Prenatal and Postnatal Exposures to 1-Methyl-4-phenyl-1,2,3,6-tetra Hydropyridine (MPTP) Impaired Mouse Midbrain Dopamine System and May Produce a Predisposing and Inducing Model for Parkinson’s Disease
نویسندگان
چکیده
Dopamine cell bodies in the substantia nigra of the midbrain and with their terminals projecting to the neostriatum form the nigrostriatum and these dopamine neurons degenerate in Parkinson’s disease (PD). Based on metabolic and functional specialization of the cell bodies versus the axon terminals, the level and disposition of dopamine, its metabolites and enzymes are different in both regions and are likely to be affected differently in PD. We examined changes in the midbrain dopamine system following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), to test the hypothesis that a predisposing/sensitization stage and a inducing/precipitating stage underlie PD. Pregnant mice were treated with a low dose of MPTP during gestation days 8 12 to model the predisposing/sensitization stage, by interrupting the fetal midbrain dopamine system during its neurogenesis. For the inducing/precipitating stage, the 12-week offspring were administered MPTP. The prenatal-MPTP offspring appear normal, but midbrain dopamine, 3,4-di-hydroxy-phenyl-aceticacid, 3-methoxytyramine, tyrosine-hydroxylase and L-aromatic-amino-acid-decarboxylase, were reduced by 49.6%, 48%, 54%, 20.9% and 25%. Postnatal-MPTP of 10, 20, 30 mg/kg administered to the prenatal-PBS vs prenatal-MPTP offspring reduced midbrain dopamine by 43.6%, 47.2%, 70.3% vs 85.4%, 89.1%, 95.2%; tyrosine-hydroxylase by 30%, 63%, 81% vs 30.7%, 70.4%, 91.4%; L-aromatic-amino-acid-decarboxylase by 0%, 2%, 40% vs 32%, 40%, 58%. The prenatal-MPTP may render the DA system sensitive by causing sub-threshold reduction of DA, its metabolites and enzymes, enabling postnatal-MPTP to reduce dopamine above the 70% 80% PD-inducing threshold. Thus, the study may produce a prenatal predisposing/sensitization and postnatal inducing/precipitation model of PD. It also indicates that some cases of PD may have a fetal basis, in which sub-threshold nigrostriatal impairments occur early in life and PD-symptoms are induced during aging by further insults to the dopaminergic system that would not cause PD symptoms in normal individuals.
منابع مشابه
The effects of aqueous cinnamon bark extract and cinnamaldehyde on neurons of substantia nigra and behavioral impairment in a mouse model of Parkinson’s disease
Background and Objective: Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons in substantia nigra. In recent years, there have been interests in the role of the free radical damage in PD. Cinnamon and its derivative, cinnamaldehyde acts as powerful antioxidant and anti-inflammatory agents. This research focused on the effects of cinnamon extract and cinnamald...
متن کاملCinnamaldehyde attenuates dopaminergic neuronal loss in substantia nigra and induces midbrain catalase activity in a mouse model of Parkinson’s disease
Background and Objective: Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease that affects 3% of the population. PD involves a progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) and subsequent loss of dopamine. Dopamine depletion leads to movement dysfunction and is accompanied with tremor, rigid muscle...
متن کاملTat-Fused Recombinant Human SAG Prevents Dopaminergic Neurodegeneration in a MPTP-Induced Parkinson’s Disease Model
Excessive reactive oxygen species (ROS) generated from abnormal cellular process lead to various human diseases such as inflammation, ischemia, and Parkinson's disease (PD). Sensitive to apoptosis gene (SAG), a RING-FINGER protein, has anti-apoptotic activity and anti-oxidant activity. In this study, we investigate whether Tat-SAG, fused with a Tat domain, could protect SH-SY5Y neuroblastoma ce...
متن کاملLobeline shows protective effects against MPTP-induced dopaminergic neuron death and attenuates behavior deficits in animals
We previously demonstrated that lobeline effectively inhibited dopamine transporter (DAT)-mediated dopamine (DA) transportation. Therefore, the present study aimed to investigate whether lobeline shows protective effects against neurotoxin-induced cell death in vivo. Mice were administered 30 mg/kg 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP) and treated with 80 mg/kg L-dopa, 10 mg/kg G...
متن کاملMicroglia-Mediated Neuroinflammation and Neurotrophic Factor-Induced Protection in the MPTP Mouse Model of Parkinson’s Disease-Lessons from Transgenic Mice
Parkinson's disease (PD) is a neurodegenerative disease characterised by histopathological and biochemical manifestations such as loss of midbrain dopaminergic (DA) neurons and decrease in dopamine levels accompanied by a concomitant neuroinflammatory response in the affected brain regions. Over the past decades, the use of toxin-based animal models has been crucial to elucidate disease pathoph...
متن کامل