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.