Cerebral malaria is diagnosed when patients are in a comatose state that is not a cause of any other complications, such as coinfection with another pathogen, and asexual malaria parasites are detected in peripheral blood, which is detected by preparing a peripheral blood smear. Convulsions and retinal changes are also common in CM patients. Aside from the timely intravenous administration of antimalarials, there are no specific treatments for the underlying causes of CM. Fever management is suggested and patients in coma must be monitored and provided supportive care to manage symptoms. Convulsions can be treated with slow intravenous administration of benzodiazepine, and in more severe cases, phenytoin or, as a last resort, phenobarbitone (World Health Organization, 2012; Taylor and Molyneux, 2015). Mechanical ventilatory support are critical but they are not readily available in many areas where malaria is endemic (Albrecht-Schgoer et al., 2022). In approximately 20-30% of cases, the current management techniques are insufficient and result in death (Song et al., 2022). It is clear that there is an urgent need for specific adjunctive therapies to treat the underlying causes of CM and prevent fatalities.

Phenobarbital is a drug normally used to treat seizures. In one clinical trial, administration of intramuscular phenobarbital to CM patients significantly reduced incidence of seizure. However, in a later study with pediatric CM patients, phenobarbital effectively prevented seizures but increased the mortality rate as well as the frequency of respiratory arrest (Crawley et al., 2000). For this reason, phenobarbital is not recommended to treat CM patients suffering from seizures unless first line treatments of benzodiazepine or phenytoin are not effective, and even then, patients’ respiratory activity must be monitored closely (World Health Organization, 2012).

Mannitol therapy is often used to reduce intracranial pressure from brain swelling in other disease contexts. In trials with pediatric CM patients, however, mannitol did not significantly impact clinical outcomes and in a randomized trial with adult CM patients, mannitol proved ineffective in reducing swelling and resulted in increased mortality rates and longer coma durations (Namutangula et al., 2007; Mohanty et al., 2011).

Platelet accumulation in the brain microvasculature has been observed in post-mortem tissue of CM patients that did not survive (Grau et al., 2003). Heparin and acetylsalicylic acid (ASA; commonly known as aspirin), which are normally used to treat blood clots and fever, were used to treat severe falciparum malaria patients. However, neither heparin nor ASA improved clinical outcomes in patients assessed by parasite clearance rate, fever alleviation, or length of hospitalization (Hemmer et al., 1991).

Dexamethasone is a corticosteroid that is often used to relieve inflammation. In several clinical trials, dexamethasone was used to treat CM patients but was not effective in reducing neurological deficits or improving survival when compared to the control groups, and in one trial, it even conferred deleterious effects (Warrell et al., 1982 ; Hoffman et al., 1988 ; Prasad and Garner, 2000).

TNF-alpha is upregulated in CM, however, modulating levels of TNF-alpha through anti-TNF monoclonal antibody treatment did not increase survival in a trial with pediatric CM patients and was correlated with increased neurological sequelae (van Hensbroek et al., 1996). Pentoxifylline is a phosphodiesterase inhibitor that reduces TNF levels and proved promising in two clinical trials with adult and pediatric patients of CM based on increased survival and shorter coma duration (Di Perri et al., 1995; Das et al., 2003). However, in another trial conducted with falciparum malaria patients, treatment with pentoxifylline did not have any effect on clinical outcome and patients reported mild adverse side effects, while in one trial with a small sample size of ten pediatric CM patients, the mortality rate was unusually high in the pentoxifylline-treated group compared to the control group (Hemmer et al., 1997; Lell et al., 2010). Intravenous administration of immunoglobulin was also shown not to be superior to placebo in a trial with pediatric CM patients and may have been associated with deleterious effects (Taylor et al., 1992).

