Reduction of experimental cerebral malaria and its related proinflammatory responses by the novel liposome-based ß-methasone nanodrug.

Cerebral malaria (CM) is a severe complication of and a leading cause of death due to Plasmodium falciparum infection. CM is likely the result of interrelated events, including mechanical obstruction due to parasite sequestration in the microvasculature, and upregulation of Th1 immune responses. In parallel, blood-brain-barrier (BBB) breakdown and damage or death of microglia, astrocytes, and neurons occurs. We found that a novel formulation of a liposome-encapsulated glucocorticosteroid, ß-methasone hemisuccinate (nSSL-BMS), prevents experimental cerebral malaria (ECM) in a murine model and creates a survival time-window, enabling administration of an antiplasmodial drug before severe anemia develops. nSSL-BMS treatment leads to lower levels of cerebral inflammation, expressed by altered levels of corresponding cytokines and chemokines. The results indicate the role of integrated immune responses in ECM induction and show that the new steroidal nanodrug nSSL-BMS reverses the balance between the Th1 and Th2 responses in malaria-infected mice so that the proinflammatory processes leading to ECM are prevented. Overall, because of the immunopathological nature of CM, combined immunomodulator/antiplasmodial treatment should be considered for prevention/treatment of human CM and long-term cognitive damage.

Glucocorticosteroids in nano-sterically stabilized liposomes are efficacious for elimination of the acute symptoms of experimental cerebral malaria.

Cerebral malaria is the most severe complication of Plasmodium falciparum infection, and a leading cause of death in children under the age of five in malaria-endemic areas. We report high therapeutic efficacy of a novel formulation of liposome-encapsulated water-soluble glucocorticoid prodrugs, and in particular ß-methasone hemisuccinate (BMS), for treatment of experimental cerebral malaria (ECM), using the murine P. berghei ANKA model. BMS is a novel derivative of the potent steroid ß-methasone, and was specially synthesized to enable remote loading into nano-sterically stabilized liposomes (nSSL), to form nSSL-BMS. The novel nano-drug, composed of nSSL remote loaded with BMS, dramatically improves drug efficacy and abolishes the high toxicity seen upon administration of free BMS. nSSL-BMS reduces ECM rates in a dose-dependent manner and creates a survival time-window, enabling administration of an antiplasmodial drug, such as artemisone. Administration of artemisone after treatment with the nSSL-BMS results in complete cure. Treatment with BMS leads to lower levels of cerebral inflammation, demonstrated by changes in cytokines, chemokines, and cell markers, as well as diminished hemorrhage and edema, correlating with reduced clinical score. Administration of the liposomal formulation results in accumulation of BMS in the brains of sick mice but not of healthy mice. This steroidal nano-drug effectively eliminates the adverse effects of the cerebral syndrome even when the treatment is started at late stages of disease, in which disruption of the blood-brain barrier has occurred and mice show clear signs of neurological impairment. Overall, sequential treatment with nSSL-BMS and artemisone may be an efficacious and well-tolerated therapy for prevention of CM, elimination of parasites, and prevention of long-term cognitive damage.

Artemisone effective against murine cerebral malaria.

BACKGROUND: Artemisinins are the newest class of drug approved for malaria treatment. Due to their unique mechanism of action, rapid effect on Plasmodium, and high efficacy in vivo, artemisinins have become essential components of malaria treatment. Administration of artemisinin derivatives in combination with other anti-plasmodials has become the first-line treatment for uncomplicated falciparum malaria. However, their efficiency in cases of cerebral malaria (CM) remains to be determined. METHODS: The efficacy of several artemisinin derivatives for treatment of experimental CM was evaluated in ICR or C57BL/6 mice infected by Plasmodium berghei ANKA. Both mouse strains serve as murine models for CM. RESULTS: Artemisone was the most efficient drug tested, and could prevent death even when administered at relatively late stages of cerebral pathogenesis. No parasite resistance to artemisone was detected in recrudescence. Co-administration of artemisone together with chloroquine was more effective than monotherapy with either drug, and led to complete cure. Artemiside was even more effective than artemisone, but this substance has yet to be submitted to preclinical toxicological evaluation. CONCLUSIONS: Altogether, the results support the use of artemisone for combined therapy of CM.

Modulation of cerebral malaria by fasudil and other immune-modifying compounds.

Malaria continues to cause millions of deaths annually. No specific effective treatment has yet been found for cerebral malaria, one of the most severe complications of the disease. The pathology of cerebral malaria is considered to be primarily immunological. We examined a number of compounds with known effects on the immune system, in a murine model of cerebral malaria. Of the compounds tested, only fasudil and curcumin had significant effects on the progression of the disease. Although neither drug caused a reduction in parasitemia, survival of the treated mice was significantly increased, and the development of cerebral malaria was either delayed or prevented. Our results support the hypothesis that an immunomodulator efficient in preventing CM should be administered together with anti-plasmodial drugs to prevent severe malaria disease; curcumin and fasudil should be further investigated to determine efficiency and feasibility of treatment.

Schistosoma mansoni infection reduces the incidence of murine cerebral malaria.

BACKGROUND: Plasmodium and Schistosoma are two of the most common parasites in tropical areas. Deregulation of the immune response to Plasmodium falciparum, characterized by a Th1 response, leads to cerebral malaria (CM), while a Th2 response accompanies chronic schistosomiasis. METHODS: The development of CM was examined in mice with concomitant Schistosoma mansoni and Plasmodium berghei ANKA infections. The effect of S. mansoni egg antigen injection on disease development and survival was also determined. Cytokine serum levels were estimated using ELISA. Statistical analysis was performed using t-test. RESULTS: The results demonstrate that concomitant S. mansoni and P. berghei ANKA infection leads to a reduction in CM. This effect is dependent on infection schedule and infecting cercariae number, and is correlated with a Th2 response. Schistosomal egg antigen injection delays the death of Plasmodium-infected mice, indicating immune involvement. CONCLUSIONS: This research supports previous claims of a protective effect of helminth infection on CM development. The presence of multiple parasitic infections in patients from endemic areas should therefore be carefully noted in clinical trials, and in the development of standard treatment protocols for malaria. Defined helminth antigens may be considered for alleviation of immunopathological symptoms.