Cerebral lesions in rats with streptozotocin-induced diabetes

Mukai, Noritsugu; Hori, Shingo; Pomeroy, M.

doi:10.1007/bf00688853

Cited by 56 publications

(30 citation statements)

References 6 publications

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“…In addition to various alterations of neuronal structure, function, and metabolism reported in insulin-dependent, type-I diabetes (Bestetti and Rossi, 1980;Mukai et al, 1980;Reagan et al, 1999;Russel et al, 1999;Magariños and McEwen, Fig. 4.…”

Section: Discussionmentioning

confidence: 91%

Hippocampal Neuropathology of Diabetes Mellitus is Relieved by Estrogen Treatment

et al. 2006

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1. A recently recognized complication of uncontrolled diabetes mellitus is the encephalopathy involving, among other regions, the hippocampus. Since estrogens bring neuroprotection in cases of brain injury and degenerative diseases, we have studied if estradiol (E2) administration counteracts some hippocampal abnormalities of streptozotocin (STZ)-diabetic adult mice. 2. We first report the ability of E2 to modulate neurogenesis in the dentate gyrus (DG) and subventricular zone (SVZ) of diabetic mice. Using bromodeoxyuridine (BrdU) to label newly generated cells, a strong reduction in cell proliferation was obtained in DG and SVZ of mice sacrificed 20 days after STZ administration. The reduction was completely relieved by 10 days of E2 pellet implantation, which increased 30-fold the circulating E2 levels. 3. Diabetic mice also showed abnormal expression of astrocyte markers in hippocampus. Thus, increased number of GFAP(+) cells, indicative of astrogliosis, and increased number of apolipoprotein-E (Apo-E)(+) astrocytes, a marker of ongoing neuronal dysfunction, was found in stratum radiatum below the CA1 hippocampal subfield of diabetic mice. Both parameters were reverted to normal by the E2 regime that upregulated cell proliferation. 4. The studies demonstrated that hippocampal neuropathology of uncontrolled diabetes is a reversible condition and sensitive to estrogen treatment. Studies in animal models may open up new venues for understanding the beneficial role of steroid hormones in diabetic encephalopathy.

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Section: Discussionmentioning

confidence: 91%

Hippocampal Neuropathology of Diabetes Mellitus is Relieved by Estrogen Treatment

et al. 2006

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“…A limitation of our study is that we do not know if the thrombotic contributions to diabetic vascular disease and the response to antiplatelet drugs are precisely the same in rats and humans. The rat is, however, a model for the diabetesinduced proneness to microthrombosis (14,15,46,47) and is widely used in preclinical studies of antiplatelet drugs (see PubMed citations under "antiplatelet therapy in rats" or "aspirin in rats"). The poor success of clopidogrel in rat diabetic retinopathy does resonate with the inconsistent results obtained with selective antiplatelet agents in human trials for retinopathy (11,12).…”

Section: Discussionmentioning

confidence: 99%

Aspirin at Low-Intermediate Concentrations Protects Retinal Vessels in Experimental Diabetic Retinopathy Through Non–Platelet-Mediated Effects

et al. 2005

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The prevention of diabetic retinopathy requires drugs that leverage the benefits of glycemic control without adding the burden of side effects. Aspirin at dosages of 1-1.5 g/day has prevented manifestations of diabetic retinal microangiopathy in a clinical trial as well as in studies with dogs. Because lower and safer doses of aspirin could be used if its beneficial effects on retinopathy were due to antithrombotic effects, we compared the effects of a selective antiplatelet drug (clopidogrel) to those of aspirin in streptozotocin-induced diabetic rats. Clopidogrel did not prevent neuronal apoptosis, glial reactivity, capillary cell apoptosis, or acellular capillaries in the retina of diabetic rats. Aspirin, at doses yielding serum levels (<0.6 mmol/l) well below the anti-inflammatory range for humans, prevented apoptosis of capillary cells and the development of acellular capillaries but did not prevent neuroglial abnormalities. The aldose reductase inhibitor sorbinil, used as the benchmark for the effect of the other drugs, prevented all abnormalities. The diabetic rat retina showed increased expression of the transcription factor CCAAT/enhancerbinding protein-␤, one of the known targets of low-intermediate concentrations of aspirin. Thus we found a spectrum of drug efficacy on the prevention of experimental diabetic retinopathy, ranging from the absent effect of a selective antiplatelet drug to the prevention of all abnormalities by an aldose reductase inhibitor. Aspirin at low-intermediate concentrations selectively prevented microangiopathy. The minimal effective dose of aspirin should now be sought. Diabetes 54:3418 -3426, 2005 D iabetic retinopathy remains a sight-threatening complication of diabetes despite decades of efforts to identify drugs that can leverage the prevention afforded by glycemic control. Aspirin has been studied several times in this context, with results that may appear inconsistent but actually are worthy of scrutiny in light of evolving knowledge. The Early Treatment Diabetic Retinopathy Study (ETDRS), the largest of the clinical trials testing aspirin, concluded that aspirin (650 mg/day) has no clinically important beneficial effects on the progression of retinopathy (1). The trial was performed in patients with mild to severe nonproliferative or early proliferative diabetic retinopathy. Having learned from the Diabetes Control and Complications Trial that intervening after retinopathy is clinically evident is much less successful than primary prevention (2), it is safe not to extrapolate the EDTRS results to prevention. The Dipyridamole Aspirin Microangiopathy of Diabetes Study, which enrolled patients with early diabetic retinopathy (a lesssevere degree of retinopathy than that seen in the ETDRS), showed that aspirin (990 mg/day) was able to slow the progression of microaneurysms by Ͼ50% over the 3-year duration of the study (3). Microaneurysms are only a surrogate end point of diabetic retinopathy, but they have high predictive value for worsening retinopathy (4,5). When aspirin ...

