Ultrastructural confirmation of neuronal protection by melatonin against the neurotoxin 6-hydroxydopamine cell damage

6-Hydroxydopamine (6-OHDA) is a neurotoxin used in the induction of experim ental Parkinson's disease in both animals and cultured neuronal cells. Bioc hemical and molecular approaches showed previously that low doses of 6-OHDA induced apoptosis in PC12 cells, while high doses of this neurotoxin induc ed necrosis. Melatonin has been shown to protect against the neuronal progr ammed cell death induced by 6-OHDA, although it was not able to prevent the massive necrotic cellular death occurring after the addition of high doses of the neurotoxin. In the present work, we demonstrate by ultrastructural analysis that although low doses of 6-OHDA induced apoptosis in PC12 cells, it also damaged the non-apoptotic cells, morphologically corresponding thi s damage to incipient and reversible necrotic lesions. When the doses of th e neurotoxin increase, there are still apoptotic cells, although most of th e cells show necrotic irreversible lesions. We also found that melatonin pa rtially prevents the incipient necrotic lesions caused by low doses of 6-OH DA. The fact that melatonin was shown in previous work to prevent apoptosis caused by low doses of 6-OHDA, but not necrosis induced by high doses of t he neurotoxin, seemed to indicate that this agent is only able to protect a gainst apoptosis. However, our present results, melatonin preventing also t he incipient necrotic neuronal lesions, suggest that this hormone may provi de a general protection against cell death, suggesting that higher doses sh ould be tried in order to prevent the necrotic cell death induced by high d oses of the neurotoxin. (C) 1999 Elsevier Science B.V. All rights reserved.