Cognitive Dysfunction in Mice Infected withPlasmodium bergheiStrain ANKA

Abstract

Cerebral malaria complicated by cognitive sequelae is a major cause of morbidity in humans infected with Plasmodium falciparum. To model cognitive function after malaria, we created a rodent model of cerebral malaria by infecting C57BL/6 mice with Plasmodium berghei strain ANKA. After 7 days, an object-recognition test of working memory revealed a significant impairment in the visual memory of infected mice. This impairment was observed in the absence of confounding effects of infection. The cognitive dysfunction correlated with hemorrhage and inflammation. Furthermore, microglial activity and morphological changes detected throughout the brains of infected mice were absent from the brains of control mice, and this correlated with the measured cognitive defects. Similar testing methods in human studies could help identify subjects at risk for an adverse cognitive outcome. This murine model should facilitate the study of adjunctive methods to ameliorate adverse neurological outcomes in cerebral malaria.

Persistent cognitive and motor deficits after successful antimalarial treatment in murine cerebral malaria

“…We previously demonstrated that during acute malarial infection, mice with CM sustain substantial hemorrhage in several regions of the brain [21]. Hematoxylin and eosin (H&E) staining of the sagittal section of acutely infected mice ( N = 6) corroborated our previous demonstration of significant hemorrhage compared to untreated controls ( N = 4) (Fig.…”

“…Similarly, the inflammation observed during acute infection [21] was also resolved after CQ as Iba1 immunoreactivity (quantified as the percent region of interest) in CM mice did not demonstrate any significant degree of monocytic infiltration in the cerebral vasculature or of microglial activation compared to control mice in the frontal cortex (PbA 0.82 ± 0.18% vs. Control 0.48 ± 0.12%; p = NS; N = 5), cerebellum (PbA 1.05 ± 0.25% vs. Control 0.68 ± 0.07%; p = NS; N = 4 PbA, 5 control) or the hypothalamus (PbA 1.14 ± 0.27% vs. Control 0.58 ± 0.11%; p = NS; N = 5), indicating that the persistent cognitive and motor impairments in CM were not due to residual vascular damage or to inflammation in the brain.…”

“…Previously, our laboratory group has demonstrated that susceptible mice sustain significant memory deficits during acute infection with PbA [21], and demonstrate many of the histopathologic features of human CM such as hemorrhage, neuronal and axonal damage [21,24,30]. With this study we present a treatment model of PbA infection that mimics the problem of persistency in neurological sequelae after parasitological cure that is observed in human CM when infected with P. falciparum .…”

“…Examination of a single midline section was also performed in each of the chloroquine-treated mice for evidence of microglial activation by immunostaining with a rabbit antibody to ionized calcium-binding adaptor molecule 1 (Iba1) (Wako Chemicals USA) [21]. Photographs were obtained of the cortex, cerebellum and hypothalamus ( N = 5 controls, 5 PbA for cortex and hypothalamus, and 5 controls, 4 PbA for cerebellum) and Iba1 intensity was quantified as a percentage of the region of interest using ImageJ 1.42v (National Institutes of Health).…”

Endothelin-1 and its role in the pathogenesis of infectious diseases

“…In addition, intraventricular injection of ET-1 results in behavioral changes, including barrel rolling, body tilting, nystagmus, facial clonus, forelimb clonus, and tail extension in rats, even at doses that do not cause any changes in CBF [94]. By virtue of its vasoactive effects and adverse neurological effects, increased levels of ET-1 during CM may be partly responsible for the reduced CBF, vasospasms, and vascular collapse observed in human cases and animal models of CM [86], and for the cognitive and motor deficits observed in CM [88, 89, 95]. …”