Effect of treatment of high fat fed/low dose streptozotocin-diabetic rats with Ilepatril on vascular and neural complications

Davidson, Eric P.; Coppey, Lawrence J.; Holmes, Amey; Dake, Brian L.; Yorek, Mark A.

doi:10.1016/j.ejphar.2011.07.016

Cited by 54 publications

(97 citation statements)

References 67 publications

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“…According to Coppey et al [25] and Reed et al [43], the diabetes in these rats is analogous to the development of human type 2 diabetes when the decline in hyperinsulinemia is not able to compensate for insulin resistance and hyperglycemia occurs. In our hands, the 4-week rat models early stage, whereas the 16-week rat models late stage, type 2 diabetes [45]. Coincidently, the rats of early diabetes did not develop notable ER stress and DPN, while those of late diabetes were characterized with severe ER stress and DPN.…”

Section: Discussionmentioning

confidence: 99%

CHOP/ORP150 Ratio in Endoplasmic Reticulum Stress: A New Mechanism for Diabetic Peripheral Neuropathy

Ren

et al. 2013

Cell Physiol Biochem

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Background/Aims: Peripheral neuropathy is a frequent and severe diabetic complication characterized by progressive loss of peripheral nerve axons and manifested by pain and eventually complete loss of sensation. Effective therapy for diabetic peripheral neuropathy (DPN) is still lacking due to our limited understanding of the mechanisms for nerve injury. Methods: Here we tested the roles of endoplasmic reticulum (ER) stress and the ER stress-activated pro-apoptotic protein CHOP and anti-apoptotic protein ORP150 in DPN in a rat model of high-fat/streptozotocin diabetes and in cultured Schwann cells (SCs). Results: No significant DPN was seen in the early stage of diabetes (4 weeks following verification of diabetes). However, after prolonged diabetes (16 weeks following verification of diabetes), DPN was severely developed as reflected by slowed motor and sensory nerve conduction velocity, blunted thermal nociception, and decreased intraepidermal nerve fiber profiles in the hindpaw. Meanwhile, while it was not noticed in sciatic nerves of early diabetes, ER stress in prolonged diabetic rats was indicated by robust increases in H₂O₂ production and expression of the ER chaperon glucose-regulated protein 78 (GRP78). ORP150 expression was substantially upregulated, accompanied by mild increase in CHOP expression, resulting in a low CHOP/ORP150 ratio, in early diabetes. In contrast, with prolonged diabetes, CHOP expression exceeded ORP150 expression, resulting in an increased CHOP/ORP150 ratio. In vivo knockdown of ORP150 induced DPN in early diabetes and exacerbated the DPN after prolonged diabetes, whereas knockdown of CHOP ameliorated DPN in rats with prolonged diabetic. On the other hand, in vitro knockdown of ORP150 promoted high glucose-induced SC apoptosis, whereas knockdown of CHOP protected SCs from apoptosis. Conclusion: Taken together, we have provided evidence for the critical role of ER stress in the development of DN and also uncovered CHOP/ORP150 ratio as an important mechanism for determining neuronal apoptosis during ER stress. In the early stage of diabetes, CHOP/ORP150 ratio was relatively low favoring neuronal cell survival, whereas after prolonged diabetes, CHOP/ORP150 ratio increased resulting in apoptotic cell death leading to accelerated DPN.

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Section: Discussionmentioning

confidence: 99%

CHOP/ORP150 Ratio in Endoplasmic Reticulum Stress: A New Mechanism for Diabetic Peripheral Neuropathy

Ren

et al. 2013

Cell Physiol Biochem

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“…One group was maintained on the normal diet and the other group was treated with Ilepatril (500 mg/kg in the diet) for 6 weeks. [10][11][12] Thus, the total duration of diabetes was 8 weeks.…”

Section: Animalsmentioning

confidence: 99%

“…12,14 Data were reported in seconds. Tear secretion was determined using phenol red-impregnated cotton threads (Zone-Quick; Showa Yakuhin Kako Co., Tokyo, Japan).…”

Section: Animalsmentioning

confidence: 99%

“…Motor nerve conduction velocity was determined as previously described using a noninvasive procedure in the sciatic-posterior tibial conducting system. 12,15 Sensory nerve conduction velocity was determined using the digital nerve as described by Obrosova et al 16 Motor and sensory nerve conduction velocity was reported in meters per second.…”

Section: Motor and Sensory Nerve Conduction Velocitymentioning

confidence: 99%

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Early Loss of Innervation of Cornea Epithelium in Streptozotocin-Induced Type 1 Diabetic Rats: Improvement with Ilepatril Treatment

Davidson

Coppey

Yorek

2012

Invest. Ophthalmol. Vis. Sci.

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“…This study used HFD and a dual dose of STZ (30mg/kg) to induce diabetes in wister rats. Davidson et al, 11 successfully induced diabetic neuropathy in 12 weeks after prolonged HFD (8 weeks) followed by single 30 mg/kg STZ in SD rats. However, a later study by Mansor et al,12 reported that such high dose of STZ might induce type 1 diabetes like features including hypoinsulinemia, hyperkalemia, and weight loss.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Peripheral Neuropathy in Rat Model of Type 2 Diabetes

Mehta¹,

Nerkar²,

Banerjee³

2017

IJPER

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Diabetic neuropathy, a microvascular complication associated with diabetes, is one of the most common forms of neuropathy. Current rodent models of type 2 diabetes are mostly transgenic which fail to mimic human type 2 diabetes and its secondary complications, including peripheral neuropathy. Our aim is to develop a non-transgenic animal model of type 2 diabetic neuropathy which closely mimics the human disease. Methods: High-fat diet (HFD; normal pellet diet + lard) and a dual dose of streptozotocin (25mg/kg) were used to induce diabetes in Sprague-Dawley rats. Developments of neuropathy in these animals were measured using behavioral parameters like tail flick latency, pain threshold using randall selitto, and gait test. Nerve conduction velocity and histopathological evaluation of sciatic nerve were also carried out. Paclitaxel treated animals served as neuropathy controls. Results: The animals developed diabetes (blood glucose >250 mg/ dl; HbA1c 11.77 ±0.14%). All the classical symptoms of painful neuropathy, reduction in tail flick latency (p<0.05), reduced vocalization threshold in randall selitto (p<0.01), gait test showing a highly negative sciatic functional index (p<0.01) and reduced nerve conduction velocity (p<0.01) were evident in HFD-STZ animals. The above response was comparable to paclitaxel-treated neuropathy controls. Histopathological evaluation of sciatic nerves showed indications of sciatic nerve damage in HFD-STZ and paclitaxeltreated animals. The above neuropathic conditions were successfully reversed upon glibenclamide treatment (10 mg/kg) in HFD-STZ treated diabetic animals. Conclusion: Hence we successfully developed a cost-efficient non-transgenic model of diabetic neuropathy which closely mimics the characteristics of the human form of the disease.

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Effect of treatment of high fat fed/low dose streptozotocin-diabetic rats with Ilepatril on vascular and neural complications

Cited by 54 publications

References 67 publications

CHOP/ORP150 Ratio in Endoplasmic Reticulum Stress: A New Mechanism for Diabetic Peripheral Neuropathy

CHOP/ORP150 Ratio in Endoplasmic Reticulum Stress: A New Mechanism for Diabetic Peripheral Neuropathy

Early Loss of Innervation of Cornea Epithelium in Streptozotocin-Induced Type 1 Diabetic Rats: Improvement with Ilepatril Treatment

Characterization of Peripheral Neuropathy in Rat Model of Type 2 Diabetes

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