Effect of memantine on neuroretinal function and retinal vascular changes of streptozotocin-induced diabetic rats.
OBJECTIVE
To test whether chronic memantine (MEM) treatment improves retinal function and prevents neurodegeneration and vascular changes in the retinas of streptozotocin (STZ)-induced diabetic rats.


METHODS
Based on basal body weight and blood glucose, Brown Norway (BN) rats were divided into three groups. One group of rats was treated with vehicle (VEH), and the other two groups were treated with 65 mg/kg STZ. After 7 days, VEH-treated rats were treated further with a second VEH, and STZ-treated diabetic rats were treated either with the second VEH or with MEM (10 mg/kg daily) for another 3 to 4 weeks using mini-osmotic pumps. At end of the study, electroretinogram findings, retinal ganglion cell (RGC) count, vitreoretinal vascular endothelial growth factor (VEGF) protein levels, and blood-retinal barrier (BRB) breakdown of the animals were measured.


RESULTS
Within 4 to 5 weeks of STZ treatment, the diabetic rats demonstrated significantly less retinal function and fewer RGCs than VEH-treated nondiabetic rats. The diabetic animals also had significantly elevated VEGF protein levels in retina and vitreous fluid and BRB breakdown compared with control nondiabetic rats. Chronic MEM treatment significantly improved retinal function and protected RGC loss in STZ-induced diabetic rats. MEM treatment also significantly decreased elevated vitreoretinal VEGF protein levels and retinal BRB leakage in the diabetic rats. This effect of MEM was not seen in nondiabetic rats.


CONCLUSIONS
These results indicate that MEM could be useful for the treatment of ocular diseases, including diabetic retinopathy with neurodegeneration, elevated vitreoretinal VEGF protein levels, and increased BRB breakdown. In addition to the neuroprotective effect of this compound, MEM can reduce vascular changes seen in diabetic retinas. These data are the first to identify the vasculoprotective effect of MEM.
Kusari
Jyotirmoy
J
Department of Biological Sciences, Allergan Inc, Irvine, CA 92623-9534, USA. kusari_jyoti@allergan.com
Zhou
Sheila
S
Padillo
Edwin
E
Clarke
Kenneth G
KG
Gil
Daniel W
DW
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001813:Blood-Retinal Barrier / Q000187:drug effects; D001835:Body Weight; D002452:Cell Count; D004396:Coloring Agents / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental; D003930:Diabetic Retinopathy / Q000378:metabolism / Q000517:prevention & control*; D004596:Electroretinography; D005070:Evans Blue / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008297:Male; D008559:Memantine / Q000494:pharmacology*; D009901:Optic Nerve Diseases / Q000378:metabolism / Q000517:prevention & control*; D051381:Rats; D011914:Rats, Inbred BN; D012160:Retina / Q000187:drug effects* / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000473:pathology; D012171:Retinal Vessels / Q000187:drug effects*; D013311:Streptozocin; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014822:Vitreous Body / Q000378:metabolism
D001786:Blood Glucose; D004396:Coloring Agents; D018691:Excitatory Amino Acid Antagonists; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D005070:Evans Blue; D013311:Streptozocin; D008559:Memantine