Neurogenesis in substantia nigra of parkinsonian brains?

Experimental Neurology, Philipps University, D-35033 Marburg, Germany.
Journal of Neural Transmission (Impact Factor: 2.87). 01/2009; DOI: 10.1007/978-3-211-92660-4_23
Source: PubMed

ABSTRACT The clinical motor dysfunction in Parkinson's disease is primarily the consequence of a progressive degeneration of dopaminergic neurons in the substantia nigra of the nigrostriatal pathway. The degeneration of this tract provokes a depletion of dopamine in the striatum, where it is required as a permissive factor for normal motor function. Despite intense investigations, no effective therapy is available to prevent the onset or to halt the progression of the neuronal cell loss. Therefore, recent years have seen research into the mechanisms of endogenous repair processes occurring in the adult brain, particularly in the substantia nigra. Neurogenesis occurs in the adult brain in a constitutive manner under physiological circumstances within two regions: the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. In contrast to these two so-called neurogenic areas, the remainder of the brain is considered to be primarily nonneurogenic in nature, implying that no new neurons are produced there under normal conditions. The occurrence of adult neurogenesis in the substantia nigra under the pathological conditions of Parkinson's disease, however, remains controversial. Here, we review the published evidence of whether adult neurogenesis exists or not within the substantia nigra, where dopaminergic neurons are lost in Parkinson's disease.

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Available from: Oscar Arias-Carrion, Aug 25, 2015
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    • "The clinical motor dysfunction in Parkinson's disease (PD) is primarily linked to the depletion of dopamine in the striatum consecutive to the loss of dopaminergic neurons in the substantia nigra (SNc). Even with the advent of powerful new tools such as genomics, proteomics, brain imaging, gene replacement therapy and knockout animal models, the desired end result of neuroprotection is still beyond our current capability [Arias-Carrió n et al. 2009]. An integrated approach towards understanding the pathogenesis of this disorder may help in discovering and developing new therapies capable of improving the disease in addition to controlling its clinical manifestations [Obeso et al. 2010; Arias-Carrió n et al. 2007]. "
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    ABSTRACT: Experimental models of Parkinson's disease (PD) are of great importance for improving the design of future clinical trials. Various neurotoxic models are available, including 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), paraquat and rotenone. However, no model is considered perfect; each has its own limitations. Based on epidemiological data, a new trend of using environmental toxins in PD modeling seems attractive and has dominated public discussions of the disease etiology. A search for new environmental toxin-based models would improve our knowledge of the pathology of the condition. Here, we discuss some toxins of natural origin (e.g. cycad-derived toxins, epoxomicin, Nocardia asteroides bacteria, Streptomyces venezuelae bacteria, annonacin and DOPAL) that possibly represent a contributory environmental component to PD.
    Therapeutic Advances in Neurological Disorders 11/2011; 4(6):361-73. DOI:10.1177/1756285611413004
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    • "Reorganization of cell migratory tracks would address the conundrum that endogenous neurogenesis is restricted to discrete brain areas, like the SVZ and SGZ, that are distinct from the brain areas where cells are lost in AD, PD, and HD. It is possible that future strategies targeting endogenous neurogenesis will facilitate migration of cells, for example, from the SVZ into the striatum to replace the medium spiny neurons lost in HD or supply DA in place of the DA terminals lost in PD (Cho et al. 2007; Arias-Carrion et al. 2009), or from the DG into the CA1 and cortex in AD. Indeed it has been shown that transplantation of exogenous NSPC in a rat model of PD triggers the expression of various trophic factors such as SDF-1α in endogenous NSPCs, leading to enhanced migration of endogenous NSPC to the graft site (Madhavan et al. 2009). "
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    ABSTRACT: With the growth of the aging population and increasing life expectancy, the diagnosis of age-related neurodegenerative diseases is predicted to increase 12% by 2030. There is urgent need to develop better and novel treatments for disorders like Alzheimer's, Huntington's, and Parkinson's diseases. As these neurodegenerative diseases are customarily defined by the progressive loss of neurons, treatment strategies have traditionally focused on replacing neurons lost during disease progression. To this end, the self-renewing and multipotent properties of neural stem/precursor cells (NSPCs) that exist in the adult brain suggest that NSPCs could contribute to a therapy for replacement of damaged or lost neurons. Although a wealth of research demonstrates the proof-of-concept that NSPC transplantation has therapeutic potential, there are considerable barriers between the theory of cell transplantation and clinical implementation. However, a new view on harnessing the power of NSPC for treatment of neurodegenerative disorders has emerged, and focuses on treating neuropathological aspects of the disease prior to the appearance of overt neuronal loss. For example, rather than merely replacing lost neurons, NSPCs are now being considered for their ability to provide trophic support. Here we review the evolution of how the field has considered application of NSPCs for treatment of neurodegeneration disorders. We discuss the challenges posed by the "traditional" view of neurodegeneration - overt cell loss - for utilization of NSPCs for treatment of these disorders. We also review the emergence of an alternative strategy that involves fine-tuning the neurogenic capacity of existing adult NSPCs so that they are engineered to address disease-specific pathologies at specific time points during the trajectory of disease. We conclude with our opinion that for this strategy to become a translational reality, it requires a thorough understanding of NSPCs, the dynamic process of adult neurogenesis, and a better understanding of the pathological trajectory of each neurodegenerative disease.
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    ABSTRACT: Dissertation Dopamine regulates movement, cognition and the rewarding effects of addictive drugs. Sex differences mediated by gonadal hormones affect each of these processes. An extensive literature suggests that estrogen augments dopaminergic function. Our laboratory found that female rats exhibit increased locomotor stimulation in response to cocaine and greater cocaine-induced dopamine overflow compared to males, sex differences that emerge in early adulthood. Currently, the underlying mechanisms for these differences are poorly understood. I hypothesized that female rats would have more dopamine neurons in midbrain regions and that ovarian hormones would exert trophic effects on dopamine neurons. Immunohistochemical and stereological techniques were used to quantitate the number of cells in the SNpc and VTA of male and female rats and mice to assess: (1) if sex differences in dopamine neuron number exist and when they emerge, (2) how gonadal hormones influence dopaminergic cell number and dopamine-mediated behaviors (3) the role of specific hormone receptors in the effects on cell number (4) the possibility that dopamine neuron number is directly linked to cocaine-stimulated behavior and electrically-stimulated dopamine release and that these responses to cocaine are mediated through gonadal hormone modulation of midbrain dopamine neuron number. I discovered sex differences in midbrain dopamine neuron number; adult female rodents have more neurons in the SNpc and VTA. We also found that gonadectomy in adulthood reduced midbrain dopamine neuron number in females and increased neuron number in males, establishing the trophic effects of estrogen in the intact midbrain and possible suppressive effects of androgens. Treatment with agonists for estrogen receptor subtypes alpha and beta and androgen receptor reversed the effects of gonadectomy on cell number in females and males, respectively. In an effort to bridge cocaine-stimulated behavior and cell number in sham ovariectomized and ovariectomized females, we discovered cocaine-stimulated behavior, dopamine release and SNpc cell density were positively correlated in intact female rats, an effect that is lost with ovariectomy. This dissertation demonstrates that estrogen is critical for the maintenance of dopaminergic cell populations that enhance behavioral responses to psychostimulants in females, thereby contributing to the observed sex differences.
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