RESUMO
Heme oxygenase (HO) catalyses the breakdown of heme to iron, carbon monoxide and biliverdin, the latter being further reduced to bilirubin. A protective role of the inducible isoform, HO-1, has been described in pathological conditions associated with the production of reactive oxygen species (ROS). The aim of this study was to investigate the role of HO-1 in the neurotoxicity induced by iodoacetate (IAA) in primary cultures of cerebellar granule neurons (CGNs). IAA, an inhibitor of the glycolysis pathway, reduces cell survival, increases ROS production and enhances HO-1 expression in CGNs. Furthermore, the induction of HO-1 expression by cobalt protoporphyrin (CoPP) prevented cell death and ROS production induced by IAA, whereas the inhibition of HO activity with tin mesoporphyrin exacerbated the IAA-induced neurotoxicity. The protective effect elicited by CoPP was reproduced by bilirubin addition, suggesting that this molecule may be involved in the protective effect of HO-1 induction in this experimental model.
Assuntos
Bilirrubina/farmacologia , Cerebelo/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Ácido Iodoacético/toxicidade , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Animais , Bilirrubina/metabolismo , Western Blotting , Doenças Cerebelares/induzido quimicamente , Doenças Cerebelares/enzimologia , Doenças Cerebelares/prevenção & controle , Cerebelo/citologia , Cerebelo/enzimologia , Indução Enzimática , Heme Oxigenase-1/antagonistas & inibidores , Heme Oxigenase-1/biossíntese , Metaloporfirinas/farmacologia , Neurônios/metabolismo , Protoporfirinas/farmacologia , Ratos , Ratos Endogâmicos BB , Espécies Reativas de Oxigênio/metabolismo , Tubulina (Proteína)/metabolismoRESUMO
Cattle in western Uruguay that were eating Solanum bonariense developed periodic episodes of ataxia, hypermetria, hyperesthesia, head and thoracic limb extension, opisthotonus, nystagmus, and falling to the side or backward. Similar clinical signs were experimentally reproduced in cattle by administration of S. bonariense via rumen cannula at a dose of 1,024 g/kg body mass. No significant gross lesions were observed in field cases or experimentally induced cases. Spontaneous and induced histologic lesions were similar and included vacuolation, degeneration, and loss of Purkinje cells. Axonal spheroids, microcavitations, and other changes of wallerian-type degeneration in cerebellar white matter were also observed. Ultrastructural changes included increased number of electron-dense residual storage bodies in membrane-bound vesicles in affected Purkinje cells, and similar vesicles and mitochondria in axonal spheroids. No histologic lesions were detected in the other examined tissues. The Purkinje-cell swelling and vacuolation with subsequent cerebellar degeneration are suggestive of Purkinje-cell specific toxin that produces abnormal lysosome function and cell specific axonal transport. This is the first report of S. bonariense toxicity.