Statins Decrease Neuroinflammation and Prevent Cognitive Impairment after Cerebral Malaria

Abstract

Cerebral malaria (CM) is the most severe manifestation of Plasmodium falciparum infection in children and non-immune adults. Previous work has documented a persistent cognitive impairment in children who survive an episode of CM that is mimicked in animal models of the disease. Potential therapeutic interventions for this complication have not been investigated, and are urgently needed. HMG-CoA reductase inhibitors (statins) are widely prescribed for cardiovascular diseases. In addition to their effects on the inhibition of cholesterol synthesis, statins have pleiotropic immunomodulatory activities. Here we tested if statins would prevent cognitive impairment in a murine model of cerebral malaria. Six days after infection with Plasmodium berghei ANKA (PbA) mice displayed clear signs of CM and were treated with chloroquine, or chloroquine and lovastatin. Intravital examination of pial vessels of infected animals demonstrated a decrease in functional capillary density and an increase in rolling and adhesion of leukocytes to inflamed endothelium that were reversed by treatment with lovastatin. In addition, oedema, ICAM-1, and CD11b mRNA levels were reduced in lovastatin-treated PbA-infected mice brains. Moreover, HMOX-1 mRNA levels are enhanced in lovastatin-treated healthy and infected brains. Oxidative stress and key inflammatory chemokines and cytokines were reduced to non-infected control levels in animals treated with lovastatin. Fifteen days post-infection cognitive dysfunction was detected by a battery of cognition tests in animals rescued from CM by chloroquine treatment. In contrast, it was absent in animals treated with lovastatin and chloroquine. The outcome was similar in experimental bacterial sepsis, suggesting that statins have neuroprotective effects in severe infectious syndromes in addition to CM. Statin treatment prevents neuroinflammation and blood brain barrier dysfunction in experimental CM and related conditions that are associated with cognitive sequelae, and may be a valuable adjuvant therapeutic agent for prevention of cognitive impairment in patients surviving an episode of CM.

Vascular endothelial growth factor (VEGF) and lovastatin suppress the inflammatory response toPlasmodium bergheiinfection and protect against experimental cerebral malaria

“…A treatment with lovastatin 20 mg/kg alone significantly ameliorated the signs of neuro-inflammation and prolonged the lifespan of the mice by 2 days in line with previous published reports. 2,17 The administration of simvastatin 20 mg/kg alone, a statin that, like lovastatin, inhibits endogenous cholesterol production by competitive inhibition of HMG-CoA reductase, failed to protect against ECM (Fig. 1A), confirming previous studies.…”

“…This is in agreement with the ability of statins to reduce iNOS expression, thereby protecting neuronal cells, while increasing endothelial NOS expression and increasing microcirculatory blood flow via local vasodilatation. 2,19 However, not all statins share the same protective properties. Simvastatin and lovastatin are both known to inhibit HMG-CoA reductase but simvastatin does not exert the same protective activity against ECM.…”

Simvastatin Attenuates Endothelial Activation through 15-Epi-Lipoxin A4 Production in Murine Chronic Chagas Cardiomyopathy

“…It has been reported that statins alter the natural course of other parasitic diseases such as cerebral malaria and intestinal toxoplasmosis (19,20). In addition, there is evidence that simvastatin decreases cardiac inflammation and fibrosis in dogs chronically infected with T. cruzi (21).…”

Role of Nitric Oxide Synthase in the Function of the Central Nervous System under Normal and Infectious Conditions

“…Our group and others have shown that eNOS is impaired during systemic infection, which leads to brain microcirculation dysfunction [46][47][48]. We showed that during different infectious diseases, there is a functional capillary rarefaction (Figure 3) that can be caused by the impairment of endothelial NO production by a reduction of eNOS activity or by reduced levels of the enzyme cofactor tetrahydrobiopterin-BH4 [49].…”

“…Interestingly, in experimental models of malaria [48] and sepsis (Reis et al, submitted) blood flow was recovered by treatment with statins. As reviewed by Giannopoulos et al [54], statins are shown to enhance eNOS expression and can contribute to the restoration of brain capillary function.…”