Abstract
The progressive degeneration of the dopamine neurons of the pars compacta of substantia nigra and the consequent loss of the dopamine innervation of the striatum leads to the impairment of motor behavior in Parkinson’s disease. Accordingly, an efficient therapy of the disease should protect and regenerate the dopamine neurons of the substantia nigra and the dopamine innervation of the striatum. Nigral neurons express Brain Derived Neurotropic Factor (BDNF) and dopamine D3 receptors, both of which protect the dopamine neurons. The chronic activation of dopamine D3 receptors by their agonists, in addition, restores, in part, the dopamine innervation of the striatum. Here we explored whether the over-expression of BDNF by dopamine neurons potentiates the effect of the activation of D3 receptors restoring nigrostriatal innervation. Twelve-month old Wistar rats were unilaterally injected with 6-hydroxydopamine into the striatum. Five months later, rats were treated with the D3 agonist 7-hydroxy-N,N-di-n-propy1-2-aminotetralin (7-OH-DPAT) administered i.p. during 4½ months via osmotic pumps and the BDNF gene transfection into nigral cells using the neurotensin-polyplex nanovector (a non-viral transfection) that selectively transfect the dopamine neurons via the high-affinity neurotensin receptor expressed by these neurons. Two months after the withdrawal of 7-OH-DPAT when rats were aged (24 months old), immunohistochemistry assays were made. The over-expression of BDNF in rats receiving the D3 agonist normalized gait and motor coordination; in addition, it eliminated the muscle rigidity produced by the loss of dopamine. The recovery of motor behavior was associated with the recovery of the nigral neurons, the dopamine innervation of the striatum and of the number of dendritic spines of the striatal neurons. Thus, the over-expression of BDNF in dopamine neurons associated with the chronic activation of the D3 receptors appears to be a promising strategy for restoring dopamine neurons in Parkinson’s disease.
Highlights
Parkinsons disease is a progressive neurodegenerative disorder characterized clinically by bradykinesia, reduced motor coordination, muscle rigidity, and gait dysfunction, among other alterations of motor behavior
Levodopa continues to be the best treatment for the disease, because it eliminates most of the motor symptoms; it does not prevent the progressive loss of dopamine neurons and produces, after 4–5 years of treatment, dyskinesia
Our results show that the transfection of the BDNF gene to dopamine neurons associated with the chronic (4 1⁄2 months) and continuous administration of the dopamine D3 receptor agonist recovers normal gait, motor coordination and postural balance in the unilateral striatal rat model of Parkinsons disease
Summary
Parkinsons disease is a progressive neurodegenerative disorder characterized clinically by bradykinesia, reduced motor coordination, muscle rigidity, and gait dysfunction, among other alterations of motor behavior. The progressive neuronal degeneration results in severe motor, mental and functional disability. This suggests that a therapeutic strategy preventing neuronal death and promoting growth and regeneration would be a valuable approach to control the disease [3]. Nigral dopamine neurons degenerate in the absence of BDNF, suggesting its involvement in the pathogenesis of Parkinsons Disease [19,20]. The reduced expression of BDNF in nigral neurons in Parkinsons disease patients and in rats with lesions of the nigrostriatal innervation suggests its participation in the pathogenesis of the disease [19,21,22]. Its reduction in the disease is because of the loss of the dopamine neurons and because the remaining neurons express less BDNF [19]
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