protein expression
using western blotting, immunohistochemistry and Golgi-cox staining to
study neuronal arborization pattern. Immunohistochemical analysis of
hippocampal and cortical tissue regions showed reduced phospho tau
expression in SR4-03 (17) and SR4-04 (18) groups compared to CM group.
Similarly, Golgi-cox images showed increased neuronal density in Cornus
Ammonis (CA1) and CA3 regions of hippocampus and cortex of SR4-02 (15),
SR4-03 (17) and SR4-04 (18) treated mice. Overall, based on our
findings, polycyclitol derivatives have the potential to alleviate tau
levels and restore cognition in ECM.