Quinolinate-induced Rat Striatal Excitotoxicity Impairs Endoplasmic Reticulum Ca2+-ATPase Function

Abstract

Excessive activation of NMDA glutamate receptors and the resulting loss of intracellular Ca(2+) homeostasis may be lethal (excitotoxic) to neurons. Such excitotoxicity can be induced in vivo by intrastriatal infusion of quinolinate, as this substance selectively activates NMDA receptors. The aim of the present research was to investigate whether the in vivo treatment of striatal tissue with quinolinate would lead to an early impairment of sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) activity or mitochondrial Ca(2+) sequestration, two intracellular mechanisms involved in Ca(2+) homeostasis and signaling. Sodium quinolinate was infused intrastriatally into adult rats, and 6 h later the brains were removed and the corpora striata dissected. At this time point, striatal sections stained with Fluoro-Jade, a cellular marker of cell death, showed initial signs of neuronal degeneration. In addition, SERCA activity decreased 39% in relation to the activity observed in the control striata. A corresponding decrease of the same magnitude in (45)Ca(2+) uptake by striatal microsomes was also found in the treated striata. Western blot analysis did not indicate any decrease in SERCA levels in striatal tissue after quinolinate infusion. Mitochondrial Ca(2+) sequestration was still preserved in quinolinate-treated striatal tissue when the assay was carried out in the presence of physiological concentrations of ATP and Mg(2+). These results suggest that impairment of the SERCA function may be an early event in excitotoxicity.

Increased Indoleamine 2,3-Dioxygenase and Quinolinic Acid Expression in Microglia and Müller Cells of Diabetic Human and Rodent Retina

“…75 QUIN neural toxicity involves the following mechanisms: (1) continuous stimulation of N -methyl- d -aspartate receptors, with calcium entry into neurons 11 ; (2) activation of second messenger-dependent protein kinases, which phosphorylate head domain sites on neurofilament subunits, potentially dysregulating intermediate filament assembly 76 ; (3) impairment of the sarco/endoplasmic reticulum calcium-ATPase pump resulting in disturbed intracellular calcium signaling 77 ; (4) increased glutamate release by neurons, inhibition of uptake by astrocytes, and inhibition of astrocyte glutamine synthesis, thereby increasing glutamate concentration in the microenvironment, leading to neurotoxicity 78 ; (5) progressive energetic dysfunction, leading to neurodegeneration 79 ; and (6) increased neuronal nitric oxide synthases, resulting in DNA damage, NAD( + ) depletion, and neuronal death. 80 …”

Quinolinic Acid: An Endogenous Neurotoxin with Multiple Targets

“…In both cases the increase in the intracellular Ca 2+ levels set off a cascade of events including activation of the second messengers-dependent protein kinases, which phosphorylate head domain sites on GFAP and neurofilaments subunits and potentially misregulating intermediate filament assembly in both glia and neuronal cells [45]. Additionally, the in vivo overstimulation of NMDA receptors by QUIN causes an early impairment of the sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) pump which may result in important disturbances in intracellular Ca 2+ signaling [46]. …”

Inhibitory Effects of Adenine Nucleotides on Brain Mitochondrial Permeability Transition

“…rises as a result of both impaired Ca 2? -removal systems and activation of glutamate receptors under conditions of severe energy deprivation, such as during ischemia/reperfusion or hypoglycemia [4][5][6][7]. During neuronal cytosolic Ca 2?…”