Angiotensin Receptor Blocker (ARB): Is it Effective to Prevent Cerebral Malaria?

• Cerebral malaria involves infected red blood cells blocking brain microvasculature, leading to vascular congestion and blood-brain barrier disruption.
• Angiotensin II type 2 receptor (AT2R) activation strengthens endothelial junctions, while type 1 receptor (AT1R) activation worsens outcomes of cerebral malaria.
• Angiotensin Receptor Blockers (ARBs) show promise as a treatment by improving survival and reducing brain hemorrhages through vasodilation, neuroprotection, and blood-brain barrier preservation.
• Blood pressure monitoring is necessary when using ARBs due to the risk of hypotension.

INTRODUCTION

Malaria is an infectious disease spread through the bite of a female Anopheles mosquito carrying the Plasmodium parasite. Among the Plasmodium species that can cause illness, Plasmodium falciparum is the primary cause of severe complications in humans.[1] World Health Organization (WHO) reported that, in 2018 malaria cases reached approximately 228 million worldwide with 405,000 deaths. Most of these cases resulted from P. falciparum infection, with 2% among them manifesting as cerebral malaria, a life-threatening complication[1–3].

Cerebral malaria is the most serious neurological complication of P. falciparum infection, which has a mortality rate of approximately 15–25%.[3–5] Even if a patient survives cerebral malaria or after antimalarial treatment eliminates the parasite, neurological deficits may persist due to irreversible brain damage, potentially affecting their quality of life.[1, 6] The sequestration of red blood cells infected with P. falciparum leads to rosette formation, obstructing the microvasculature and causing vasoconstriction. This process damages the blood-brain barrier (BBB) and results in various clinical manifestations of cerebral malaria, including altered mental status.[1, 6–8] MRI results from most patients with severe cerebral 12BJKI malaria indicate increased intracranial pressure, reduced cerebrospinal fluid volume, thalamic lesions, and even cerebral edema.[1]

Further research about treatment strategies is necessary to reduce the occurrence of cerebral malaria and enhance patients' quality of life. Several studies suggest that angiotensin receptor blockers (ARBs) may offer a promising approach to preventing cerebral malaria. Studies indicate that human brain microvascular endothelial cells express numerous angiotensin II type 1 and type 2 receptors, and susceptibility to cerebral malaria is modulated by angiotensin II receptors.[8, 9] Therefore, the angiotensin II-mediated pathophysiology may indirectly worsen cerebral malaria in hypertensive patients. Research shows that activating angiotensin II type 2 (AT2) or inhibiting angiotensin II type 1 (AT1) may enhance BBB protection.[8, 10] Since ARBs are antihypertensive medications that inhibit AT1, they could potentially mitigate complications for individuals with falciparum malaria. Therefore, the possibility and potential of ARBs as an additional prophylaxis for patients with falciparum malaria infection require further review to ascertain their feasibility and effects.

MATERIALS AND METHODS

A comprehensive review of PubMed and ScienceDirect databases was performed to synthesize information on cerebral malaria and the preventive potential of angiotensin receptor blockers (ARBs). The search utilized keywords adhering to Medical Subject Headings (MeSH) terms, including "cerebral malaria," "angiotensin receptor blocker," "hypertension," "β-catenin," "angiotensin II," "prevention," and "treatment," employing Boolean operators "AND" and "OR" to optimize search comprehensiveness. Publications lacking full text, those in languages other than English, non-peer-reviewed studies, and research with incomplete data were excluded. Any disagreements were resolved through discussion among the authors.

RESULT AND DISCUSSION

Severity and Clinical Features of Cerebral Malaria

Cerebral malaria is a life-threatening complication of P. falciparum malaria characterized by severe neurological symptoms, including coma, seizures, and altered mental status. This complication results in a bad prognosis, including high mortality rates and life-long post-cerebral malaria sequelae. Life-long post-cerebral malaria sequelae can often be presented as neurological deficits, leading to a decrease in quality of life. It persists in up to 25% of surviving cerebral malaria patients. These sequelae include hemiplegia, seizures, cognitive impairments, and neurocognitive deficits like Attention Deficit Hyperactivity Disorder (ADHD). MRI findings, such as brain swelling, cerebral edema, and microhemorrhages, are associated with poor outcomes, such as coma depth and a high increase in mortality. Cerebral malaria is characterized by the following three criteria: parasitemia of P. falciparum, Blantyre coma score ≤ 2 in children or Glasgow coma score ≤ 9 in adults, and other possible causes of coma or encephalopathies have been excluded.[11] Children diagnosed with cerebral malaria exhibit a range of symptoms suggesting widespread involvement of the central nervous system, including generalized tonic-clonic convulsions, focal seizures, posturing (opisthotonos, decerebrate or decorticate rigidity), conjugate gaze deviations, and respiratory rhythm abnormalities (including Cheyne–Stokes respirations).[8]

