Neuronal apoptosis, metallothionein expression and proinflammatory responses during cerebral malaria in mice
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BACKGROUND: Cerebral malaria (CM) is an acute encephalopathy in humans due to the infection with Plasmodium falciparum. Neuro-cognitive impairment following CM occurs in about 10% of the treated survivors, while the precise pathophysiological mechanism remains unknown. Metallothionein I + II (MT-I + II) are increased during CNS pathology and disorders. As previously shown, MT-I + II are neuroprotective through anti-inflammatory, antioxidant and antiapoptotic functions. We have analyzed neuronal apoptosis and MT-I + II expression in brains of mice with experimental CM. METHODS: C57BL/6j mice, infected with Plasmodium berghei ANKA, were studied on day 7, day 9, and when presenting signs of CM on days 10-12. We investigated brain histopathology by immunohistochemistry and TUNEL (Terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP)-digoxigenin nick end labeling). For statistics, we used quantitation (cellular counts) of the analyzed variables. RESULTS: During CM, we observed significant inflammatory responses of F4/80+ microglia/macrophages and GFAP+ reactive astrocytes and increased immunoreactivity of 8-oxoguanine (marker of oxidative stress). As novel findings, we show: (1) a localized CM-induced neuronal apoptosis (detected by TUNEL) indicating severe and irreversible pathology. (2) A significant increase in MT-I + II expression in reactive astrocytes, macrophages/microglia and vascular endothelium. INTERPRETATION: This is the first report showing apoptosis of neurons in CM by TUNEL, pointing out a possible pathophysiological mechanism leading to persisting brain damage. The possible neuroprotective role of MT-I + II during CM deserves further attention.
Original language | English |
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Journal | Experimental Neurology |
Volume | 200 |
Issue number | 1 |
Pages (from-to) | 216-26 |
Number of pages | 10 |
ISSN | 0014-4886 |
DOIs | |
Publication status | Published - 2006 |
Bibliographical note
Keywords: Animals; Apoptosis; Female; Gene Expression Regulation; Inflammation Mediators; Malaria, Cerebral; Metallothionein; Mice; Mice, Inbred C57BL; Neurons; Plasmodium berghei
ID: 13620379