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 m...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 func- tional 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 mid- brain dopamine system during its neurogenesis. For the inducing/precipitating stage, the 12-weeks offspring were ad- ministered MPTP. The prenatal-MPTP offspring appear normal, but midbrain dopamine, 3,4-di-hydroxy-phenyl-acetic- acid, 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 en- zymes, 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 indi-viduals.展开更多
Monoamine neurotransmitters play an important role in the modulation of sensory, motor and autonomic functions in the spinal cord. Although traditionally it is believed that in mammalian spinal cord, monoamine neurotr...Monoamine neurotransmitters play an important role in the modulation of sensory, motor and autonomic functions in the spinal cord. Although traditionally it is believed that in mammalian spinal cord, monoamine neurotransmitters mainly originate from the brain, accumulating evidence indicates that especially when the spinal cord is injured, they can also be produced in the spinal cord. In this review, I will present evidence for a possible pathway for two-step synthesis of dopamine and serotonin in the spinal cord. Published data from different sources and unpublished data from my own ongoing projects indicate that monoenzymatic cells expressing aromatic L-amino acid decarboxylase（AADC）, tyrosine hydroxylase（TH） or tryptophan hydroxylase（TPH） are present in the spinal cord and that these TH and THP cells often lie in close proximity to AADC cells. Prompted by the above evidence, I hypothesize that dopamine and serotonin could be synthesized sequentially in two monoenzymatic cells in the spinal cord via a TH-AADC and a TPH-AADC cascade respectively. The monoamines synthesized through this pathway may compensate for lost neurotransmitters following spinal cord injury and also may play specific roles in the recovery of sensory, motor and autonomic functions.展开更多
基金This work was supported by grants from the National Basic Research Priorities Programme (Brain Science G1999054008) and National Natural Science Foundation of China (No. 30240055).
文摘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 func- tional 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 mid- brain dopamine system during its neurogenesis. For the inducing/precipitating stage, the 12-weeks offspring were ad- ministered MPTP. The prenatal-MPTP offspring appear normal, but midbrain dopamine, 3,4-di-hydroxy-phenyl-acetic- acid, 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 en- zymes, 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 indi-viduals.
基金supported by the Crafoord Foundationthe Lundbeck Foundationthe Danish Medical Research Council
文摘Monoamine neurotransmitters play an important role in the modulation of sensory, motor and autonomic functions in the spinal cord. Although traditionally it is believed that in mammalian spinal cord, monoamine neurotransmitters mainly originate from the brain, accumulating evidence indicates that especially when the spinal cord is injured, they can also be produced in the spinal cord. In this review, I will present evidence for a possible pathway for two-step synthesis of dopamine and serotonin in the spinal cord. Published data from different sources and unpublished data from my own ongoing projects indicate that monoenzymatic cells expressing aromatic L-amino acid decarboxylase（AADC）, tyrosine hydroxylase（TH） or tryptophan hydroxylase（TPH） are present in the spinal cord and that these TH and THP cells often lie in close proximity to AADC cells. Prompted by the above evidence, I hypothesize that dopamine and serotonin could be synthesized sequentially in two monoenzymatic cells in the spinal cord via a TH-AADC and a TPH-AADC cascade respectively. The monoamines synthesized through this pathway may compensate for lost neurotransmitters following spinal cord injury and also may play specific roles in the recovery of sensory, motor and autonomic functions.
