Cognitive Dysfunction Is Sustained after Rescue Therapy in Experimental Cerebral Malaria, and Is Reduced by Additive Antioxidant Therapy

Abstract

Neurological impairments are frequently detected in children surviving cerebral malaria (CM), the most severe neurological complication of infection with Plasmodium falciparum. The pathophysiology and therapy of long lasting cognitive deficits in malaria patients after treatment of the parasitic disease is a critical area of investigation. In the present study we used several models of experimental malaria with differential features to investigate persistent cognitive damage after rescue treatment. Infection of C57BL/6 and Swiss (SW) mice with Plasmodium berghei ANKA (PbA) or a lethal strain of Plasmodium yoelii XL (PyXL), respectively, resulted in documented CM and sustained persistent cognitive damage detected by a battery of behavioral tests after cure of the acute parasitic disease with chloroquine therapy. Strikingly, cognitive impairment was still present 30 days after the initial infection. In contrast, BALB/c mice infected with PbA, C57BL6 infected with Plasmodium chabaudi chabaudi and SW infected with non lethal Plasmodium yoelii NXL (PyNXL) did not develop signs of CM, were cured of the acute parasitic infection by chloroquine, and showed no persistent cognitive impairment. Reactive oxygen species have been reported to mediate neurological injury in CM. Increased production of malondialdehyde (MDA) and conjugated dienes was detected in the brains of PbA-infected C57BL/6 mice with CM, indicating high oxidative stress. Treatment of PbA-infected C57BL/6 mice with additive antioxidants together with chloroquine at the first signs of CM prevented the development of persistent cognitive damage. These studies provide new insights into the natural history of cognitive dysfunction after rescue therapy for CM that may have clinical relevance, and may also be relevant to cerebral sequelae of sepsis and other disorders.

Current Advances in Cerebral Malaria Associated Encephalopathy

“…Similar phenomenon was found in an animal study by Reis et al (Reis, Comim et al 2010), who support the view that cognitive dysfunction is sustained after rescue treatment in PbA-infected CM-sensitive C57BL/6 mice, an animal model for CM. In addition, treatment of CM-sensitive C57BL/6 mice with additive antioxidants such as malondialdehyde, MDA and conjugated dienes along with chloroquine prevented the development of persistent cognitive damage.…”

Synthesis of Artemiside and Its Effects in Combination with Conventional Drugs against Severe Murine Malaria

“…In this case, a delayed treatment may eliminate the parasites and prevent death but not neurological damage (25,28). Cognitive dysfunction might be sustained after rescue therapy in ECM, but it is reduced by additive antioxidant therapy (40). This might be a hint to consider drug combinations that also include components that reduce oxidant stress.…”

Toxoplasma gondii Upregulates Interleukin-12 To Prevent Plasmodium berghei-Induced Experimental Cerebral Malaria

“…Removal of immune cells, such as T or NK cells, or the cytokines gamma interferon (IFN-␥) and lymphotoxin alpha (LT␣) prevents P. berghei ANKA-induced ECM (13)(14)(15)(16)(17)(18)(19)(20)(21). Understanding the immune response in ECM has allowed the investigation of potential treatments via regulation of innate immunity (22)(23)(24)(25)(26)(27). Additionally, investigating the immune response during coinfection, either with other Plasmodium spp.…”