Malaria remains as a critical infectious disease with severe public health implications, caused by protozoa of the genus Plasmodium and transmitted through the bites of female Anopheles mosquitoes during their blood-feeding process (Khanam, 2017; WHO, 2022). Among more than 100 species of Plasmodium, seven can infect humans, although P. falciparum and P. vivax are the most common. Annually, more than 247 million new cases of malaria are reported worldwide, and even though it is a preventable and treatable disease, about 619,000 people die yearly (WHO, 2022). Although the African continent accounts for 95% of cases, malaria has a wide distribution in 84 endemic countries located in Asia, India, Central America and South America (WHO, 2022). Two-thirds of the number of deaths are children under five years old, with 94% of cases being on the African continent with a higher incidence of malaria induced by P. falciparum (WHO, 2020) that can trigger the most severe aspect of the disease, making it potentially fatal (Miller et al., 2002; Tuteja, 2007; McQueen and McKenzie, 2008; Kantele and Jokiranta, 2011; White et al., 2014). Infections caused by P. falciparum are linked to a severe complication impacting the central nervous system known as cerebral malaria (CM). Especially in tropical regions, cerebral malaria diagnosis is particularly associated with several neurological signs. CM is diagnosed in around 1% of P. falciparum cases and its mortality rate fluctuates between 15% and 25%. Survivors often face acute or persistent physical disabilities and neurological syndromes, persisting even after the infection has been treated (Daniyan et al., 2022; WHO, 2022).

Obstacles faced by countries to eliminate malaria are related to the parasite resistance to treatment and mosquito resistance to insecticides (WHO, 2017; Daniyan, 2021; Sabina, 2017). Furthermore, severe complications of the disease exacerbate the malaria issue, primarily due to limited understanding of their pathogenesis. Consequently, numerous studies are being conducted to elucidate these complications. Regarding the establishment of neurological complications associated with cerebral malaria, a comprehensive understanding of all underlying mechanisms is crucial as the disease complications endure even after the treatment of the Plasmodium infection (Desruisseaux et al., 2010; Ghazanfari et al., 2018). Therefore, this review aims to elucidate the latest hypotheses concerning the pivotal role of cellular mechanism and cerebral neurochemistry in the pathogenesis of cerebral malaria.

Understanding the clinical aspects of the disease involves critical stages of the complex Plasmodium life cycle, implicating both intracellular and extracellular phases, which results in the disease rapid progression. Human malaria infection begins when sporozoites are inoculated by mosquitoes, initiating the asexual phase of the cycle, which includes the pre-erythrocytic and erythrocytic stages. In the pre-erythrocytic phase, sporozoites migrate to the liver and infect hepatocytes, where they proliferate to produce approximately 30,000 merozoites. These merozoites then infect erythrocytes, marking the onset of the asexual erythrocytic phase (Tuteja, 2007). During the asexual erythrocytic phase, merozoites progress through three stages: ring, trophozoite, and schizont. The ring stage represents the young trophozoite with a ring-shaped structure. The trophozoite matures with increased metabolic activity, including hemoglobin ingestion and proteolysis, leading to schizont formation characterized by multiple cell cycles without cell division (Natarajan et al., 2001; Miller et al., 2002; Tuteja, 2007).

The first clinical symptoms of malaria are nonspecific, initiated from the rupture of parasitized erythrocytes, which release antigens into the bloodstream, activating the host immune response (De Souza and Riley, 2002). Among them, febrile episodes, chills, tremors, headache, nausea, vomiting and other clinical signs stand out, however, in the case of P. falciparum infection, severe conditions such as anemia, respiratory distress, organ dysfunction and malaria brain damage are also common, which potentially can lead to cognitive deficits, declining the survivors overall life quality (Hunt and Grau, 2003; Combes et al., 2006; Carvalho et al., 2014; Martins et al., 2009a; Trampuz et al., 2003; Medana and Turner, 2006). Given the impacts of cerebral malaria on patients, multiple approaches are being explored to unravel all the counterpoints involving the pathogenesis of these neurological complications.

