Protection in Glutamate-Induced Neurotoxicity by Imidazoline Receptor Agonist Moxonidine

Abstract

In the present study we investigated the effects of mixed imidazoline-1 and alpha(2)-adrenoceptor agonist, moxonidine, in glutamate-induced neurotoxicity in frontal cortical cell cultures of rat pups by dye exclusion test. Also, phosphorylated p38 mitogen activated protein kinases (p-p38 MAPK) levels were determined from rat frontal cortical tissue homogenates by two dimensional gel electrophoresis and semidry western blotting. Glutamate at a concentration of 10(-6) M was found neurotoxic when applied for 16 hr in cell cultures. Dead cell mean scores were 12.8 +/- 0.5 for control and 52.3 +/- 4.8 for glutamate (p < .001). On the other hand, p-p38 MAPK levels start to increase at a glutamate concentration of 10(-7) M for 20 min application. Moxonidine was found to have an U-shape neuroprotective effect in glutamate-induced neurotoxicity in neuronal cell culture experiments. Even though moxonidine did not induce neurotoxicity alone between the doses of 10(-8) to 10(-4) M concentrations in cell culture series, it caused the reduction of glutamate-induced dead cell population 23.07 +/- 3.6% in 10(-6) M and 26.7 +/- 2.1% in 10(-5) M concentrations (p <.001 for both, in respect to control values). The protective effect of moxonidine was confirmed in 10(-8) and 10(-7) M, but not in higher concentrations in glutamate neurotoxicity in gel electrophoresis and western blotting of p-p38 MAPK levels. In addition to other studies that revealed an antihypertensive feature of moxonidine, we demonstrated a possible partial neuroprotective role in lower doses for it in glutamate-mediated neurotoxicity model.

Restoration of Rostral Ventrolateral Medulla Cystathionine-γ Lyase Activity Underlies Moxonidine-Evoked Neuroprotection and Sympathoinhibition in Diabetic Rats

“…1 and 2) in diabetic rats. These findings agree with neuroprotective effects of moxonidine against ischemic insults in neuronal cultures (Milhaud et al, 2000;Bakuridze et al, 2009) and against glutamate-evoked neurotoxicity (Keller and García-Sevilla, 2016). However, the mechanism of the neuroprotective effect of moxonidine was not investigated in the reported studies.…”

Inhibition of Neuronal p38α, but not p38β MAPK, Provides Neuroprotection Against Three Different Neurotoxic Insults

“…L-glutamate is a standard neurotoxic stimulus that is a model of excitotoxic cell death (Choi et al 1987 ), and p38 has been reported to be involved in excitotoxic pathways leading to neuron damage/death (Kawasaki et al 1997 ; Chen et al 2003 ; Pi et al 2004 ; Chaparro-Huerta et al 2008 ; Molz et al 2008 ; Bakuridze et al 2009 ; Izumi et al 2009 ). Therefore, we compared the degree of neuron death and neurite degeneration induced by L-glutamate in primary cortical neurons derived from WT and p38β KO mice.…”

Current Therapeutic Approaches from Imidazoline and Opioid Receptors Modulators in Neuroprotection

“…In vitro experimental researches have shown that activation of I2 receptors via the agmatine endogenous ligand exerts neuroprotective effects by increasing the expression of glial fibrillary acidic protein in astrocyte cultures and by inhibiting MAO activity [26,27]. Moreover, the beneficial effects of agmatine have been observed on ischemic-hypoxic lesions, on glutamate-induced neurotoxicity by activating the imidazoline receptors [28,29].…”

“…In vitro cell culture studies from the rat frontal cortex with glutamate-induced neurotoxicity revealed the partial neuroprotective effects of moxonidine, with a significant decrease in the number of dead cells [26]. Moxonidine has shown beneficial effects on cerebral spasm in an experimental rabbit model of subarachnoid hemorrhage [40,56].…”