A further update on the role of excitotoxicity in the pathogenesis of Parkinson’s disease

Abstract

Increased levels of extracellular glutamate and hyperactivation of glutamatergic receptors in the basal ganglia trigger a critical cascade of events involving both intracellular pathways and cell-to-cell interactions that affect cell viability and promote neuronal death. The ensemble of these glutamate-triggered events is responsible for excitotoxicity, a phenomenon involved in several pathological conditions affecting the central nervous system, including a neurodegenerative disease such as Parkinson's disease (PD). PD is an age-related disorder caused by the degeneration of dopaminergic neurons within the substantia nigra pars compacta, with a miscellaneous pathogenic background. Glutamate-mediated excitotoxicity may be involved in a lethal vicious cycle, which critically contributes to the exacerbation of nigrostriatal degeneration in PD. Since excitotoxicity is a glutamate-receptor-mediated phenomenon, growing interest and work have been dedicated to the research for modulators of glutamate neurotransmission that might enable new therapeutic interventions to slow down the neurodegenerative process and ameliorate PD motor symptoms.

Role for VGLUT2 in selective vulnerability of midbrain dopamine neurons

“…Increased release of glutamate is associated with excitotoxicity, and some evidence indicates that DA neurons are particularly sensitive to excitotoxic stress (31). Thus, the selective vulnerability of DA neurons to VGLUT2 expression could be linked to the release of glutamate from DA release sites, resulting in excess activation of presynaptic glutamate receptors.…”

GLT-1 transporter: An effective pharmacological target for various neurological disorders

“…In PD, the degeneration of dopaminergic neurons is believed to lead to an overactivation of the subthalamic nucleus (Rodriguez et al, 1998). This increases the firing rate of the glutamatergic excitatory projections to the substantia nigra (Bamford et al, 2004;Ambrosi et al, 2014). This sustained exposure to glutamate could accelerate the degeneration of dopaminergic neurons by intense stimulation of Nmethyl-D-aspartate (NMDA) and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors (Oster et al, 2014).…”

Destination Brain: the Past, Present, and Future of Therapeutic Gene Delivery

“…Similar to microglia, astrocytes secrete neuromodulatory molecules, which can be either protective or damaging depending on the stage of injury, making astrogliosis a ‘double-edged’ sword (Buffo et al, 2010). Other astrocyte intracellular processes that contribute to NDD pathologies include oxidative and mitochondrial stress (Manfredi and Xu, 2005), reduced excitatory amino acid transporter (EAAT)2 levels that lead to excitotoxicity (Ambrosi et al, 2014), calcium dysregulation (Alberdi et al, 2013) and attenuated neurotrophin secretion (Giralt et al, 2010). …”

“…Additionally, altered BBB permeability can increase neuroinflammation and contribute to disease. These mechanisms precede or succeed neurodegeneration and overlap in diseases such as Alzheimer’s disease (AD) [A1(Uylings and De Brabander, 2002), A2 (Wake et al, 2013), A3 (Wyss-Coray and Rogers, 2012), A4 (Alberdi et al, 2013), A5 (Fuller et al, 2009), A6 (Allen and Barres, 2009)], Amyotrophic lateral sclerosis (ALS) [B1 (Evans et al, 2013), B2 (Manfredi and Xu, 2005), B3 (Grosskreutz et al, 2010)], HIV-associated neurocognitive disorders (HAND) [C1 (Lu et al, 2011), C2 (Cisneros and Ghorpade, 2012), C3 (Persidsky et al, 2000), C4 (Steiner et al, 2006), C5 (Vartak-Sharma et al, 2014)], Huntington’s disease (HD) [D1 (Wang et al, 2013), D2 (Giralt et al., 2010), D3 (Fan and Raymond, 2007)], Multiple Sclerosis (MS) [E1 (Franklin and Kotter, 2008), E2 (Popescu and Lucchinetti, 2012)], Parkinson’s disease (PD) [F1 (Van Spronsen and Hoogenraad, 2010), F2 (Hu et al, 2008), F3 (Zinger et al, 2011), F4 (Niranjan, 2014), F5 (Drinkut et al, 2012), F6 (Ambrosi et al, 2014)], and stroke [G1 (Ceulemans et al, 2010), G2 (Xia et al, 2004), G3 (Lai et al, 2014)].…”