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      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

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          Abstract

          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.

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          Deep brain stimulation for Parkinson's disease.

          Deep brain stimulation at high frequency was first used in 1997 to replace thalamotomy in treating the characteristic tremor of Parkinson's disease, and has subsequently been applied to the pallidum and the subthalamic nucleus. The subthalamic nucleus is a key node in the functional control of motor activity in the basal ganglia. Its inhibition suppresses symptoms in animal models of Parkinson's disease, and high frequency chronic stimulation does the same in human patients. Acute and long-term results after deep brain stimulation show a dramatic and stable improvement of a patient's clinical condition, which mimics the effects of levodopa treatment. The mechanism of action may involve a functional disruption of the abnormal neural messages associated with the disease. Long-term changes, neural plasticity and neural protection might be induced in the network. Similar effects of stimulation and lesioning have led to the extension of this technique for other targets and diseases.
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            Pathogenesis of nigral cell death in Parkinson's disease.

            Parkinson's disease (PD) is primarily a sporadic condition which results mainly from the death of dopaminergic neurons in the substantia nigra. Its etiology remains enigmatic while its pathogenesis begins to be understood as a multifactorial cascade of deleterious factors. As of yet, most insights into PD pathogenesis are derived from toxic models of PD and show that the earlier cellular perturbations arising in dopaminergic neurons include oxidative stress and energy crisis. These alterations, rather than killing neurons, trigger subsequent death-related molecular pathways including elements of apoptosis. The fate of dopaminergic neurons in PD may also be influenced by additional factors such as excitotoxicity, emanating from the increased glutamatergic input from the subthalamic nucleus to the substantia nigra, and the glial response that arises in the striatum and the substantia nigra. In rare instances, PD can be familial, and those genetic forms have also provided clues to the pathogenesis of nigrostriatal dopaminergic neuron death including abnormalities in the mechanisms of protein folding and degradation as well as mitochondrial function. Although more remains to be elucidated about the pathogenic cascade in PD, the compilation of all of the aforementioned alterations starts to shed light on why and how nigral dopaminergic neurons may degenerate in this prominent disease, that is PD.
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              Subthalamic nucleus lesions are neuroprotective against terminal 6-OHDA-induced striatal lesions and restore postural balancing reactions.

              Inactivation of the subthalamic nucleus (STN) by deep brain stimulation or lesioning can ameliorate symptoms in Parkinson' disease (PD) and may alter the underlying progressive degenerative process. We evaluated the effects of STN lesions in a terminal lesion model of PD in rats. Multiple intrastriatal 6-OHDA injections (4 x 7 microg) resulted in a partial loss of striatal TH-positive innervation (-30 to -40%) and nigral dopaminergic neurons (-60%), which was associated with behavioral deficits as observed in drug-induced rotational asymmetry, side-stepping, and postural balancing reactions. Unilateral ibotenic acid lesions of the STN did produce a 50-60% loss of STN neurons based on stereological analysis, which did not induce a functional impairment in rotational asymmetry or spontaneous sensorimotor behaviors. When STN lesions were performed 1 week prior to the 6-OHDA terminal striatal lesions, a significant rescue effect (+23%) on nigral dopaminergic neurons against terminal 6-OHDA neurotoxicity could be demonstrated, whereas striatal TH-positive fiber loss was not attenuated in these animals. In addition, animals with combined STN and striatal lesions exhibited a significant recovery in postural balancing reactions induced by 6-OHDA terminal lesions and did not show a significant impairment in any of the other behavioral parameters examined. Taken together, STN lesions can exert neuroprotective effects on nigral dopamine neurons in a partial lesion model of PD which result in recovery of spontaneous sensorimotor behavior. These findings may therefore provide new insights into the functional interaction between the glutamatergic and the dopaminergic neurotransmitter systems and foster novel therapeutic concepts for the early and middle phases of Parkinson's disease. Copyright 2001 Academic Press.
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                Author and article information

                Contributors
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                Journal
                bjmbr
                Brazilian Journal of Medical and Biological Research
                Braz J Med Biol Res
                Associação Brasileira de Divulgação Científica (Ribeirão Preto )
                1414-431X
                January 2010
                : 43
                : 1
                : 85-95
                Affiliations
                [1 ] Universidade Federal do Paraná Brazil
                [2 ] Universidade de São Paulo Brazil
                [3 ] Pontifícia Universidade Católica do Rio Grande do Sul Brazil
                [4 ] Universidade Federal do Rio Grande do Sul Brazil
                [5 ] Universidade Federal do Paraná Brazil
                Article
                S0100-879X2010000100012

                http://creativecommons.org/licenses/by/4.0/

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                Categories
                BIOLOGY
                MEDICINE, RESEARCH & EXPERIMENTAL

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