Human cerebral malaria (HCM) is a neurological disorder resulting from complications of malaria caused by Plasmodium falciparum infection, which commonly affects adolescents and children (Desruisseaux et al., 2010). According to the World Malaria Report (WHO, 2022), 610,000 patients died from malaria, with CM accounting for 90% of deaths. CM complications include high fever, recurrent chills, lethargy, severe headache, delirium, seizures, manifests as encephalopathy with a coma state, accompanied by neurological disorders stemming from hemorrhagic events (Bangirana et al., 2014; Lou et al., 2001; Rosa-Gonçalves et al., 2022).

Despite infection treatment, approximately a quarter of surviving patients experience enduring neurologic and cognitive deficits, including behavioral abnormalities, epilepsy, learning and memory deficits, as well as impaired motor functions, both short and long after clinical episodes (MacCormick et al., 2014; Idro et al., 2006; Birbeck et al., 2010).

The greatest risk of deficits in motor, language and social development is for children younger than 5 years of age (Sierro and Grau, 2019). Three to six months after infection, working memory-specific cognitive deficits can be intensified, with language development being the most consistently affected in pediatric survivors (Idro et al., 2016). Added to this, Carter et al. (2005) demonstrated that after the development of severe malaria, some children present neurocognitive deficiencies that are evident up to nine years later, which become more evident with the children’s age. Children progress and face more complex cognitive and linguistic demands, highlighting that the child’s neurological status at the time of medical discharge was not a good predictor of later neurocognitive impairment (Schiess et al., 2020).

John et al. (2008) demonstrated that cerebral malaria was shown to be associated with long-term cognitive impairment in 1 of 4 surviving children. Newton (1995) demonstrated that of 14 CM unconscious children in Kenya, 6 had cerebral edema and 4 of them showed evidence of ischemic damage associated with critically reduced cerebral perfusion pressure, all 4 of which had severe neurological sequelae. However, even though it is well described in the literature that the development of CM can lead the patient to death and/or induce the development of irreversible sequelae after years of its incidence, the pathogenesis of this condition is still under intense discussion (Newton et al., 1994).

The pathology linked to CM exhibits intricate and multifaceted characteristics. Among these elements, the mechanism of cytoadherence of parasitized erythrocytes to the brain microvasculature is emphasized. This process relies on the interaction between antigens found on the surface of parasitized erythrocytes (PfEMP1) and host receptors, including CD36, CD54, ICAM-1 and Endothelial Protein C Receptors (EPCR) (Turner et al., 1994; Storm et al., 2019). In the brain, the adherence of erythrocytes to the endothelium can lead to ischemic processes with the appearance of hemorrhages focus, being the main responsible for the coma state in CM (Berendt et al., 1994). In addition, the production of pro-inflammatory cytokines such as TNF-α and Lymphotoxin α (LT-α) promotes the increase in the expression of ICAM-1, potentiating the sequestration of parasitized erythrocytes, leukocytes and platelets, decreasing the irrigation and oxygenation of various organs of the body, including the brain (Ma et al., 1997; Engwerda et al., 2002; Good et al., 2005; Miller et al., 2002; Hunt and Grau, 2003; Idro et al., 2005).

Studies have confirmed that the increase in the levels of pro-inflammatory cytokines is also a fundamental event for the development and establishment of CM (Brown et al., 1999; Hunt and Grau, 2003). Among these cytokines, TNF-α and Interferon-γ (IFN-γ) secreted by macrophages, CD4+ T and CD8+ T cells stand out. The production of TNF-α in the initial phase of CM seems to be related to the reduction in the parasite load. However, the excessive production of this cytokine in the later phase is associated with the severity of the disease (Omer et al., 2000; Schiess et al., 2020). This divergent role of TNF-α suggests that the regulation and timing of pro-inflammatory cytokine production is of fundamental importance for infection control (Omer et al., 2000).

The release of anti-inflammatory cytokines, mainly interleukin 10 (IL-10) has a protective role by regulating the synthesis of pro-inflammatory cytokines in response to the parasite (Abosalif et al., 2023). Kossodo et al. (1997) demonstrated that the in vivo neutralization of IL-10 induces the appearance of the neurological syndrome in animals that were previously resistant to CM, suggesting that this protection mechanism via the release of anti-inflammatory cytokines may be deficient in individuals susceptible to this condition. In this context, the mismatch between the process of releasing pro-inflammatory and anti-inflammatory cytokines seems to be crucial for the development of CM.

