There is an increasing amount of experimental evidence that oxidative stress is a causal, or at least an ancillary, factor in the neuropathology of several adult neurodegenerative disorders, as well as in stroke, trauma, and seizures. At the same time, excessive or persistent activation of glutamate-gated ion channels may cause neuronal degeneration in these same conditions. Glutamate and related acidic amino acids are thought to be the major excitatory neurotransmitters in brain and may be utilized by 40 percent of the synapses. Thus, two broad mechanisms--oxidative stress and excessive activation of glutamate receptors--are converging and represent sequential as well as interacting processes that provide a final common pathway for cell vulnerability in the brain. The broad distribution in brain of the processes regulating oxidative stress and mediating glutamatergic neurotransmission may explain the wide range of disorders in which both have been implicated. Yet differential expression of components of the processes in particular neuronal systems may account for selective neurodegeneration in certain disorders.

https://science.sciencemag.org/content/sci/262/5134/689.full.pdf

Oxidative stress, glutamate, and neurodegenerative disorders

This review is directed at understanding how neuronal death occurs in two distinct insults, global ischemia and focal ischemia. These are the two principal rodent models for human disease. Cell dea...

Ischemic Cell Death in Brain Neurons

Physiological actions of taurine

Dennis W. ChoiDepartment of Neurology, Stanford University, Stanford,California 94305Steven M. RothmanDepartments of Pediatrics, Neurology, and Anatomy and Neurobiology,Washington University, St. Louis, Missouri 63110The human brain depends on its blood supply for a continuous supply ofoxygen and glucose. Irreversible brain damage occurs if blood flow isreduced below about 10 ml/100 g tissue/min and if blood flow is completelyinterrupted, damage will occur in only a few minutes. Unfortunately, suchreductions (ischemia) are common in disease states: either localized individual vascular territories, as in stroke; or globally, as in cardiac arrest.Cerebral hypoxia can also occur in isolation, for example in respiratoryarrest, carbon monoxide poisoning, or near-drowning; pure glucose depri-vation can occur in insulin overdose or a variety of metabolic disorders.As a group, these disorders are a leading cause of neurological disabilityand death; stroke alone is the third most common cause of death in NorthAmerica.Despite its clinical importance, little is known about the cellular patho-genesis of hypoxic-ischemic brain damage, and at present there is noeffective therapy. A critical question has been why brain, more than mostother tissues, is so vulnerable to hypoxic-ischemic insults. In particular,certain neuronal subpopulations, such as hippocampal field CA1 andneocortical layers 3, 5, and 6, are characteristically destroyed after sub-maximal hypoxic-ischenfic exposure. A possible answer has emerged inthe last few years: At least some of this special vulnerability may beaccounted for by the central neurotoxicity of the endogenous excitatory1710147-006X/90/0301 ~:1171 $02.00www.annualreviews.org/aronline Annual Reviews

The role of glutamate neurotoxicity in hypoxic- ischemic neuronal death

Excitatory amino acid neurotoxicity and neurodegenerative disease

Brain ischemia was induced for 10 or 30 min by clamping the common carotid arteries in rabbits whose vertebral arteries had previously been electrocauterized. EEG and tissue content of high energy phosphates were used to verify the ischemic state and to evaluate the degree of postischemic recovery. Extracellular levels and total contents of amino acids were followed in the hippocampus during ischemia and 4 h of recirculation. At the end of a 30-min ischemic period, GABA had increased 250 times, glutamate 160 times, and aspartate and taurine 30 times in the extracellular phase. The levels returned to normal within 30 min of reflow. A delayed increase of extracellular phosphoethanolamine and ethanolamine peaked after 1–2 h of reflow. Ten minutes of ischemia elicited considerably smaller but similar effects. With respect to total amino acids in the hippocampus, glutamate and aspartate decreased to 30–50% of control while GABA appeared unaffected after 4 h of reflow. Alanine, valine, phenylalanine, leucine, a...

https://journals.sagepub.com/doi/pdf/10.1038/jcbfm.1985.56

Ischemia-Induced Shift of Inhibitory and Excitatory Amino Acids from Intra- to Extracellular Compartments

