Birth, Life and Death of Dopaminergic Neurons in the Substantia Nigra (eBook)

Preface 6
Contents 7
Birth of Dopaminergic Neurons 10
Ontogeny of Substantia Nigra Dopamine Neurons 11
SNc Dopaminergic Neurons 27
Phenotype, Compartmental Organization and Differential Vulnerability of Nigral Dopaminergic Neurons 28
Specific Vulnerability of Substantia Nigra Compacta Neurons 45
The Nigrostriatal Pathway: Axonal Collateralization and Compartmental Specificity 54
The Localization of Inhibitory Neurotransmitter Receptors on Dopaminergic Neurons of the Human Substantia Nigra 64
Basal Ganglia Control of Substantia Nigra Dopaminergic Neurons 76
Substantia Nigra Control of Basal Ganglia Nuclei 96
Electrophysiological Characteristics of Dopamine Neurons: A 35- Year Update 107
Chaotic Versus Stochastic Dynamics: A Critical Look at the Evidence for Nonlinear Sequence Dependent Structure in Dopamine Neurons 124
Age-Dependent Changes in Dopaminergic Neuron Firing Patterns in Substantia Nigra Pars Compacta 132
The Neurobiology of the Substantia Nigra Pars Compacta: from Motor to Sleep Regulation 137
Non-motor Function of the Midbrain Dopaminergic Neurons 148
The Substantia Nigra, the Basal Ganglia, Dopamine and Temporal Processing 162
Electrophysiological and Neurochemical Characterization of 7- Nitroindazole and Molsidomine Acute and Sub- Chronic Administration Effects in the Dopaminergic Nigrostrial System in Rats 173
Death of SNc Dopaminergic Neurons 183
Involvement of Astroglial Fibroblast Growth Factor-2 and Microglia in the Nigral 6- OHDA Parkinsonism and a Possible Role of Glucocorticoid Hormone on the Glial Mediated Local Trophism and Wound Repair 184
Age and Parkinson’s Disease-Related Neuronal Death in the Substantia Nigra Pars Compacta 202
Neurodegeneration in Parkinson’s Disease: Genetics Enlightens Physiopathology 213
In Vivo Microdialysis in Parkinson’s Research 220
Inflammatory Response in Parkinsonism 241
Increase of Secondary Processes of Microglial and Astroglial Cells After MPTP-Induced Degeneration in Substantia Nigra Pars Compacta of Non Human Primates 249
Distinct Effects of Intranigral L-DOPA Infusion in the MPTP Rat Model of Parkinson’s Disease 255
Cannabinoid CB1 Receptors are Early DownRegulated Followed by a Further UpRegulation in the Basal Ganglia of Mice with Deletion of Specific Park Genes 265
Saving the SNc Dopaminergic Neurons 272
Neurogenesis in Substantia Nigra of Parkinsonian Brains? 273
Stem Cells and Cell Replacement Therapy for Parkinson’s Disease 280
Gene Therapy for Parkinson’s Disease 293
Immunization as Treatment for Parkinson’s Disease 302
A Diet for Dopaminergic Neurons? 307
Intake of Tomato-Enriched Diet Protects from 6- Hydroxydopamine- Induced Degeneration of Rat Nigral Dopaminergic Neurons 322
Subject Index 351

Chapter 15 Involvement of Astroglial Fibroblast Growth Factor-2 and Microglia in the Nigral 6-OHDA Parkinsonism and a Possible Role of Glucocorticoid Hormone on the Glial Mediated Local Trophism and Wound Repair (p. 185)

Camila Silva, Kjell Fuxe, and Gerson Chadi

Abstract We have observed in previous studies that 6- hydroxydopamine (6-OHDA)-induced lesions in the nigrostriatal dopamine (DA) system promote increases of the astroglial basic fibroblast growth factor (FGF-2, bFGF) synthesis in the ascending DA pathways, event that could be modified by adrenosteroid hormones. Here, we first evaluated the changes of microglial reactivity in relation to the FGF-2-mediated trophic responses in the lesioned nigrostriatal DA system. 6-OHDA was injected into the left side of the rat substantia nigra. The OX42 immunohistochemistry combined with stereology showed the time course of the microglial activation. The OX42 immunoreactivity (IR) was already increased in the pars compacta of the substantia nigra (SNc) and ventral tegmental area (VTA) 2 h after the 6-OHDA injection, peaked on day 7, and remained increased on the 14th day time-interval. In the neostriatum, OX42 immunoreactive (ir) microglial profiles increased at 24 h, peaked at 72 h, was still increased at 7 days but not 14 days after the 6-OHDA injection. Two-colour immunofluorescence analysis of the tyrosine hydroxylase (TH) and OX42 IRs revealed the presence of small patches of TH IR within the activated microglia. A decreased FGF-2 IR was seen in the cytoplasm of DA neurons of the SNc and VTA as soon as 2 h after 6-OHDA injection. The majority of the DA FGF-2 ir cells of these regions had disappeared 72 h after neurotoxin. The astroglial FGF-2 IR increased in the SNc and VTA, which peaked on day 7. Two-colour immunofluorescence and immunoperoxidase analyses of the FGF-2 and OX42 IRs revealed no FGF-2 IR within the reactive or resting microglia. Second, we have evaluated in a series of biochemical experiments whether adrenocortical manipulation can interfere with the nigral lesion and the state of local astroglial reaction, looking at the TH and GFAP levels respectively. Rats were adrenalectomized (ADX) and received a nigral 6-OHDA stereotaxical injection 2 days later and sacrificed up to 3 weeks after the DA lesion.

Western blot analysis showed time-dependent decrease and elevation of TH and GFAP levels, respectively, in the lesioned versus contralateral midbrain sides, events potentiated by ADX and worsened by corticosterone replacement. ADX decreased the levels of FGF-2 protein (23 kDa isoform) in the lesioned side of the ventral midbrain compared contralaterally. The results indicate that reactive astroglia, but not reactive microglia, showed an increased FGF-2 IR in the process of DA cell degeneration induced by 6-OHDA. However, interactions between these glial cells may be relevant to the mechanisms which trigger the increased astroglial FGF-2 synthesis and thus may be related to the trophic state of DA neurons and the repair processes following DA lesion. The findings also gave further evidence that adrenocortical hormones may regulate astroglial-mediated trophic mechanisms and wound repair events in the lesioned DA system that may be relevant to the progression of Parkinson´s disease.

Keywords Parkinson • Astrocyte • Microglia • Dopamine • Fibroblast growth factor-2 • Wound repair • Neuroregeneration