Study of antidiabetic activity of two novel Schiff base derived dibromo and dichloro substituted compounds in streptozotocin-nicotinamide-induced diabetic rats: pilot study

Abstract Schiff bases are aldehyde-or ketone-like chemical compounds in which an imine or azomethine group replaces the carbonyl group. Such compounds show various beneficial biological activities, such as anti-inflammation and antioxidants. The present study addresses comprehensiveevaluation of antidiabetic effect of two novel dibromides and dichlorides substituted Schiff bases substituted Schiff bases (2,2'-[1,2-cyclohexanediylbis (nitriloethylidyne)]bis[4-chlorophenol] (CNCP) and 2, 2'-[1,2-cyclohexanediylbis(nitriloethylidyne)]bis[4-bromophenol] (CNBP) with two different doses, high (LD) and low (LD) in streptozotocin and nicotinamide induced diabetic rats. The rats were separated into normal, untreated, treated and reference groups. Except for the normal group, diabetes traits were induced in the rest animals. Insulin level was measured, and the effect of the compounds on biochemical parameters of liver function and lipid profile were evaluated. High glucose and decreased insulin level are observed in the groups. The histological evaluation confirms that the hepatic architecture in the treated animals with a low dose of CNCP is quite similar to that of the normal hepatic structure and characterized by normal central vein, hepatocytes without any fatty alterations and mild red blood cell infiltration. CNCP (LD) and CNBP (HD) are more successful in enhancing cell survival in the diabetic rat's liver and can be responsible for causing much healthier structure and notable morphology improvement.

Quercetin Exhibits α7nAChR/Nrf2/HO-1-Mediated Neuroprotection Against STZ-Induced Mitochondrial Toxicity and Cognitive Impairments in Experimental Rodents.

The objective of the present study was to investigate the α7nAChR-mediated Nrf2-dependant protective activity against streptozotocin (STZ)-induced brain mitochondrial toxicity in Alzheimer's disease (AD)-like rats. STZ (3 mg/kg) was injected through an intracerebroventricular route to induce AD-like dementia. Repeated Quercetin (50 mg/kg, i.p.) administration attenuated cognitive impairments in the STZ-challenged animals during Morris water-maze and Y-maze tests. Quercetin significantly mitigated the STZ-induced increase in cholinergic dysfunction, such as the increase in acetylcholinesterase activity, decrease in acetylcholine level, and activity of choline acetyltransferase, and increase in amyloid-beta aggregation and mitochondrial toxicity in respect of mitochondrial bioenergetics, integrity, and oxidative stress in memory-challenged rat hippocampus, prefrontal cortex and, amygdala. Further, Quercetin significantly attenuated STZ-induced reduction in the α7nAChRs and HO-1 expression levels in the selected rat brain regions. On the contrary, trigonelline (10 mg/kg, i.p.) and methyllycaconitine (2 mg/kg; i.p.) abolished the neuroprotective effects of Quercetin against STZ-induced behavioral, molecular, and biochemical alterations in the AD-like animals. Hence, Quercetin exhibits α7nAChR/Nrf2/HO-1-mediated neuroprotection against STZ-challenged AD-like animals. Thus, Quercetin could be considered as a potential therapeutic option in the management of AD.

A Novel Rhynchophylline Analog, Y396, Inhibits Endothelial Dysfunction Induced by Oxidative Stress in Diabetes Through Epidermal Growth Factor Receptor.

Aims: Endothelial dysfunction appears in early diabetes mellitus partially because of epidermal growth factor receptor (EGFR) abnormal activation and downstream oxidative stress. The aim of this study was to determine whether Y396, a synthesized analog of rhynchophylline, could protect against endothelial dysfunction in diabetes and the underlying molecular mechanism. Results: Y396 could directly target the EGFR and inhibit its phosphorylation induced by high glucose and EGF, downstream translocation to the nucleus of E2F1, and its transcriptional activity and expression of Nox4. Diabetes-induced endothelium malfunction was ameliorated by Y396 treatment through EGFR inhibition. Downstream oxidative stress was decreased by Y396 in the aortas of type 1 diabetes mellitus mice and primary rat aorta endothelial cells (RAECs). Y396 could also ameliorate tunicamycin-induced oxidative stress in the aorta and RAECs. In addition, we again determined the protective effects of Y396 on high-fat diet/streptozotocin-induced type 2 diabetes mellitus. Innovation: This is the first study to demonstrate that Y396, a novel rhynchophylline analog, suppressed high-glucose-induced endothelial malfunction both in vivo and in vitro by inhibiting abnormal phosphorylation of EGFR. Our work uncovered EGFR as a novel therapeutic target and Y396 as a potential therapy against diabetes-induced complication. Conclusion: Y396 could directly bind with EGFR, and inhibit its phosphorylation and downstream E2F1 transcriptional activity. It could also preserve tunicamycin-evoked endothelial dysfunction and oxidative stress. It could protect against diabetes-induced endothelium malfunction in vivo through EGFR inhibition and downstream oxidative stress. Antioxid. Redox Signal. 32, 743-765.