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“…Similarly, when hypertension developed following chronic exposure to shaker stress, responsiveness was also reduced probably because of adaptation within the brain. 20 By contrast, brains from streptozotocin diabetic rats show no gross abnormalities, 49 and hypothalamic depression during experimental diabetes can hardly be considered analogous to inhibition caused by physiologic adaptation. Selective reduction of pressor but not of behavioral or tachycardiac responses, as was seen here, implies that only those hypothalamic neurons concerned with blood pressure regulation were depressed during streptozotocin-induced diabetes.…”

Section: Discussionmentioning

confidence: 99%

Streptozotocin diabetic rats are hypertensive despite reduced hypothalamic responsiveness.

Buñag¹,

Tomita²,

Sasaki³

1982

Hypertension

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SUMMARY To determine whether diabetes predisposes rats to hypertension, tail-cuff systolic pressures were measured in male rats made diabetic by pretreatment with streptozotocin. From Weeks 2 through 7, diabetic rats weighed less but had higher systolic pressures than nondiabetic ones. Further comparisons made while the rats were anesthetized with urethane showed that pressor and sympathetic nerve responses to ventromedial hypothalamic stimulation, as well as pressor responses to injected vasopressin, were significantly reduced in the diabetic group. A generalized reduction of cardiovascular reactivity was considered unlikely because systemic pressor responses to norepinephrine and tyramine were unimpaired. Yet reflex bradycardia elicited by norepinephrine was enhanced indicating that baroreceptor resetting had not occurred. Thus, diabetic rats were characterized by hypertension, narrowed pulse pressure, bradycardia with increased reflex responses to norepinephrine, and reduced pressor responses to hypothalamic stimulation and to vasopressin. The successful induction of diabetes was confirmed not only by the presence of hyperglycemia, hypoinsulinemia, glycosuria, and abnormal glucose tolerance, but also by reductions in pancreatic weight, insulin, and /3-cell content. Although our results suggest that diabetic rats are predisposed to become hypertensive, other mechanisms such as hypothalamic depression may be activated to restrict further elevations in blood pressure. H YPERTENSION is generally believed to be more prevalent among diabetics than nondiabetics, 1 -2 but why this might be so is uncertain. Previous attempts to record blood pressure in rats with experimental diabetes have yielded equivocal results. Although blood pressure in normotensive rats is usually elevated by either alloxan 2 " 1 or streptozotocin, 5 -6 it has also been found unaffected 7 or even slightly decreased by streptozotocin. 8 In spontaneously hypertensive rats (SHR), blood pressure falls during the first few weeks after alloxan diabetes is induced, 4 6 9 but several months later becomes even higher than before. 3 From the Department of Pharmacology, College of Health Sciences and Hospital, University of Kansas Medical Center, Kansas City, Kansas.Supported by Research Grant AM 27660 from the National Institute of Arthritis, Metabolism, and Digestive Diseases.An abstract of this paper was published in Federation Proceedings 40: 391, 1981. Dr. Susumu Sasaku is a postdoctoral research fellow from the Second Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.Address for reprints: Dr. Ruben D. Bunag, Department of Pharmacology, University of Kansas Medical Center, 39th and Rainbow Boulevard, Kansas City, Kansas 66103.Received May 27, 1981; revision accepted December 7, 1981. While trying to characterize the cardiovascular changes occurring in normotensive rats that had been pretreated with streptozotocin, we found the ensuing diabetes accompanied by mild hypertension. Both blood pressure 10 and blood sugar" a...

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Cerebral lesions in rats with streptozotocin-induced diabetes

Cited by 56 publications

References 6 publications

Hippocampal Neuropathology of Diabetes Mellitus is Relieved by Estrogen Treatment

Hippocampal Neuropathology of Diabetes Mellitus is Relieved by Estrogen Treatment

Aspirin at Low-Intermediate Concentrations Protects Retinal Vessels in Experimental Diabetic Retinopathy Through Non–Platelet-Mediated Effects

Streptozotocin diabetic rats are hypertensive despite reduced hypothalamic responsiveness.

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