Stress exacerbates neuron loss and cytoskeletal pathology in the hippocampus

Abstract

Glucocorticoids (GCs), the adrenal steroids secreted during stress, endanger the hippocampus, compromising its ability to survive neurological insults. GCs probably do so by disrupting energetics in the hippocampus, thus impairing its ability to contain damaging fluxes of excitatory amino acids and calcium. Superficially, these observations suggest that stress itself should also exacerbate the toxicity of neurological insults. However, most studies have involved unphysiologic GC manipulations, limiting speculations about the endangering effects of stress. In this study, rats were infused with the excitotoxin kainic acid (KA) after either having been adrenalectomized and replaced with a range of physiologic concentrations of GCs, or having been stressed intermittently. We observed that within the CA3 region, increasing CORT concentrations exacerbated the KA-induced neuron loss, the extent of tau immunoreactivity, and of spectrin proteolysis. The transitions from low to high basal GC concentrations and from high basal to stress GC values were both associated with significant exacerbation of neuron loss and tau immunoreactivity; the extent of spectrin proteolysis was less sensitive to increments in GCs. As would be expected from these data, exposure to intermittent stress prior to KA infusion also exacerbated neuron loss, tau immunoreactivity, and spectrin proteolysis in CA3. Thus, physiological elevations of GCs, and stress itself, can exacerbate hippocampal neuron loss and the attendant degenerative markers following an excitotoxic insult. Of significance, seizure and hypoxia-ischemia provoke considerable GC stress responses, which may thus worsen the resultant damage. Furthermore, a number of neuropsychiatric disorders, as well as aging, are associated with elevated basal GC concentrations, which may endanger the hippocampus in the event of neurological insult.

Chronic stress enhances methamphetamine‐induced extracellular glutamate and excitotoxicity in the rat striatum

“…Because METH administration to rats preexposed to CUS increased the 145-kDa SBP without a change in 120-kDa SBP, these findings indicate that the synergistic interaction between stress and METH on spectrin proteolysis is selective to calpain activation and is similar to the excitotoxic cell death that occurs in response to traumatic brain injury (Pike et al, 2001) and ischemia (Neumar et al, 2001). This finding is in agreement with previous reports that exposure to high glucocorticoids levels or psychological stress exacerbate neuron loss and cytoskeletal pathology caused by the excitotoxin, kainic acid (Stein-Behrens et al, 1994a).…”

“…Exposure to elevated glucocorticoids or stress has been shown to exacerbate kainic acidinduced GLU accumulation and spectrin proteolysis (Stein-Behrens et al, 1992, 1994a. Therefore, the current study examined how chronic stress enhances METH toxicity, and tested the hypothesis that prior exposure to stress will augment the acute METH-induced increases in GLU and the production of spectrin proteolysis.…”

Relationships Among Seizures, Extracellular Amino Acid Changes, and Neurodegeneration Induced by 4‐Aminopyridine in Rat Hippocampus: A Microdialysis and Electroencephalographic Study

“…In this respect, it is noteworthy that the resistance of CA2 to the 4-AP-induced damage is strikingly similar to that observed after intrahippocampal microinjection of agonists of different EAA receptor types (Ben-Ari, 1985;Stein-Behrens et al, 1994;Arias et al, 1997). It is interesting that some members of the family of dendrotoxins, which are also K+ channel blockers, produce neurodegeneration in CA 1, CA3, and CA4 subfields and that this damage is prevented by EAA receptor antagonists (Bagetta et al, 1994(Bagetta et al, , 1996.…”

“…However, although neuronal damage in the hippocampus has been observed after treatment with agonists of glutamate receptors (Ben-Ari, 1985;Stein-Behrens et al, 1994;Arias et al, 1997), an accumulation of endogenous extracellular glutamate, resultant from inhibition of its transporters in vivo, surprisingly did not result in neuronal damage and induced only weak signs of hyperexcitability (Massieu et al, 1995;Obrenovitch et al, 1996;Massieu and Tapia, 1997).…”

Tau protein is essential for stress-induced brain pathology

“…Three well-characterized behavioral endpoints (cognition, coping styles, and anxiety) that are disrupted by CUS served as the primary assay endpoints; these were complemented with measures of hippocampal structural and functional integrity. The hippocampus is a central component of the neurocircuitries that control these behaviors and displays overt lesions in both stress-and Tau-related pathologies; in the latter, the hippocampus is one of the earliest brain regions to show signs of neurodegeneration (1,4,7,(10)(11)(12)(13)17). …”