Silibinin ameliorates STZ-induced impairment of memory and learning by up- regulating insulin signaling pathway and attenuating apoptosis.

Alzheimer's disease (AD) is a neurodegenerative disease, mainly characterized by cognitive dysfunction and memory impairment. Due to its pathological similarities to type 2 diabetes mellitus (T2DM), such as ß-amyloid deposition, oxidative stress, inflammation, disordered glucose metabolism, impaired signaling pathways of insulin and insulin-like growth factor-1 (IGF-1), we speculate that AD is another form of brain diabetes. Clarifying the relationship between T2DM and AD is important for us to better understand the exact pathological mechanisms of AD. Silibinin, a polyphenolic flavonoid extracted from the seeds of Silybum marianum, exerts hepatoprotective, anti- diabetic and neuroprotective effects. Streptozotocin (STZ), which is used to disrupt the insulin signal transduction pathway, could well mimic the sporadic AD models by intracerebroventricular (ICV) injection. Therefore, we selected ICV injection of STZ (ICV-STZ) to investigate the neuroprotective effects of silibinin in rats and to make a foundation for further exploring the relationship between AD and T2DM. ICV-STZ obviously caused memory damage, sharply reduced the number of nissl bodies and destroyed morphological structure of hippocampal neuronal cells, while silibinin attenuated the damages. Moreover, silibinin significantly decreased STZ-induced tau hyperphosphorylation (ser404) in hippocampus and cerebral cortex, markedly inhibited apoptosis of neurons induced by STZ, and up-regulated insulin signal transduction pathway. Silibinin exerts neuroprotective effect in STZ-treated rats, indicating the potential of silibinin for the treatment of AD patients with T2DM in future.

ß-Carotene: A Natural Compound Improves Cognitive Impairment and Oxidative Stress in a Mouse Model of Streptozotocin-Induced Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by a cascade of changes in cognitive, behavioral, and social activities. Several areas of the brain are involved in the regulation of memory. Of most importance are the amygdala and hippocampus. Antioxidant therapy is used for the palliative treatment of different degenerative diseases like diabetes, cirrhosis, and Parkinson's, etc. The objective of this study was to assess the effectiveness of exogenous antioxidants, in particular, ß carotene (1.02 and 2.05 mg/kg) against intracerebroventricular injected streptozotocin-induced memory impairment in mice. Streptozotocin (3 mg/kg, i.c.v) was administered in two separate doses (on 1st and 3rd days of treatment) for neurodegeneration. Fifty Albino mice (male) were selected in the protocol, and they were classified into five groups (Group I-control, Group II-disease, Group III-standard, Group IV-V-ß-carotene-treated) to investigate the cognitive enhancement effect of selected antioxidants. The cognitive performance was observed following the elevated plus-maze, passive avoidance, and open field paradigms. Acetylcholine esterase, ß-amyloid protein, and biochemical markers of oxidative stress such as glutathione peroxidase, superoxide dismutase, and catalase were analyzed in brain homogenates. In silico activity against acetylcholinesterase (AChE) was determined by the molecular modeling of ß-carotene. ß-carotene at a dose of 2.05 mg/kg was found to attenuate the deleterious effects of streptozotocin-induced behavioral and biochemical impairments, including the inhibition of acetylcholinesterase activity. The in silico studies confirmed the binding capacity of ß-carotene with the acetylcholinesterase enzyme. The administration of ß-carotene attenuated streptozotocin-induced cognitive deficit via its anti-oxidative effects, inhibition of acetylcholinesterase, and the reduction of amyloid ß-protein fragments. These results suggest that ß-carotene could be useful for the treatment of neurodegenerative diseases such as Alzheimer's disease.

Analgesic effects of ASP3662, a novel 11ß-hydroxysteroid dehydrogenase 1 inhibitor, in rat models of neuropathic and dysfunctional pain.

