Introduction:
Cerebral malaria (CM) is a fatal form of malaria caused by the infection of protozoan parasite, Plasmodium falciparum transferred by a female anopheles mosquito bite. More precisely, CM is a multi-organ disease severely damaging cerebrovasculature and compromises blood-brain barrier (BBB) integrity, resulting in neurological sequelae. In sub-Saharan Africa, children under five years of age are primarily affected with CM, reporting long-term neurological complications (Muppidi et al., 2023). Approximately, 25% of survivors develop neurocognitive and behavioral sequelae (Bruneel, 2019). One of the salient features of CM is leakage of blood brain barrier followed by progressive atrophy of neurons, affecting molecular, cellular and histological functions which in turn hamper the learning and memory functions of the brain. Artemether (ARM) is well known anti-malarial drug used as a therapeutic agent against severe forms of malaria. Despite its effective anti-malarial response, survivors of CM suffer from severe cognitive decline especially with spatial memory deficits (Dai et al., 2010; Reis et al., 2010). Several reports state that administration of ARM can eradicate parasite, improves survivability but cannot alleviate cognitive impairment (Gallego-Delgado et al., 2016; Pena et al., 2012; Serghides et al., 2014). Therefore, previous reports comply with adjunctive therapy (additional therapy that modulates the metabolic pathways) along with ARM for restoration of cognition in experimental models of CM (Dai et al., 2012a; John et al., 2010; Reis et al., 2010). In the neurodegenerative setting, neuronal loss reduces regional neuronal plasticity in critical cognitive domains such as the cortex and hippocampus, further leading to executive dysfunction of planning, working and spatial memory (McIsaac et al., 2018). Cornus Ammonis (CA) regions are densely packed with pyramidal neurons in hippocampus. CA1 is one of the critical regions which regulates memory consolidation and acts as a bridge for relaying information between hippocampus and sub-cortical areas (Basu and Siegelbaum, 2015; Van Strien et al., 2009). Dentate gyrus (DG), a region in hippocampus which consists of granule cells and long projecting neurons in the hilus region that receives information from entorhinal cortex and sends excitatory information to CA3 region through mossy fibers (Andersen et al., 2006; Jonas and Lisman, 2014). CA3 region is known for retrieval of spatial pattern information during short-term memory tasks including working memory, novelty and one-trial experiments (Kesner, 2007). Spatial memory impairment is dependent on two critical events i.e. Cdk5 overexpression and tau hyperphosphorylation in hippocampus.
Cdk5 is a serine or threonine protein kinase involved in cell cycle progression, ubiquitously expressed in most mammalian tissues, especially in the brain (Kanungo et al., 2009; Tsai et al., 1993). Cdk5 and its activator p35 are vital for maintaining the neuronal activity, migration and growth of neurites thereby regulating neuronal morphology (Dhavan and Tsai, 2001). p25 is the cleaved product of p35 which hyperactivates Cdk5, forming cdk5/p25 complex which phosphorylates tau at Ser396 and Thr231 thereby reducing microtubule assembly in disease states (Patrick et al., 1999; Zheng et al., 2010). Most of the studies have shown a significant accumulation of phospho tau Ser396 in the hippocampus which is critical for long-term depression but not long-term potentiation (Regan et al., 2015; Taylor et al., 2021). Currently, the advanced state of therapy against tau accumulation is immunotherapy using humanized antibodies targeting the amino and carboxy terminus, bound to proline rich or microtubule domains in the neurons. As the strategy of inhibiting Aβ aggregation and hyper phosphorylation of tau has increasingly gained acceptance, greater numbers of inhibitors have been developed and their structure-activity relationship was also explored. These small molecules hold considerable promise as the starting point for the development of new therapies related to Alzheimer’s disease (Cummings et al., 2020; Malek et al., 2019). Small organic molecules such as polyphenols like cyanidin (1 ), emodin (2 ) and epigallocatechin gallate (EGCG, 3 ), anthraquinone antibiotic daunorubicin (4 ), imidazole derived sulfone (5 ) and carbohydrate related scyllo-inositol (6 ), Fig. 1. have shown substantial potential to disaggregate Alzheimer’s disease tissue derived Amyloid-β and tau fibrils in various studies (Bulic et al., 2010; Seidler et al., 2022).
At present about 20% of molecules undergoing clinical trials for AD target Aβ and Tau proteins. Reduction of Aβ aggregation and addressing the tau hyperphosphorylation or the removal of already formed deposits of misfolded proteins has remained the focus of recent research. As a result, several protein aggregation inhibitors, antibodies, and enzyme inhibitors have been investigated (Loera-Valencia et al., 2019). The concept of dual inhibitors, Aβ and tau aggregation inhibitors is also emerging as one of the actively investigated research areas in this domain. For instance, a curcumin derivative, PE859, acts as a dual aggregation inhibitor for restoring the cognitive dysfunction in mouse model (Okuda et al., 2017). Recently, Więckowska et al. discovered several 1,3-aminoalcohol and indole based compounds as potential dual inhibitors of Aβ and tau aggregation with Aβ disintegrating potential (Szałaj et al., 2020). These studies prompted us to revisit one of the important molecules,scyllo -inositol (6 ), discovered several years ago as one of the potential Aβ inhibitors. Evaluation of thescyllo -inositol as a potential therapeutic has confirmed the blocking of fibril formation through its direct interaction with the target peptide which eventually results in a pronounced change in the secondary structure and further stabilization of the mono- and oligomeric units of otherwise normal protein. These studies prompted many research groups and industries to devise strategies towards the diversity-oriented synthesis of inositol analogues and probe their molecular interactions with the aggregation cascade of concerned proteins. Keeping in view these observations, there is a scope for more rational efforts in this direction which can address the issues of weak binding interactions and non-specificity of scyllo -inositol.
In this article, using the experimental model for CM, we administered SR4-01 to SR4-04 polycyclitol compounds synthesized recently as an adjunctive along with the ARM. After 30 day survivability period, we studied the expression of cdk5, p35/p25, phospho tau Ser396 in the whole brains of all the experimental groups. Our outcome shows significant improvement in the neuronal morphology with decreased tau hyperphosphorylation levels in the animals that survived after rescue treatment, restoring learning and memory functions especially with SR4-02 and SR4-04, which might have tremendous implications in AD and ECM therapeutics.