Protein kinase C beta inhibitor prevents diabetic peripheral neuropathy, but not histopathological abnormalities of retina in Spontaneously Diabetic Torii rat

Abstract

Spontaneously Diabetic Torii (SDT) rat shows severe ocular complications such as tractional retinal detachment. In the present study, effect of protein kinase C beta (PKCβ) inhibitor JTT-010 was evaluated to clarify the involvement of PKCβ in complications of SDT rat. SDT rats were administered JTT-010 (10 or 50 mg/kg/day) for 48 weeks. SDT rats showed delayed oscillatory potentials in electroretinogram. Delayed motor nerve conduction velocity, decreased coefficients of variation of R-R intervals in electrocardiogram and thermal hypoalgesia were also observed. These functional disorders were prevented by administration of JTT-010. Abnormal retinal vascular was formed and the optic disc was protruded in SDT rat; however, JTT-010 did not prevent these hyperglycaemia-induced retinal abnormalities. These findings indicate that PKCβ is intimately involved in diabetic complications; however, it seems that other factor(s) are primary contributors to histopathological abnormalities in retina. Therefore, PKCβ inhibitors require concurrent administration of antihyperglycaemic drugs to achieve maximum effect on diabetic complications.

Prophylactic Medical Treatment of Diabetic Retinopathy

“…The rats had delayed oscillatory potentials on electroretinography, but DR developed eventually. We concluded that PKC inhibitors may require concurrent administration of antihyperglycemic drugs to achieve maximal therapeutic effects on DR (Sasase et al, 2009). …”

Animal Models of Diabetic Retinopathy

“…The Vhl zebrafish have a mutation in the von Hippel-Lindau tumor suppressor gene and are characterized by increased blood vessel formation, along with upregulation of the hypoxiainducible factor, which triggers expression of Vegf [162]. This model is characterized by an increased number of hyaloid vasculature with concomitant vascular leakage, macular edema, retinal detachment, and severe neovascularization [151].…”

“…SDT rats are characterized by retinal dysfunction, which includes retinal detachment with fibrous proliferation, absence of retinal ischemia in the presence of neovascularization, leukostasis, increased number of apoptotic cells in the GCL and INL, vascular lesions, and pericyte loss [151][152][153][154]. A distinct feature of this model is the appearance of large retinal folds with extensive leakage around the optic disc, similar to retinal detachment observed in humans [151][152][153][154]. The SDT rat is the rat model that most closely resembles the pathophysiology seen in humans; however, the absence of microaneurysm makes them a more suitable model for studying NPDR.…”

“…Boxes represent the point in the pathway targeted by animal models. Italicized text corresponds to the induced models and bold text corresponds to the genetic models [ 20,[145][146][147][148] SDT QTL Gisdt1, 2, 3 [149][150][151][152][153][154][155] develop proliferative retinopathy [50]. Monkeys thus appear to be surprisingly resilient to induction of DR despite removal of the pancreas, long-term diabetes, and poor control of blood sugar levels.…”

Neuropeptides, Trophic Factors, and Other Substances Providing Morphofunctional and Metabolic Protection in Experimental Models of Diabetic Retinopathy

“…In 44-week-old animals, a and b waves and the OPs were significantly reduced with prolonged implicit times in the SDT rats compared with SpragueDawley rats (Okuno et al, 2008). The depressed ERG may reflect vascular and neuronal damage throughout the retina as are seen in the advanced stages of human DR. Further, in SDT rat, hyperglycemia-induced abnormal retinal vascular bed was formed and the optic disc protruded (Sasase et al, 2009). Thus, the SDT rat can be used to study the physiology of DR. s0155 3.2.4 GK rats p0845 The GK rat is a spontaneous model of noninsulin-dependent diabetes mellitus without obesity, which was developed by repeated selective breeding of normal Wistar rats using glucose intolerance as a selection index (Goto and Kakizaki, 1981).…”