| Dopaminergic (DA) neurons in the mammalian brain regulate many important neural functions, including motor integration, neuroendocrine hormone release, cognition, emotive behaviors and reward. The disorder of DA neurons could induce several disease, for example Parkinson's disease(PD), schizophrenia, drug abuse, and so on. So a number of laboratories have contributed to unravel the process of DA phenotype induction, maturation, aging and death, elucidate the mechanisms of DA- associated neurological diseases and search for the method of potential treatment.In the development process of mammals, the key genes involved in the phenotype and function of DA neurons express in a strict time- and space- order. The activation of these genes involved in DA neurotransmission takes place at different time in development under the control of various environmental cues. During late development in embryonic period, the synthesis and secretion of DA is the prime mover to promote maturation of DA neurons. Meanwhile, it is essential that autocrine, paracrine, glial-mediated and target-derived trophic factorsare required to achieve maturation and survival/maintenance of postmitotic DA neurons.Parkinson's disease is one of the most common neurodegenerative disorder. It is characterized clinically by parkinsonism (resting tremor, bradykinesia, rigidity, and postural instability) and pathologically by the loss of DA neurons in the substantia nigra. Although the cause of the disease is still unknown, recent studies have provided evidence that sensitive genes associated PD and environmental toxin may play an important role in the pathogenesis of PD. Levodopa therapy has markedly improved the symptom of patients with PD, however, the long term use of levodopa could induce adverse reactions including the wearing-off phenomenon, on-off phenomenon, dyskinesia and psychiatric adverse effects. Furthermore, several lines of evidence suggest that dopamine derived from exogenous levodoa and related catechols may increase oxidative stress, thereby contributing to the pathogenesis of PD. Therefore, new therapeutic strategies have advocated the use of putative neuroprotective agents.Unless levodopa's neurotoxin, more and more evidences support that DA receptor agonist may have neuroprotective effects via direct scavenging of free radicals or increase the activities of radical-scavenging enzymes, and enhancing neurotrophic activity. There have been several evidence indicating that neurotrophic factors, such as GDNF and BDNF, influence growth of developing and adult nigral DA neurons. These dopaminotrophic factors and their role in the pathogenesis and potential treatment of DA- associated neurological diseases, have been extensively researched in recent years. Data in vitro and in vivo suggests that GDNF and BDNF could be a useful therapy for PD and other neurodegenerative disorders, but these neurotrophic factors can't penetrate BBB(barrier), which limits the usage of neurotrophic factors in clinic.The present study discussed that the new D3 receptor agonists, pramipexole and ropinirole, mediate neurotrophic effects on DA neurons in fetal rat ventral mesencephalic cultures.Result.1. Pramipexole and ropinirole increased the number of cultured mesencephalic DA neurons with up-regulation of mRNA and protein levels of TH (tyrosine hydroxylaso).2. This promoting effect of pramipexole and ropinirole could be transferable via conditioned medium.3. This promoting effect of pramipexole and ropinirole could not be blocked by selective D2 antagonist, while could partly be counteracted by selective D3 antagonist.4. The conditioned medium derived from substantia nigra have the similar support effect.5. Pramipexole and ropinirole can exert neuroprotective effects against MPP+ and rotenohe- induced cytotoxicity.6. The conditioned medium have the similar neuroprotective effects.7. Selective D2 and D3 antagonist can not block the neuroprotective effects of pram... |
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