Neurodegeneration and cellular stress in the retina and optic nerve in rat cerebral ischemia and hypoperfusion models

• Published in: Neuroscience 2008-08, Vol.155 (3), p.937-947
• Main Authors: Kalesnykas, G, Tuulos, T, Uusitalo, H, Jolkkonen, J
• Format: Article
• Language: English
• Subjects: alpha-Crystallin B Chain - metabolism; Animals; apoptosis; Biological and medical sciences; Cell Count - methods; cerebral ischemia; Disease Models, Animal; Eye and associated structures. Visual pathways and centers. Vision; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - physiology; Glial Fibrillary Acidic Protein - metabolism; heat shock proteins; Heat-Shock Proteins - metabolism; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; In Situ Nick-End Labeling; Infarction, Middle Cerebral Artery - complications; Infarction, Middle Cerebral Artery - pathology; Male; Medical sciences; Myelin Sheath - metabolism; Nerve Degeneration - etiology; Nerve Degeneration - metabolism; neurodegeneration; Neurology; Optic Nerve - pathology; Optic Nerve - physiopathology; Phosphopyruvate Hydratase - metabolism; Proto-Oncogene Proteins c-fos - metabolism; Rats; Rats, Wistar; Retina - pathology; Retina - physiopathology; stereology; Time Factors; Vascular diseases and vascular malformations of the nervous system; Vertebrates: nervous system and sense organs
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2008.06.038

Abstract Experimental cerebral ischemia induces a stress response in neuronal and non-neuronal cells. In the present study we aimed to evaluate detailed cellular stress responses and neurodegenerative changes in the retinas in rat focal cerebral ischemia and hypoperfusion models involving invasive vascular manipulations. Independent groups of adult male Wistar rats were subjected to i) transient middle cerebral artery occlusion (tMCAO), ii) permanent middle cerebral artery occlusion (pMCAO), iii) cortical photothrombosis of the sensorimotor cortex using Rose Bengal dye or iv) bilateral common carotid artery occlusion (BCCAO). Rats were killed, and their eyes with the optic nerves enucleated and processed for histology, immunohistochemistry for neuronal nuclei (NeuN), glial fibrillary acidic protein (GFAP), hypoxia-inducible factor 1α (HIF-1α), c-fos , αB-crystallin, heat shock protein (HSP) 27, HSP60 and HSP70, and detection of DNA defragmentation. The total number of the retinal ganglion cell layer (RGCL) neurons and GFAP-immunoreactive astrocytes located in the nerve fiber layer were estimated using unbiased stereological counting. Our findings indicate that although permanent and transient MCAO does not cause detectable morphological alterations in the retina or optic nerve, it evokes ischemic stress as revealed by HIF-1α and HSPs expression in the RGCL neurons and reactive gliosis in the Müller cells. Severe neurodegenerative changes in the retina and optic nerve of the BCCAO rats are accompanied by a significant increase in immunoreactivities for the c-fos , HSP27 and HSP70 as compared with the sham-operated animals. The retinas from the ipsilateral side of the Rose Bengal model showed a significant decrease in the total number of NeuN-positive neurons in the RGCL as compared with the contralateral ones. However, these eyes did not differ between each other in the HSPs and HIF-1α expression or in the GFAP-immunoreactivity of the Müller cells. In conclusion, our data suggest differential expression of various HSPs in the retina and possibly their distinct roles in the cerebral ischemia-mediated stress response and neurodegeneration.