Chronic NMDA Administration Increases Neuroinflammatory Markers in Rat Frontal Cortex: Cross-Talk Between Excitotoxicity and Neuroinflammation

Abstract

Chronic N-Methyl-D-aspartate (NMDA) administration, a model of excitotoxicity, and chronic intracerebroventricular lipopolysaccharide infusion, a model of neuroinflammation, are reported to upregulate arachidonic acid incorporation and turnover in rat brain phospholipids as well as enzymes involved in arachidonic acid metabolism. This suggests cross-talk between signaling pathways of excitotoxicity and of neuroinflammation, involving arachidonic acid. To test whether chronic NMDA administrations to rats can upregulate brain markers of neuroinflammation, NMDA (25 mg/kg i.p.) or vehicle (1 ml saline/kg i.p.) was administered daily to adult male rats for 21 days. Protein and mRNA levels of cytokines and other inflammatory markers were measured in the frontal cortex using immunoblot and real-time PCR. Compared with chronic vehicle, chronic NMDA significantly increased protein and mRNA levels of interleukin-1beta, tumor necrosis factor alpha, glial fibrillary acidic protein and inducible nitric oxide synthase. Chronic NMDA receptor overactivation results in increased levels of neuroinflammatory markers in the rat frontal cortex, consistent with cross-talk between excitotoxicity and neuroinflammation. As both processes have been reported in a number of human brain diseases, NMDA receptor inhibitors might be of use in treating neuroinflammation in these diseases.

Matrix Metalloprotease 8-Dependent Extracellular Matrix Cleavage at the Blood-CSF Barrier Contributes to Lethality during Systemic Inflammatory Diseases

“…This was expected because there is no direct evidence for entry of immune cell into the CNS across the BCSFB (Engelhardt and Sorokin, 2009). However, based on GFAP (Beurel and Jope, 2009) and iNOS (Chang et al, 2008) measurements, we did observe an increase in activated astrocytes and microglia, respectively, in MMP8 ϩ/ϩ mice but not in MMP8 Ϫ/Ϫ mice. Activation of the HPA axis has a key role in the crosstalk between the immune and the neuroendocrine systems and is crucial in restoring physiological homeostasis after immune activation (Beishuizen and Thijs, 2003).…”

“…5e). The inducible isoform of nitric oxide synthase (iNOS) is a marker of activated microglia and astrocytes, known to be induced by LPS (Chang et al, 2008;Lu et al, 2010). iNOS is a well-established source of nitric oxide during inflammation of the CNS and was shown to play an important role in neurotoxicity after systemic LPS injection (Sierra et al, 2008).…”

Extracellular-derived calcium does not initiate in vivo neurotransmission involving docosahexaenoic acid

“…Our observations may be relevant to excitotoxicity, which involves high brain glutamate concentrations. In rodent models, excitotoxicity is associated with increased brain concentrations of AA and of its proinfl ammatory metabolites and with increased cPLA 2 -IVA expression, without a signifi cant change in DHA concentration or iPLA 2 -VI expression ( 43,49,50 ). High concentrations of AA and its metabolites can be neurotoxic ( 51 ), whereas DHA and its metabolites are considered neuroprotective ( 1 ).…”

Evaluation of neuroprotective effect of flupirtine in brain of albino rats

“…1 Glutamate binds to NMDA receptors, which results in Ca 2+ entry from extracellular space into the cell. This leads to activation of Ca 2+ -dependent enzymes like calpain, 2 calcineurin, 3 inducible nitric oxide synthase (iNOS) expression 4 and cytosolic phospholipase A 2 (cPLA 2 ). 5,6 In frontal cortex and hippocampal CA 1 region NMDA receptors (NMDAR) are present predominantly.…”