A major cause of morbidity and mortality of
Plasmodium falciparum malaria is cerebral malaria (CM). It presents as a diffuse encephalopathy with alteration of consciousness, ranging from drowsiness to deep coma and is frequently accompanied by seizures [
1]. Mortality is high and neurological sequelae are observed in approximately 10% of the survivors [
2]. The pathophysiological mechanisms of CM are yet not fully understood. Most researchers agree that the immune response of the host is a critical factor in the pathogenesis of CM. Different aspects have been studied and in particular pro-inflammatory cytokines and activated T-lymphocytes have been shown to be related to the development of CM [
3‐
5]. Importantly, recent studies suggest a critical role of interferon-responsive mechanisms in murine and human CM [
6,
7]. Therefore, immunomodulatory drugs have been considered as potential adjunctive treatment regimens for severe malaria. Despite beneficial effects in the mouse model [
8,
9], corticosteroids have been shown to be ineffective or even deleterious in human CM [
10,
11]. Similar findings were observed with TNF-alpha antagonists. While TNF-alpha blockage reduces the rate of CM in mice, the data from human trials are far from clear [
12‐
14]. In rodents positive effects were achieved with thalidomide, a potent inhibitor of TNF-alpha and inductor of a Th2-based immune response [
15,
16]. Recent studies implicate, that the potent immunosuppressive agent cyclosporin A may inhibit parasite development [
17] and decrease neurological complications in
Plasmodium berghei infected mice, when applied in low dose [
18]. The neuropathological alterations in murine CM resemble in some aspects the neuro-inflammatory response seen in experimental allergic encephalitis (EAE), an animal model for multiple sclerosis [
19,
20]. Therefore the current study was designed to evaluate the efficacy of glatiramer acetate (GA), an immuno-modulatory and potentially neuro-protective substance which is in clinical use for the treatment of relapsing remitting multiple sclerosis, for the prevention of mortality from CM.
GA, also known as copolymer 1, is a heterogeneous mix of polypeptides containing the four amino acids alanine, lysine, glutamic acid and tyrosine in definite ratios but with no uniform sequence with an average molecular weight of 5,000–9,000 daltons [
21]. GA was synthesized to resemble the structure of myelin basic protein (MBP), one of the major components involved in EAE and multiple sclerosis but instead of inducing the disease, it was found to be protective [
22]. GA was approved by the FDA for the treatment of relapsing remitting multiple sclerosis in 1996. GA has been shown to be of benefit in different experimental diseases models as amyotrophic lateral sclerosis (ALS) [
23], Alzheimer disease [
24] and experimental colitis [
25]. In addition, GA exerts beneficial effects on neuronal degeneration after facial nerve axonotomy [
23], graft rejection and graft versus host disease [
26,
27]. Recently murine HIV-1 encephalitis [
28] was successfully ameliorated by GA treatment. These promising results warrant the evaluation of this drug in experimental CM.