Neuronal apoptosis, metallothionein expression and proinflammatory responses during cerebral malaria in mice.
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.


CONCLUSIONS
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.
Wiese
Lothar
L
Section of Neuroprotection, Department of Medical Anatomy, The Panum Institute, Faculty of Health Sciences, University of Copenhagen, Denmark. Lothar.Wiese@rh.dk
Kurtzhals
Jørgen A L
JA
Penkowa
Milena
M
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D018836:Inflammation Mediators / Q000378:metabolism* / Q000502:physiology; D016779:Malaria, Cerebral / Q000378:metabolism* / Q000473:pathology*; D008668:Metallothionein / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D010962:Plasmodium berghei
D018836:Inflammation Mediators; D008668:Metallothionein