The underlying mechanism of cerebral malaria is the sequestration of infected red blood cells in the brain microvasculature. Sequestration of infected red blood cells, a defining factor of P. falciparum malaria, occurs as a result of molecular interaction between the P. falciparum erythrocyte membrane protein-1 (PfEMP-1) and the host endothelial receptors.[8] Sequestration of infected red blood cells led in vascular congestion, blood-barrier disruption, cytokine storm, and oxidative stress. While progress in understanding the pathogenesis of cerebral malaria is already significant, there is no effective adjunctive neuroprotective therapy.[1]

The Crucial Roles of Angiotensin II and β-Catenin in Blood Brain Barrier Damage

Cerebral malaria results from the interaction between Plasmodium falciparum-infected red blood cells (pf-iRBC) and brain endothelial cells. pf-iRBC directly affect the endothelial cells with the sequestration in the microvasculature. This process is driven by cytoadherence, where increased expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM-1) facilitates pf-iRBC binding. The adhesion and the formation of rosettes-cluster as a consequence of the binding between pf-iRBCs with the uninfected red blood cell lead to blood flow impairment and microvascular obstruction. This process facilitated the sequestration, where pf-iRBCs accumulate in the microvasculature, disrupting the endothelial junction.[12] In addition, activated endothelial cells release cytokines and chemokines. This condition elevates the recruitment of immune cells, including CD8+ T cells, platelets, and infected erythrocytes, resulting in heightened microvascular obstruction and vasoconstriction. Prolonged events further compromise vascular permeability, causing bleeding and albumin extravasation, which is neurotoxic and disrupts the blood-brain barrier. Pf-iRBC rupture on human brain microvascular endothelial cells (HBMECs) activates β-catenin, a mediator of interendothelial junction (IEJ) disruption in these cells. β-catenin serves a dual role in the cell; as a structural protein interendothelial junction and acts as transcriptional activator in nucleus. Underresting conditions, it acts as a structural protein that maintains the integrity of the endothelial barrier. However, the disruption of pf-iRBC over human microvascular endothelial cells induces the activation of β-catenin, a key factor in interendothelial junction disruptions. β-catenin will detach from adherens junctions and migrate to the nucleus, leading to binding with TCF/LEF. Those bindings will trigger the transcription of genes that disrupt interendothelial junctions, causing the opening of intercellular gaps and endothelial cell detachment[8].

The activation of the angiotensin II type 2 receptor (AT2R) pathway, which can be promoted by inhibiting angiotensin II type 1 receptor (AT1R), inhibits the activation of β-catenin and increases the integrity of inter endothelial junctions.[8] Additionally, AT1Rs also act as a pro-inflammatory stimulus. Elevation of its amount resulted in a higher inflammation rate, activation of endothelial cells, and worse outcomes in severe malaria.[9] Angiopoietin/Tie2 signalling pathway is crucial in regulating endothelial activation and vascular permeability associated with AT1/AT2 activities, mainly through vascular endothelial growth factor (VEGF) and influence the pathogenesis of cerebral malaria.[8] Other studies have attempted to use synthetic Angiotensin II in treating cerebral malaria and have found positive results in reducing the severity of the disease. Angiotensin II has also been shown to exhibit anti-plasmodial activity against P. Falciparum.[6, 7] Supporting those studies, the study by Silva-Filho et al. also showed that AT1R was involved in T-cell activation, which could in turn promote perforin expression and sequestration of CD8+ T cells. Furthermore, AT1R promotes the expression of chemokine receptors such as CCR5 and CXCR3, thereby facilitating the migration and accumulation of CD8+ T cells into brain microvasculature. This process will result in the release of the cytotoxic molecules. This mechanism is responsible for harmful events in the brain, such as cerebral edema, vascular leakage, and behavioral impairment.[14]

