Excitotoxicity as a Target Against Neurodegenerative Processes

Abstract

: The global burden of neurodegenerative diseases is alarmingly increasing in parallel to the aging of population. Although the molecular mechanisms leading to neurodegeneration are not completely understood, excitotoxicity, defined as the injury and death of neurons due to excessive or prolonged exposure to excitatory amino acids, has been shown to play a pivotal role. The increased release and/or decreased uptake of glutamate results in dysregulation of neuronal calcium homeostasis, leading to oxidative stress, mitochondrial dysfunctions, disturbances in protein turn-over and neuroinflammation. : Despite the anti-excitotoxic drug memantine has shown modest beneficial effects in some patients with dementia, to date, there is no effective treatment capable of halting or curing neurodegenerative diseases such as Alzheimer’s disease, Parkinson disease, Huntington’s disease or amyotrophic lateral sclerosis. This has led to a growing body of research focusing on understanding the mechanisms associated with the excitotoxic insult and on uncovering potential therapeutic strategies targeting these mechanisms. : In the present review, we examine the molecular mechanisms related to excitotoxic cell death. Moreover, we provide a comprehensive and updated state of the art of preclinical and clinical investigations targeting excitotoxic- related mechanisms in order to provide an effective treatment against neurodegeneration.

Neuroprotective Function of High Glycolytic Activity in Astrocytes: Common Roles in Stroke and Neurodegenerative Diseases

“…The excessive release of glutamate triggers neuronal injury, i.e., excitatory cell death, and this mechanism has been implicated as a main component in the pathogenesis underlying ischemic neuronal cell death, as well as neurodegenerative diseases such as ALS [ 58 , 59 ]. In addition to glutamate toxicity, the hyperexcitation of motor neurons per se induces oxidative stress leading to mitochondrial dysfunction and eventual cell death [ 58 , 59 ]. To prevent glutamate-induced excitotoxicity, glutamate must be taken up by astroglial endfeet that envelope the synapse immediately after its release into the synaptic cleft.…”

“…The degeneration of dopaminergic neurons in the substantia nigra and the resultant deficiency in dopamine release in striata causes Parkinson’s disease. The precise mechanism by which dopaminergic neurons degenerate, especially in idiopathic Parkinson’s disease without any apparent mutation in mitochondrial metabolism, remains to be solved [ 44 , 59 , 62 ]. One of the hypothetical mechanisms is oxidative stress induced by the continuous activity of dopaminergic neurons.…”

“…One of the hypothetical mechanisms is oxidative stress induced by the continuous activity of dopaminergic neurons. In fact, dopaminergic neurons in the substantia nigra exhibit a pace-making activity at 2–4 Hz to maintain the dopamine concentration in the striata at a certain level ( Figure 3 ) [ 44 , 59 , 62 , 63 , 64 ]. This activity, in turn, causes oxidative stress in the mitochondria of dopaminergic neurons.…”

Synaptopathy Mechanisms in ALS Caused by C9orf72 Repeat Expansion

“…The actin dynamics in neurons regulate extension and direction of axon growth, whereas in the dendritic spines, it (Matsuo et al, 1994;Castellani, 2020) Yes (Terry et al, 1991;Kril et al, 2002;Selkoe, 2002;Coleman et al, 2004) Yes (Swerdlow, 2018;Wang et al, 2020b) Yes (Hynd et al, 2004;Binvignat and Olloquequi, 2020) Yes (Oddo, 2008;Gong et al, 2016) Yes (Fernandez-Perez et al, 2020;George et al, 2020) Yes (DeKosky and Games et al, 1995;Mucke et al, 2000;Scheff and Price, 2003;Coleman et al, 2004;Bjorklund et al, 2012) Parkinson's disease Alpha synuclein Lewy body (Spillantini et al, 1997) Yes (Janezic et al, 2013) Yes (Reinhardt et al, 2013;Pickrell and Youle, 2015) Yes…”

Brain Insulin Resistance: Focus on Insulin Receptor-Mitochondria Interactions

“…It has already been shown that glutamate excitotoxicity is implicated in the pathogenesis of TBI [133] and AD [134]. However, the existence of the causal relationship between excitotoxicity and brain insulin resistance indicates that list of disorders associated with brain insulin resistance is much broader and may include stroke [135], PD [136], HD, amyotrophic lateral sclerosis [137], depression, autism spectrum disorder, schizophrenia [138], and multiple sclerosis [139], for which glutamate excitotoxicity has already been demonstrated as a pathogenic factor.…”