Statins Alone Are Ineffective in Cerebral Malaria but Potentiate Artesunate

Statins are a family of lipid-lowering drugs widely used to control the cholesterol level and to prevent stroke and cardiac failure in patients at high risk of coronary artery disease. Recently, statins demonstrated pleiotropic cholesterol-independent effects (2). Used after stroke, statins proved to be neuroprotective in the setting of cerebral ischemia, with improved functional outcome in patients (5). Used after septic insult, statins demonstrated increased survival time due to restoration of cardiac function and haemodynamic status (4). These effects occur before cholesterol lowering and without pretreatment. According to these benefits, we postulate that statins could be considered as new potential drugs during acute cerebral infectious diseases. Among these, cerebral malaria due to Plasmodium falciparum is still one of the worst killers in tropical countries. Considering the role of inflammatory and ischemic injuries during cerebral malaria, we addressed the place of statins as emergency treatment in a clinically relevant murine model.

Statins differ in terms of their chemical structures, pharmacokinetic profiles, and lipid-modifying efficacy (7). As differences could be expected in 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition, several statins were tested for neuroprotective potential. The effects of pravastatin, fluvastatin, simvastatin, and atorvastatin were compared to the neuroprotective effect of erythropoietin, known to provide 60% survival in an experimental model of cerebral malaria (3). Pravastatin and fluvastatin were administrated at high doses (40 to 200 mg/kg of body weight), simvastatin at 40 mg/kg, and atorvastatin at 20 mg/kg, once per day for three to five days at the onset of the disease. Surprisingly, all statins used alone failed to prevent death from cerebral malaria (Table 1), and this raised questions for the scientific community during a recent meeting (1). Despite the in vitro antimalarial effect of atorvastatin described by Pradines et al. (6), none of these statins showed an effect on parasitemia in mice when used at the same range of doses as the concentrations used in vitro (20 to 300 μM). There is a growing body of literature suggesting that the pleiotropic effects of statins may be useful in a wide range of indications, including poststroke reperfusion, septic insult, anticancer drug resistance, and inflammatory rheumatoid diseases.

TABLE 1.

Treatment of mice presenting cerebral malaria with statins under different regimens^a

Treatmentb	Dosage (mg/kg)	Time administered (days postinfection)	Parasitemia (day 6)		Survival (day 7)
			Mean ± SD (%)	Student's t test (drug vs control)	No. of surviving mice	Kaplan-Meier log rank test (P value)
Control 1		5, 6, 7	9.9 ± 2.2		0
Pravastatin
Low dose	40	5, 6, 7	11.5 ± 1.4	0.33	0	>0.5
High dose	200	5, 6, 7	11.8 ± 1.6	0.26	0	0.36
Control 2		5, 6, 7	8.3 ± 1.3		2
Fluvastatin
Low dose	20	5, 6, 7	7.4 ± 1.5	0.20	0	>0.5
High dose	100	5, 6, 7	7.4 ± 2.2	0.33	0	0.013c
Control 3		3-8	8.0 ± 1.6		3
Simvastatind	40	3-8	8.5 ± 1.2	0.50	1	0.19
Control 4		4-6	8.7 ± 1.4		2
Atorvastatin	20	4-6	9.5 ± 1.5	0.11	3	>0.5
Atorvastatin-artesunate	20, 40	4-6	2.1 ± 0.9	<0.02	15	<0.02

^aThere were 15 mice in each group. Treatment was given intraperitoneally. Parasitemia (Student's t test) and survival (Kaplan-Meier log rank; SPSS 11.5) data are compared between treated groups and infected untreated control groups. All treated and untreated mice had comparable weight and parasitemia before treatment.

^bSaline was used as the control.

^cFluvastatin had a toxic effect at high doses, as demonstrated by the P value and the premature death of mice compared to controls.

^dSimvastatin was chemically activated by alkaline hydrolysis prior to injection.

While statins failed to prevent death, it could be speculated that they could act as an adjuvant therapy. Mice were treated with a drug combination of artesunate and atorvastatin under the same conditions as described above, and we observed a significant improvement in survival at day 13 postinfection compared to survival with atorvastatin alone (P < 0.02; log rank test, cumulative survival analysis) (Fig. 1).

FIG. 1.

Univariate analysis of survival (SPSS 11.5). Benefit of the drug combination artesunate-atorvastatin for survival compared to atorvastatin treatment alone. The results of the log rank test revealed that artesunate-atorvastatin given from day 4 to day 6 postinfection had an effect on survival (P < 0.02). AS, artesunate; ATV, atorvastatin.

Considering sepsis, we speculated that statins could be a panacea (8). In the light of our observations during cerebral malaria, this new paradigm should rather be reconsidered as an adjuvant effect. As pleiotropic effects may largely depend on the pathophysiology of the respective disease and on the patient's status, convincing clinical trials are needed to explore the scope of these drugs. The safety of statins when administrated after the insult also needs to be addressed, since these molecules were not originally designed for these therapeutic approaches.

(This work was presented in part at the Annual Meeting of the American Society of Tropical Medicine and Hygiene, Philadelphia, PA, 2007.)