The Association Between Hypertension and Cerebral Malaria

Cerebral malaria, a lethal complication of P. falciparum, is characterized by endothelial dysfunction at the vascular level, mirroring similar manifestations observed in hypertension.[15, 16] Endothelial dysfunction due to hypertension may decrease the bioavailability of local vasodilators like nitric oxide and prostacyclin. Furthermore, endothelial dysfunction can lead to increased production of reactive oxygen species and vasoconstricting agents, potentially reducing oxygen supply to vital organs and increasing systemic vascular resistance.[16] This pathophysiology of hypertension illustrates a mechanism by which it might worsen malaria infection in individuals.

Research conducted by Hoffmeister et al. indicated a threefold increase in the risk of severe falciparum malaria in malaria patients with hypertension compared to those without. Hypertension may cause diffuse structural changes in systemic microcirculation, including rarefaction and remodelling, increasing the severity of falciparum malaria infection. Rarefaction is characterized by abnormally low arterioles, capillaries, and potentially venule density. Remodelling, involving a decrease in resistance due to structural changes in the diameters of small arterial lumens and arterioles, may lead to increased longterm systemic vascular resistance in the affected individual. Consequently, patients presenting with both falciparum malaria and hypertension are highly susceptible to increased afterload, hypertensive cardiomyopathy, and microangiopathy. These conditions could impact multiple vital organs, including the brain.[16]

Multiple studies demonstrated a correlation between hypertension and β-catenin, an agent involved in cerebral malaria pathogenesis.[17] Activation of the Renin-Angiotensin System (RAS) and β-catenin can form a vicious cycle since β-catenin activation further increases RAS activation, thus affecting blood pressure and cerebral malaria development, as demonstrated in the experiments conducted in mice by Ziki et al.[17, 18]. Stimulation of the AT1R, a key contributor to hypertension, can disrupt cerebral blood flow, trigger inflammation, and generate reactive oxygen species within the central nervous system endothelium.[7] Furthermore, AT1 contributes to BBB damage in cerebral malaria through excessive β-catenin expression.[19]

The activation of β-catenin due to the rupture of Pf-iRBCs in human brain microvascular endothelial cells (HBMECs), coupled with the accompanying hypertensive condition, may disrupt the interendothelial junctions that form the BBB.[8, 9] Prolonged disruption could lead to cerebral malaria due to impaired blood flow in the brain's small capillaries and compromised endothelial cell connections, ultimately disrupting the BBB's homeostasis. This progression of cerebral malaria can lead to brain tissue swelling and bleeding in patients.[7]

Angiotensin Receptor Blocker (ARB) for Cerebral Malaria

Angiotensin Receptor Blocker (ARB)'s' possible therapeutic application in cerebral malaria has been investigated in several studies. Gallego et al.'s study demonstrated that even when mice were treated at the onset of neurological symptoms, blocking the AT1 receptor with Irbesartan or activating the AT2 receptor with compound 21 in combination with chloroquine produced a higher survival rate than when treated with the anti-malarial drug alone.[8] Mota et al. also demonstrated that administering an atorvastatin-irbesartan combination and conventional antimalarial drugs reduced endothelial activation biomarkers, such as von Willebrand factor and angiopoietin-1. This combination also increased the experimental animals’ survival rates 3 to 4 times compared to antimalarial drug treatment alone. The animal subjects presented fewer and smaller hemorrhages in the brain.[15] ARBs have an essential role in regulating the pathogenesis of cerebral malaria by inhibiting the AT1 receptor and activating the AT2 receptor.

ARBs are being studied for possible therapeutic roles in cerebral malaria due to their immunomodulatory and neuroprotective effects. These medicines work primarily by regulating the activities of angiotensin II. ARBs diminish vasoconstriction, inflammation, and oxidative stress by inhibiting the AT1 receptor, hence preventing BBB rupture and cerebral edema, which are fundamental to the pathogenesis of cerebral malaria.[15] Furthermore, blocking AT1 receptors allows for unopposed activation of AT2 receptors, which increases vasodilation, anti-inflammatory effects, and neuroprotection. ARBs decrease inflammation by inhibiting the production of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, which can cause endothelial activation and BBB disruption. This anti-inflammatory impact also reduces leukocyte migration to the brain vasculature, which limits local inflammation and microvascular blockage.[8]