In the Central Nervous System (CNS), CM induces damage to the Blood-Brain Barrier (BBB) structure, allowing antigens and inflammatory mediators to enter the brain parenchyma, resulting in microglia activation, neuronal damage, and redistribution of astrocytic cells (Ma et al., 1997; Medana et al., 2001; Adams et al., 2002; Hunt and Grau, 2003). However, the mechanisms involved in BBB alterations, microvascular obstructions, astrocyte degeneration, as well as the homeostasis of neurotransmitter systems, associated with the development of CM still remain poorly understood.

The brain tissue is highly sensitive to fluctuations in blood molecules and its homeostasis is meticulously regulated (Menaceur et al., 2021). BBB is a semipermeable membrane that separates peripheral blood from the brain parenchyma, formed by a monolayer of endothelial cells joined by very close junctions and the underlying basal lamina (Nishanth and Schluter, 2019). This structure is considered a part of the neurovascular unit, a concept that emphasizes an interconnection between the different components of the brain for optimal brain functions. BBB integrity is promoted by astrocytes, which are in direct contact with neurons and microglia, being critical to minimizing local inflammation and neuronal damage (Obermeier et al., 2013; Nishanth and Schluter, 2019).

Maintenance of homeostasis is mainly due to brain endothelial cells, which are on the luminal side of the blood-brain barrier and correspond to the actual site of the barrier. They are held together by tight junctions of high electrical resistance, preventing the passage of molecules, and do not contain small openings called cleft pores that allow the diffusion of molecules (Shimizu et al., 2018). Thus, to reach brain parenchyma, essential nutrients need to be actively transported by transport systems to pass through the capillary wall. Brain endothelial cells also have important roles in mediating and regulating the immune response in the central nervous system (Muldoon et al., 2013; Shimizu et al., 2018). The inner part of the BBB is composed by pericytes and glial cells such as astrocytes which work essentially to protect neurons from toxic products released in the bloodstream. In this context, glial cells are responsible for maintaining homeostasis for neuronal functions, contributing and regulating the brain endothelial cell phenotype (Dotiwala et al., 2023). In particular, endothelial cells are in contact with astrocyte foot processes. In several CNS disorders, the dysfunction of the blood-brain barrier is associated with the emergence of substantial neurological conditions such as traumatic brain injury, ischemia and Alzheimer’s disease (Rosenberg, 2012).

During infection with P. falciparum, activation of the cerebral endothelium can progress to vascular permeability and loss of BBB integrity, as indicated by hemorrhages in the brains of patients with CM and leakage of dyes or antibodies into the brain parenchyma in experimental cerebral malaria (ECM) (Rénia et al., 2012). Although the extent of pathological events related to BBB function in human CM is variable, BBB dysfunction appears to be associated with brain disease progression (Medana and Turner, 2006). Several studies in patients from Africa and Asia have shown that interruption of BBB in CM leads to serious neurologic complications, including intracerebral hemorrhage, seizures resulting from an electrolyte imbalance, and an increase in intracranial pressure due to generalized edema, resulting in axonal damage, dysfunctions in CNS, activation of glial cells as astrocytes and microglia and neuronal death (Gitau and Newton, 2005; Trivedi and Chakravarty, 2022).

Experimental studies have also illustrated that alterations in the arrangement of astrocytic cells belonging to the blood-retinal barrier contribute to structural impairment and subsequent exposure to vascular contents (MacCormick et al., 2022). Medana et al. (1996) observed a pathological reorganization of retinal astrocytes preceding the development of neurological alterations in ECM. These events precipitate the changes responsible for the retinopathy observed in the progression of CM.

Continuing with vascular alterations in different regions of the CNS, numerous studies indicate that cerebellar atrophy and loss of Purkinje cells, pivotal neurons of the cerebellum, are associated with the characteristic motor manifestations in CM patients (Farahna et al., 2010; Hijazi et al., 2022; Sakaria et al., 2013). Furthermore, cerebellar ataxia after the disease establishment appears to be linked to the cellular loss in this region (Sakaria et al., 2013).

