Mechanisms of Neuronal Protection against Excitotoxicity, Endoplasmic Reticulum Stress, and Mitochondrial Dysfunction in Stroke and Neurodegenerative Diseases

Abstract

In stroke and neurodegenerative disease, neuronal excitotoxicity, caused by increased extracellular glutamate levels, is known to result in calcium overload and mitochondrial dysfunction. Mitochondrial deficits may involve a deficiency in energy supply as well as generation of high levels of oxidants which are key contributors to neuronal cell death through necrotic and apoptotic mechanisms. Excessive glutamate receptor stimulation also results in increased nitric oxide generation which can be detrimental to cells as nitric oxide interacts with superoxide to form the toxic molecule peroxynitrite. High level oxidant production elicits neuronal apoptosis through the actions of proapoptotic Bcl-2 family members resulting in mitochondrial permeability transition pore opening. In addition to apoptotic responses to severe stress, accumulation of misfolded proteins and high levels of oxidants can elicit endoplasmic reticulum (ER) stress pathways which may also contribute to induction of apoptosis. Two categories of therapeutics are discussed that impact major pro-death events that include induction of oxidants, calcium overload, and ER stress. The first category of therapeutic agent includes the amino acid taurine which prevents calcium overload and is also capable of preventing ER stress by inhibiting specific ER stress pathways. The second category involves N-methyl-D-aspartate receptor (NMDA receptor) partial antagonists illustrated by S-Methyl-N, N-diethyldithiocarbamate sulfoxide (DETC-MeSO), and memantine. DETC-MeSO is protective through preventing excitotoxicity and calcium overload and by blocking specific ER stress pathways. Another NMDA receptor partial antagonist is memantine which prevents excessive glutamate excitation but also remarkably allows maintenance of physiological neurotransmission. Targeting of these major sites of neuronal damage using pharmacological agents is discussed in terms of potential therapeutic approaches for neurological disorders.

Edaravone improves spatial memory and modulates endoplasmic reticulum stress-mediated apoptosis after abdominal surgery in mice

“…Emerging evidence suggests that neuronal cell apoptosis induced by ERS is a predominant pathological issue in several neurological disorders (25,26). ERS-driven apoptosis is accompanied by the increased expression of ERS indicators, such as CHOP and GRP78 (27).…”

Neurophysiological Repercussions of Anabolic Steroid Abuse: A Road into Neurodegenerative Disorders

“…Physiologically, activation of these receptors triggers calcium influx and plasma membrane depolarization and exerts a pivotal role in the neurotransmission and LTP process. However, overactivation of NMDA and AMPA receptors results in calcium overload, mitochondrial dysfunction, redox imbalance, and recruitment of pro-apoptotic pathways [98]. Excitotoxicity is thought to develop a prominent role in the cellular damage and tissue injury during the progression of neurodegenerative diseases, as well as major depression-associated loss of neuronal viability and decline on cognitive capacity [98].…”

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“…Stroke or ischemia leads to an increase in the extracellular concentrations of excitatory amino acids, mainly in glutamate [4,5]. This increase in glutamate could be allied to increasing release from neurons, resulting from energy failure, or to reducing clearance of glutamate by glial transporters.…”