Reactive Astrocytes as Potential Manipulation Targets in Novel Cell Replacement Therapy of Parkinsons Disease

Abstract

Parkinson' disease (PD) is a most common and debilitating degenerative disease resulted from massive loss of dopamine neurons in the substantia nigra pars compacta, which is characterized by severe motor symptoms of tremor, bradykinesia, rigidity and postural instability. Protection of nigral dopamine neurons from progressive degenerative death and cell replacement of novel dopamine neurons are hopeful strategies against PD in humans. The reactive astrocytes or functional activation of astrocytes abundantly occurred in brain insults including trauma, ischemia, and 6-OHDA or MPTP-treated PD animal models. Although they were traditionally assumed to impede neuronal regeneration by forming glial scars, growing evidence has indicated that reactive astrocytes do offer crucial benefits in functional recovery of brain injuries. The reactive astrocytes can produce various neurotrophic factors for neuron survival, synthesize extracellular substrates for axonal outgrowth and synaptogenesis, act as scavengers for free radical and excess glutamate, and promote neurogenesis of neural progenitor cells in the adult brains. We thereafter hypothesize that reactive astrocytes may also play important roles in the protection of nigral dopamine neurons or transplanted dopamine cells through their neurotrophic functions and active interaction with dopamine neurons or neural progenitor cells. Future approaches deserve to target on neurotrophic functions of reactive astrocytes in the basal ganglia and interventions to facilitate survival and axonal regeneration of dopamine neurons or differentiation of dopamine progenitor cells. Novel pharmaceutical and cell replacement strategies will hopefully be developed by potential manipulation of reactive astrocytes in the basal ganglia in prevention and treatment of Parkinson's disease.

Driving GDNF expression: The green and the red traffic lights

“…Activated astrocytes up-regulate antioxidant molecules, membrane transporters, and trophic factors that support neuronal and glial survival, and tissue repair (reviewed by Liberto et al, 2004). Recent reports suggest that astrocytes can be important targets for the development of neuroprotective drugs (Chen et al, 2005b;Darlington, 2005). Supporting this view, most of the works reviewed here about the regulation of GDNF expression were performed in astrocyte or glial cell line cultures and fewer studies used mesencephalic (Guo et al, , 2002Nitta et al, 2004) or hippocampal neuronal cultures (Lenhard et al, 2002;Nitta et al, 2004;Cen et al, 2006).…”

Astrocytes protect glioma cells from chemotherapy and upregulate survival genes via gap junctional communication

“…Under physiological conditions, astrocytes function as housekeeping cells and maintain homeostasis in the brain microenvironment (14)(15)(16)(17). In pathological conditions, astrocytes become activated, via the upregulation of glial fibrillary acid protein (GFAP), and have been demonstrated to be capable of protecting neurons from various injuries, including trauma and ischemic insult (18)(19)(20)(21). GJC, the molecular channel allowing the transmission of critical survival-associated secondary messengers, has been shown to be one of the mechanisms underlying this process (22,23).…”

The impact of age and gender on the striatal astrocytes activation in murine model of Parkinson’s disease

“…The degeneration of DA-ergic neurons is coupled with the inflammatory responses in nigro-striatal system involving astrocytes activation [2,3]. The astrogliosis is one of the components of neurodegenerative processes in nigro-striatal system, which may be implicated in both progression and/or suppression of these processes [4][5][6].…”