Additionally, recent data have endeavored to elucidate the relationship between changes in glial cells and the pathogenesis of CM. The complication appears to accelerate cellular aging, leading to neuroinflammation resulting from the release of CCL2, CCL5, CXCL9, and CXCL10 from senescent astrocytes. The onset of neuroinflammation can exacerbate the disease by recruiting leukocytes in the brain and reducing neuronal survival during CM (Strangward et al., 2017). The process of senescence in these glial cells may contribute not only to inflammatory changes but also to synaptic impairments, which are responsible for altering the physiology of the CNS.

In response to blood-brain barrier disruption resulting from infections, such as that which underlies CM, a notable alteration in microglial cell activity is often observed. These cells, representing the resident immune system of the CNS, respond to cerebral ischemia and extravasate contents into the parenchyma through the expression of pro-inflammatory cytokines and phenotypic alterations in cellular structure (Medana et al., 2000; Andoh and Gyan, 2021; Shaikh et al., 2024). However, alterations in microglial cell activity can be observed in the early stages of the disease in murine models, which may not be a consequence of tissue changes but rather one of the factors responsible for them. Microglial activation may arise either from direct interaction with parasites or from changes occurring in the microenvironment surrounding the tissue housing parasitic lesions (Mendana et al., 2000).

Indeed, the mechanisms contributing to BBB rupture in cerebral malaria remain elusive. Nishanth and Schlüter (2019) propose several mutually non-exclusive events associated with BBB disorders, as observed in human and murine studies. These include the sequestration of infected red blood cells (iRBCs) to brain endothelial cells (Lau et al., 2015; Ghazanfari et al., 2018), an excessive inflammatory response marked by increased intracerebral pro-inflammatory cytokines (Idro et al., 2010; Lennartz et al., 2017; Trivedi and Chakravarty, 2022) and dysregulation of vascular endothelial cells (Storm et al., 2019). Notably, these events include the involvement of host pathways in tryptophan metabolism and the release of extracellular vesicles, known as microparticles, by both the host and the parasite. Both the sequestration of iRBCS in the vascular endothelium and the aspects of the exacerbated immune response were previously addressed. The clotting process, along with the cytoadherence and the increased host immune response promote brain endothelial cell dysregulation (Storm and Craig, 2014; Plewes et al., 2018). In addition, adjacent factors such as activation and alteration in the distribution of astrocytic cells, activation of microglial cells, as well as pericyte dysfunction and neuronal injury are effects arising from cerebral malaria, which together contribute to BBB degeneration (Dunst et al., 2017). In this context, several other factors must be evaluated, regarding the neurological impairment in CM, making studies in neurochemistry of great importance to bring light to the mechanisms involved in this process.

Even among individuals treated with antimalarials and upon recovery, sequelae persist, compromising the functioning of the CNS (Schiess et al., 2020). These sequelae involve a spectrum of challenges, spanning from cognitive impairment and cerebellar-associated motor skill deficits to issues with visual coordination, seizures, and attention deficit hyperactivity disorder. Their impact can extend to up to 25% of pediatric survivors (Idro et al., 2006; Kihara et al., 2009; Schiess et al., 2020), putting them at a heightened risk for deficits in motor, language, and social development. Notably, seizures are a prevalent occurrence in children with CM (Idro et al., 2016; Ouma et al., 2021). Furthermore, as a lasting consequence, sustained seizure disorders may emerge, proving resistant to at least one antiepileptic medication, persisting for months after an episode of CM. Despite numerous studies aiming to elucidate the mechanisms underlying CM development, the pathogenesis of this disease remains poorly understood. Several hypotheses are actively explored to comprehend the intricate elements that contribute to the onset of this complication.

Cerebral malaria, a deadly complication of P. falciparum malaria, has the potential to last cognitive sequelae, even in patients who undergo treatment for the infection. The exposure of the brain parenchyma to vascular and hemorrhagic events, extensively described in the literature, results in tissue disorganization and disruption of communication between neuronal cells, particularly mediated by signaling molecules known as neurotransmitters ( Figure 1 ). Recognizing the significance of these molecules in brain physiology, this review highlights studies that offer a new perspective, emphasizing a more crucial role for neurotransmitters in the pathogenesis of cognitive and behavioral changes associated with the disease. Therefore, gaining a better understanding of the neurochemical and physiological effects of the interaction between the parasite and the host becomes crucial in the development of novel therapeutic approaches.