Extracellular (EC) adenosine, hypoxanthine, xanthine, and inosine concentrations were monitored in vivo in the striatum during steady state, 15 min of complete brain ischemia, and 4 h of reflow and compared with purine and nucleotide levels in the tissue. Ischemia was induced by three-vessel occlusion combined with hypotension (50 mm Hg) in male Sprague-Dawley rats. EC purines were sampled by microdialysis, and tissue adenine nucleotides and purine catabolites were extracted from the in situ frozen brain at the end of the experiment. ATP, ADP, and AMP were analyzed with enzymatic fluorometric techniques, and adenosine, hypoxanthine, xanthine, and inosine with a modified HPLC system. Ischemia depleted tissue ATP, whereas AMP, adenosine, hypoxanthine, and inosine accumulated. In parallel, adenosine, hypoxanthine, and inosine levels increased in the EC compartment. Adenosine reached an EC concentration of 40 microM after 15 min of ischemia. Levels of tissue nucleotides and purines normalized on reflow. However, xanthine levels increased transiently (sevenfold). In the EC compartment, adenosine, inosine, and hypoxanthine contents normalized slowly on reflow, whereas the xanthine content increased. The high EC levels of adenosine during ischemia may turn off spontaneous neuronal firing, counteract excitotoxicity, and inhibit ischemic calcium uptake, thereby exerting neuroprotective effects.

Extracellular Adenosine, Inosine, Hypoxanthine, and Xanthine in Relation to Tissue Nucleotides and Purines in Rat Striatum During Transient Ischemia

Effects of status epilepticus on extracellular amino acids in the hippocampus.

This study addresses the possible involvement of an agonist-induced postischemic hyperactivity in the delayed neuronal death of the CA1 hippocampus in the rat. In two sets of experiments, dialytrodes were implanted into the CA1 either acutely or chronically (24 h of recovery). During 20 min of cerebral ischemia (four-vessel occlusion model) and 8 h of reflow, we followed extracellular amino acids and multiple-unit activity. Multiple-unit activity ceased within 20 sec of ischemia and remained zero during the ischemic insult and for the following 1 h of reflow. During ischemia, extracellular aspartate, glutamate, taurine, and gamma-aminobutyric acid increased in both acute and chronic experiments (seven- to 26-fold). Multiple-unit activity recovered to preischemic levels following 4-6 h of reflow. In the group with dialytrodes implanted acutely, the continuous increase in multiple-unit activity reached 110% of basal at 8 h of reflow. In the group with dialytrodes implanted chronically, multiple-unit activity recovered faster and reached 140% of control at 8 h, paralleled by an increase in extracellular aspartate (5.5-fold) and glutamate (twofold). In conclusion, the postischemic increase of excitatory amino acids and the recovery of the neuronal activity may stress the CA1 pyramidal cells, which could be detrimental in combination with, e.g., postsynaptic impairments.

Changes in extracellular amino acids and spontaneous neuronal activity during ischemia and extended reflow in the CA1 of the rat hippocampus.

Extracellular calcium concentration changes in the CA1 of the hippocampus during burst activity were measured during postischemic reflow, and the involvement of N-methyl-D-aspartate (NMDA) receptors was evaluated. In adult Wistar rats global ischemia was induced by four-vessel occlusion for 20 min. After 6 h of postischemic reflow, the animals were halothane-anesthetized and reintubated. A double-barrelled calcium-sensitive microelectrode was advanced through stratum oriens, pyramidale, and radiatum in 50-micron steps. At each step the perforant pathway was stimulated (15 Hz, 30 s), and changes in extracellular calcium concentration were recorded. High-frequency stimulation elicited burst firing and transient decreases in extracellular calcium concentration, which are interpreted as neuronal calcium uptake. In control hippocampus, the extracellular calcium decreases were maximal in the stratum pyramidale. Six to eight hours after ischemia, a threefold enhancement of extracellular calcium decreases was found in the dendritic layers of the CA1. The NMDA-receptor antagonist ketamine (15-30 mg/kg intraperitoneally) reduced these electrically evoked calcium decreases. Seven days after ischemia, there was a 60-90% loss of pyramidal cells in the CA1. In conclusion, the cellular calcium uptake, possibly through NMDA receptors evoked by neuronal activity, is enhanced during early postischemia and precedes delayed neuronal death.

https://journals.sagepub.com/doi/pdf/10.1038/jcbfm.1988.135

Calcium uptake evoked by electrical stimulation is enhanced postischemically and precedes delayed neuronal death in CA1 of rat hippocampus: involvement of N-methyl-D-aspartate receptors.

Ingemar Jacobson

Papers

Ischemia-Induced Shift of Inhibitory and Excitatory Amino Acids from Intra- to Extracellular Compartments

Extracellular Adenosine, Inosine, Hypoxanthine, and Xanthine in Relation to Tissue Nucleotides and Purines in Rat Striatum During Transient Ischemia

Effects of status epilepticus on extracellular amino acids in the hippocampus.

Changes in extracellular amino acids and spontaneous neuronal activity during ischemia and extended reflow in the CA1 of the rat hippocampus.

Calcium uptake evoked by electrical stimulation is enhanced postischemically and precedes delayed neuronal death in CA1 of rat hippocampus: involvement of N-methyl-D-aspartate receptors.