Immunomodulation has become a popular method of disease intervention in recent years. In CM, the inflammatory response, initiated by release of DAMPs and PAMPs upon PfiRBC rupture and then bolstered by endothelial activation, can create a hyperinflammatory environment that can have deleterious effects. Inhibiting T-cell metabolism and proliferation via administration of Gln analog 6-diazo-5-oxo-l-norleucine (DON) improved survival rates in mice with ECM when administered after presentation of neurological signs of CM. Moreover, DON treatment improved neurological outcomes, reduced brain swelling, and helped recover the BBB integrity in these mice (Gordon et al., 2015). The efficacy of DON as an adjunctive treatment for CM is currently being determined in clinical trials ( Table 1 ).

There are other promising agents such as oral activated charcoal which was shown to reduce pro-inflammatory cytokine levels and improve survival in a murine model of ECM. When administered to healthy humans in a phase 1 clinical trial, it did not interfere with the pharmacokinetics of artesunate (de Souza et al., 2010). While potentially an effective treatment, oral activated charcoal however, must be administered to infants and young children in a comatose state through a nasogastric tube which may not always be available in resource-limited areas where malaria is endemic. In a murine model of CM, administration of recombinant human erythropoietin successfully attenuated inflammation by inhibiting the function of splenic dendritic cells and promoting increased circulation of regulatory T cells (Wei et al., 2014). In another study, artemisone, a relatively new artemisinin derivative, was administered to mice with ECM via subcutaneous injection of a pasty polymer form of the drug. This method of administration ensured a slow release of the drug and was given prophylactically. The result was reduced parasitemias and improved survival of mice that were treated versus those that were not. TNF levels were also reduced while anti-inflammatory cytokines IL-4 and IL-10 were increased in artemisone-treated mice. The treatment also counteracted BBB disruption, making it a potential candidate for clinical trials (Golenser et al., 2020).

Endothelial activation/dysfunction plays a major role in CM pathogenesis and is a therapeutic target worth consideration (Kim et al., 2011). Beta-catenin, one of the proteins that form the adherens junctions in BMECs, is activated in response to PfiRBC rupture in vitro. Beta-catenin is regulated by the Angiotensin II receptors type 1 and 2 (AT1 and AT2). In a murine model of ECM, administration of irbesartan, an AT1 inhibitor, or Compound 21, an AT2 agonist, in combination with the antimalarial drug chloroquine, rescued around 60% of the mice with critical signs of CM compared to 14% of mice treated with chloroquine alone. These, and other modulators of the AT1/2 receptors such as losartan or CGP-42112A, may be promising adjunctive therapies that have yet to be tested in clinical trials (Gallego-Delgado et al., 2016).

The angiopoietin (Ang)-Tie2 axis is another important regulator of endothelial activation and potential therapeutic target. Ang1 and Ang2 are competitive ligands of the tyrosine kinase receptor Tie2, which is expressed on endothelial cells. Under normal conditions, Ang1 concentrations greatly surpass those of Ang 2 so that Ang1 binds Tie2, which phosphorylates AKT to prevent BMEC apoptosis and maintain homeostatic activity. In CM, Ang2 concentrations increase and prevent Ang1 from binding Tie2, ultimately resulting in weakening of intercellular junctions and expression of leukocyte adhesion molecules ICAM1 and VCAM1(Sack et al., 2020). Administration of Ang1 protein in combination with artesunate increased survival in mice with ECM, compared to mice treated with artesunate alone (Higgins et al., 2016). Additionally, inhibition of Ang2 binding using an Ang2 antibody treatment significantly reduced mortality in a murine model of sepsis in which endothelial activation also contributes to pathogenesis (Ziegler et al., 2013). In another sepsis murine model, an Ang2 antibody that could both neutralize Ang2 and activate Tie2 greatly ameliorated disease progression (Han et al., 2016). Restoring the ratio of Ang1:Ang2 activity to improve disease outcome has been successfully demonstrated in the context of other infections in which endothelial activation and BBB disruption contributes to the pathogenesis, such as anthrax, Ebola hemorrhagic fever, and dengue fever (Ghosh et al., 2012; Rasmussen et al., 2014; Phanthanawiboon et al., 2016).

