Lesion of the subthalamic nucleus reverses motor deficits but not death of nigrostriatal dopaminergic neurons in a rat 6-hydroxydopamine-lesion model of Parkinson's disease

The objective of the present study was to determine whether lesion of the subthalamic nucleus (STN) promoted by N-methyl-D-aspartate (NMDA) would rescue nigrostriatal dopaminergic neurons after unilateral 6-hydroxydopamine (6-OHDA) injection into the medial forebrain bundle (MFB). Initially, 16 mg 6-OHDA (6-OHDA group) or vehicle (artificial cerebrospinal fluid - aCSF; Sham group) was infused into the right MFB of adult male Wistar rats. Fifteen days after surgery, the 6-OHDA and SHAM groups were randomly subdivided and received ipsilateral injection of either 60 mM NMDA or aCSF in the right STN. Additionally, a control group was not submitted to stereotaxic surgery. Five groups of rats were studied: 6-OHDA/NMDA, 6-OHDA/Sham, Sham/NMDA, Sham/Sham, and Control. Fourteen days after injection of 6-OHDA, rats were submitted to the rotational test induced by apomorphine (0.1 mg/kg, ip) and to the open-field test. The same tests were performed again 14 days after NMDA-induced lesion of the STN. The STN lesion reduced the contralateral turns induced by apomorphine and blocked the progression of motor impairment in the open-field test in 6-OHDA-treated rats. However, lesion of the STN did not prevent the reduction of striatal concentrations of dopamine and metabolites or the number of nigrostriatal dopaminergic neurons after 6-OHDA lesion. Therefore, STN lesion is able to reverse motor deficits after severe 6-OHDA-induced lesion of the nigrostriatal pathway, but does not protect or rescue dopaminergic neurons in the substantia nigra pars compacta.

cytological effects of a neurotrophic peptide [MPF] in Parkinsonian rats

Substantia nigra [SN] samples from rats with 6-hydroxdopamine [6-OHDA] -induced lesions of right nigrostriatal pathways were retrieved and examined by transmission electron microscopy [TEM] 15-17 months after a single intrastriatal injection of a metabolically-stable analogue of Lys-Lys-Gly-Glu [MPF] in Krebs-Hensleitt buffer, given two weeks after the lesioning. The results were compared with those from control samples taken from rats which had been similarly lesioned and kept for 15-17 months, but which had received only Krebs-Hensleitt buffer, and with samples taken from two age matched, non-lesioned rats. Compared with the age matched, non-lesioned rats, there was a 37% overall loss of and extensive damage to all surviving SN neurons in samples from control rats [lesioned, buffer only]. There was widespread collapse of mitochondria [63% in the case of dopaminergic neurons], loss of cell membranes [in 4.4% of cases], myelin abnormalities [9.0%] and increased vacuolation [10.9%]. In contrast, most of the SN neurons from MPF-treated rats were healthy reflected in a high degree of cellular organization and integration; only 9.0% of the mitochondria were collapsed, and the cell membranes damage [2.9%] myelin abnormalities [1.5%], and the increased vacuolation [2.6%] were significantly less than found in the control rats. We have previously reported a significant reduction in the amphetamine-induced turning behaviour of lesioned rats following injection of the MPF analogue, beginning 6 weeks after the MPF injection, and reaching marked and consistent levels after 12 weeks. This time course, in conjunction with the present results and known neurotrophic properties of MPF, suggest that the favourable behavioural effects of MPF arise by restoration of nigrostriatal pathways