Hyperthermic pre-conditioning protects retinal neurons from N-methyl- d-aspartate (NMDA)-induced apoptosis in rat

• Published in: Brain research Vol. 970; no. 1; pp. 119 - 130
• Main Authors: Kwong, Jacky M.K., Lam, Tim T., Caprioli, Joseph
• Format: Journal Article
• Language: English
• Published: London Elsevier B.V 25-04-2003; Amsterdam Elsevier; New York, NY
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Biological and medical sciences; Excitotoxicity; Eye and associated structures. Visual pathways and centers. Vision; Fundamental and applied biological sciences. Psychology; Ganglion cell; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Glaucoma; Heat shock protein; Heat-Shock Proteins - analysis; Heat-Shock Proteins - biosynthesis; HSP70 Heat-Shock Proteins - analysis; HSP70 Heat-Shock Proteins - biosynthesis; HSP72 Heat-Shock Proteins; Hyperthermia, Induced - methods; Male; N-Methyl- d-aspartate; N-Methyl-D-aspartic acid; N-Methylaspartate - toxicity; Rats; Rats, Sprague-Dawley; Retinal Ganglion Cells - chemistry; Retinal Ganglion Cells - drug effects; Retinal Ganglion Cells - metabolism; Time Factors; Vertebrates: nervous system and sense organs; Glaucoma; Disorders of the nervous system; Excitotoxicity; Heat shock protein; N-Methyl- d-aspartate; Ganglion cell; Apoptosis; Rat; Toxicity; N-Methyl-D-aspartate; Rodentia; Retina; Eye; Visual system; Vertebrata; Mammalia; NMDA; Hyperthermia; Preconditioning; Ganglion cell Glaucoma
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/S0006-8993(03)02298-4

Glutamate-induced excitotoxicity is associated with a selective loss of retinal neurons after retinal ischemia and possibly in glaucoma. Since heat shock protein (HSP) 70 is known to play a protective role against ischemic neuronal injury, which is also linked to excitotoxicity, we studied the expression of inducible (HSP72) and constitutive (HSC70) forms of HSP70 in apoptosis of retinal ganglion cells (RGCs) after intravitreal injection of 8 nmoles
N-methyl-
d-aspartate (NMDA), a glutamate receptor agonist. Approximately 18 h after NMDA injection, there were increased numbers of TUNEL-positive cells and cells with elevated HSP72 immunoreactivity in the retinal ganglion cell layer (RGCL), but there were no noticeable changes in HSC70 immunoreactivity. These HSPs positive cells were also Thy-1 positive, a marker for RGCs. Hyperthermic pre-conditioning, which is known to induce HSPs, given 6 or 12 h prior to NMDA injection ameliorated neuronal loss in the RGCL as counted 7 days after NMDA injection but pre-conditioning at 18 h prior to NMDA injection did not have any ameliorative effect. Quercetin, an inhibitor of HSP synthesis, abolished the ameliorative effect of hyperthermic pre-conditioning. Pre-conditioning elevated HSP72 but not HSC70 immunoreactivity and reduced the number of TUNEL-positive cells in the RGCL at 18 h. Our results suggest that intravitreal injection of NMDA induces an up-regulation of HSP72 in a time-dependent manner but not HSC70 in RGCs, indicating a stress response of HSP72 in RGCs and other inner retinal neurons after exposure to NMDA. Hyperthermic pre-conditioning given within a therapeutic window is neuroprotective to the retina against NMDA-induced excitotoxicity, likely by inhibiting apoptosis through the modulation of HSP72 expression.