Mangiferin in combination with primaquine reduces disease progression and transmission potential while alleviating cerebral pathology through suppression of neural cell apoptosis in experimental cerebral malaria.

Despite the availability of effective antimalarial drugs, cerebral malaria (CM) remains one of the deadliest manifestations of malaria and is associated with high mortality and severe neurological sequelae. The World Health Organization (WHO) has taken an initiative for reduction of 90% malaria case incidence and death rates by 90% by 2030 with respect to the 2015 baseline. To address this challenge ,we have studied the effect of mangiferin in combination with primaquine on a mouse model of CM by infecting with Plasmodium berghei ANKA (PbA), a homolog of Plasmodium falciparum in humans. Treatment with a single dose of primaquine (40 mg/kg) reduced parasitemia and markedly decreased circulating gametocyte levels, highlighting its effectiveness in limiting transmission. However, primaquine alone failed to ameliorate PbA-induced cerebral pathology. In contrast, mangiferin (100 mg/kg) provided substantial neuroprotection and improved brain pathology but had a comparatively limited effect on gametocyte burden. Mechanistic analyses revealed that mangiferin attenuated NF-κB activation and downstream inflammatory signaling, thereby reducing endoplasmic reticulum (ER) stress and intracellular calcium overload. This was associated with decreased activation of calpains (calpain-1 and calpain-2), inhibition of mitochondrial dysfunction, reduced cytochrome-c release, and suppression of apoptosis. So, these findings suggest that the primaquine-mangiferin combination can offer a promising strategy for simultaneously reducing malaria transmission and protecting against CM-associated brain injury.