Rosigliatazone is a peroxisome proliferator-activated receptor-γ (PPARγ) agonist used to treat type 2 diabetes mellitus. Treatment with rosigliatazone and artesunate together resulted in increased levels of circulating Ang1 and decreased Ang2 transcription in the brains of mice with ECM, as compared to control mice treated with only artesunate. Similarly, human patients with non-severe falciparum malaria that were treated with rosigliatazone and artesunate combination therapy were found to have a lower plasma Ang2:Ang1 ratio in (Serghides et al., 2014). This drug has also been demonstrated to induce secretion of neuroprotective brain-derived neurotrophic factor (BDNF), improve neurocognitive outcomes, and reduce biomarkers of inflammation in non-severe malaria (Boggild et al., 2009; Serghides et al., 2014). Rosigliatazone may be a promising candidate for adjuvant treatment of CM.

Statins are drugs currently approved for use to treat high cholesterol and in a few studies have been shown to improve outcomes from ECM, though the exact mechanism of action is not completely understood. Treatment with a combination of atorvastatin and irbesartan, an angiotensin II receptor inhibitor clinically used to treat hypertension, in combination with antimalarial drugs significantly increased survival rates of mice with ECM when compared to mice treated with antimalarial drugs alone. Moreover, this combination treatment reduced the quantity and size of brain hemorrhages, as well as, levels of plasma biomarkers of endothelial activation, including soluble Ang1 (Mota et al., 2022). Atorvastatin treatment has been demonstrated to increase Ang1 transcription and decrease Ang2 expression in the brain tissue of mice with ECM (Wilson et al., 2013). Another statin that has proven effective in reducing mortality and improving neurocognitive outcomes in a murine model of ECM is lovastatin. Edema, ICAM-1, and CD11b mRNA levels were reduced in brain tissue of mice treated with lovastatin in combination with antimalarial drugs (Reis et al., 2012).

Sphingosine-1 phosphate (S1P) is a sphingolipid that acts as a signaling molecule via G-protein coupled receptors S1P1-5 to regulate BMEC homeostasis, and it has been implicated in CM. Fingolimod is an S1P receptor modulator that regulates BMEC intercellular adhesion by stabilizing VE-cadherin. In a murine model of ECM, fingolimod, in combination with artesunate, significantly improved survival rates, reduced levels of soluble ICAM, increased Ang1 levels, and decreased BBB permeability when compared to mice treated with artesunate alone (Finney et al., 2011). Fingolimod is already approved to treat multiple sclerosis and may be a promising candidate for trials with CM patients.

Rho kinase activation is another mechanism that has been implicated in BBB disruption and brain edema; furthermore, it has been demonstrated that PfiRBC adhesion to endothelial cells stimulates Rho signaling in vitro. Rho kinase inhibitor, Fasudil, reduced endothelial cell apoptosis and restored endothelial barrier integrity after exposure to PfiRBCs in vitro (Taoufiq et al., 2008). In another study, Fasudil either completely prevented or delayed the onset of ECM in mice injected with Plasmodium berghei ANKA, and those mice treated with Fasudil exhibited significantly higher survival rates compared to the untreated controls. Interestingly, in the same study, curcumin treatment had a similar effect (Waknine-Grinberg et al., 2010).Fasudil is a drug that is already in clinical use that is used to treat brain ischemia and cerebral vasospasm.

In a similar fashion, neuregulin-1 protects BMECs from apoptosis and reduces disruption of BBB integrity in a model of heme-induced BBB disruption in vitro. Moreover, in a murine model of ECM, neuregulin-1 treatment reduced mortality by stimulating ErbB4 phosphorylation which ultimately leads to AKT activation (Liu et al., 2018). In another study of ECM, the use of vitamin D co-administered with intramuscular arteether (an ethyl ether derivative of artemisinin) significantly improved survival rates when compared to untreated mice or mice that were treated with either vitamin D or arteether alone. BBB integrity was also protected and levels of endothelial activation markers ICAM-1 and VCAM-1, as well as inflammation markers, were greatly reduced (Dwivedi et al., 2016).