ARBs preserve the blood-brain barrier by increasing endothelial function and lowering oxidative stress, preventing plasma proteins and immune cells from leaking into brain tissue. Furthermore, these medications have antithrombotic and anticoagulant characteristics, indirectly reducing microvascular constriction produced by the sequestration of infected red blood cells (iRBCs) and microthrombosis.[19] Another key aspect of ARBs is their neuroprotective properties, which improve cerebral perfusion, minimize ischemia damage, and block apoptotic pathways in neurons and glial cells, improving neuronal survival during hypoxia. ARBs also mitigate the oxidative stress caused by angiotensin II by lowering the formation of reactive oxygen species, sparing both endothelial and brain tissues from damage.[8]

Medication Safety for Hypotensive Patients

Clinicians concur that using ARBs as an adjuvant treatment can lower the fatality rates in cerebral malaria. Angiotensin II receptor modulators to strengthen interendothelial junctions might be a novel technique for developing supplementary therapies for cerebral malaria, providing a "buy time" while standard anti-plasmodium medications kill the parasite.[8] However, the use of ARBs with the primary effect of AT1 blockers (often used for hypertensive patients) necessitates follow-up monitoring, mainly linked to blood pressure. The patient's blood pressure level should be continuously monitored throughout therapy, especially when paired with quinidine, which has hypotensive side effects.[20] Compound 21 may be an effective therapy option for hypotensive patients since the AT2 agonist inhibits β-catenin and provides a protective effect towards the risk of hypotension.[21] Intradermal injection of ARBs may potentially be an alternative for treating cerebral malaria with hypotension.[6] Gallego et al conducted a study by injecting ARBs intradermally in experimental mice with cerebral malaria and discovered that blood pressure levels remained steady despite high amounts of plasma Angiotensin II.[22]

CONCLUSION

Cerebral malaria, a life-threatening complication of P. falciparum malaria, presents with severe neurological manifestations, high mortality rates, and persistent neurological deficits in surviving patients. The pathogenesis involves sequestration of infected erythrocytes within the brain microvasculature, leading to microvascular obstruction and endothelial barrier disruption. Unfortunately, effective neuroprotective treatment is still lacking. Studies show a link between hypertension and an increased risk of severe malaria. Hypertension's effects on the microcirculation and the interaction of β-catenin and the renin-angiotensin system contribute to cerebral malaria's development and severity, potentially disrupting the blood-brain barrier. The AT2R pathway inhibits β-catenin activation and improves barrier integrity, while the AT1R pathway promotes inflammation and worsens disease severity. ARBs, currently used in hypertension management, show promise as adjunctive therapy for cerebral malaria, demonstrating improved survival rates and reduced cerebral edema in preclinical studies. Their benefits stem from inhibiting AT1 and activating AT2 receptors, leading to vasodilation, neuroprotection, and blood-brain barrier preservation. However, the use of ARBs necessitates blood pressure monitoring, particularly when used concurrently with hypotensive medications like quinidine. Alternatively, intradermal ARB injection appears promising for blood pressure maintenance during the treatment of cerebral malaria.

ACKNOWLEDGEMENTS

Not applicable.

ETHICAL CONSIDERATION

Not applicable.

FUNDING

This research received no external funding.

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.

ABBREVIATIONS

WHO: World Health Organization; BBB: Blood-brain barrier; ARB: Angiotensin receptor blocker; AT1: Angiotensin II type 1; AT2: Angiotensin II type 2; ADHD: Attention Deficit Hyperactivity Disorder; PfEMP-1: P. falciparum erythrocyte membrane protein-1; pf-iRBC: Plasmodium falciparum-infected red blood cells; ICAM-1: intercellular adhesion molecule-1; VCAM-1: vascular cell adhesion molecule (VCAM-1); AT1R: Angiotensin II type 1 receptor; AT2R: Angiotensin II type 2; RAS: Renin-Angiotensin System; HBMEC: human brain microvascular endothelial cell; iRBC: Infected red blood cell

Author contribution: We declare that all listed authors have made substantial contributions to all of the following three parts of the manuscript:

- Research design, or acquisition, analysis or interpretation of data;

- drafting the paper or revising it critically;

- approving the submitted version.

We also declare that no-one who qualifies for authorship has been excluded from the list of authors.