BACKGROUND AND PURPOSE: Glucocorticoids are a major class of stress hormones known to participate in stress-induced hyperalgesia. Although 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) is a key enzyme in the intracellular regeneration of glucocorticoids in the CNS, its role in pain perception has not been assessed. Here, we examined the effects of ASP3662, a novel 11ß-HSD1 inhibitor, on neuropathic and dysfunctional pain. EXPERIMENTAL APPROACH: The enzyme inhibitory activities and pharmacokinetics of ASP3662 were examined, and its antinociceptive effects were evaluated in models of neuropathic pain, fibromyalgia and inflammatory pain in Sprague-Dawley rats. KEY RESULTS: ASP3662 inhibited human, mouse and rat 11ß-HSD1 but not human 11ß-HSD2, in vitro. ASP3662 had no significant effect on 87 other possible targets (enzymes, transporters and receptors). ASP3662 inhibited in vitro conversion of glucocorticoid from its inactive to active form in extracts of rat brain and spinal cord. Pharmacokinetic analysis in Sprague-Dawley rats showed that ASP3662 has CNS-penetrability and long-lasting pharmacokinetic properties. Single oral administration of ASP3662 ameliorated mechanical allodynia in spinal nerve ligation (SNL) and streptozotocin-induced diabetic rats and thermal hyperalgesia in chronic constriction nerve injury rats. ASP3662 also restored muscle pressure thresholds in reserpine-induced myalgia rats. Intrathecal administration of ASP3662 was also effective in SNL rats. However, ASP3662 had no analgesic effects in adjuvant-induced arthritis rats. CONCLUSIONS AND IMPLICATIONS: ASP3662 is a potent, selective and CNS-penetrable inhibitor of 11ß-HSD1. The effects of ASP3662 suggest that selective inhibition of 11ß-HSD1 may be an attractive approach for the treatment of neuropathic and dysfunctional pain, as observed in fibromyalgia.

Involvement of glucose related energy crisis and endoplasmic reticulum stress: Insinuation of streptozotocin induced Alzheimer's like pathology.

The present study was conducted to correlate the cellular and molecular alterations in Alzheimer's pathology employing streptozotocin (STZ) induced experimental rat model. The STZ was administered in rat brain bilaterally by intracerebroventricular route using stereotaxic surgery followed by donepezil dosing. The Alzheimer's related pathological marker like acetylcholinesterase (AChE) activity, tau phosphorylation and amyloid aggregation were observed after STZ administration. STZ treatment showed decreased glucose and glucose transporters (GLUT) level along with augmented level of calcium in both cortical and hippocampal regions of rat brain. Increased calcium level may correlate with endoplasmic reticulum (ER) stress and significantly increased expression of ER stress markers like GRP78, GADD and caspase-12 were observed in STZ treated rat brain. Cellular communication was also affected by STZ administration as observed by increased expression connexin 43. With this view the activation of astrocytes and microglia was also assessed and observed by augmented GFAP and cd11b expression which were partially inhibited with donepezil treatment. The significantly increased level of degenerating neurons, caspase-3 and DNA fragmentation was also observed in rat brain regions which were not inhibited with donepezil treatment and validating the clinical observations. In conclusion, study indicated the STZ induced occurrence of Alzheimer's pathology. Further, STZ administration also caused depleted glucose level, inhibited mitochondrial activity, augmented calcium levels, ER stress, altered cellular communication and neuronal death which were partially attenuated with donepezil treatment.

Intracerebroventricular Administration of Streptozotocin as an Experimental Approach to Depression: Evidence for the Involvement of Proinflammatory Cytokines and Indoleamine-2,3-Dioxygenase.

There is a lack of information about the molecular events underlying the depressive-like effect of an intracerebroventricular injection of streptozotocin (ICV-STZ) in mice. Elevated activity of the tryptophan-degrading enzyme indoleamine-2,3-dioxygenase (IDO) has been proposed to mediate depression in inflammatory disorders. In this study, we report that ICV-STZ activates IDO in the hippocampus of mice and culminates in depressive-like behaviors, measured by an increased duration in immobility time in the forced swimming test and decreased total time of grooming in the splash test. Indirect blockade of IDO activation with the cytokine inhibitor minocycline prevents the development of depressive-like behaviors and attenuates STZ-induced upregulation of proinflammatory cytokines in the hippocampus. Minocycline abrogates the increase in tryptophan and kynurenine levels as well as prevents serotonin dysfunction in the hippocampus of STZ-injected mice. These results suggest that hippocampal IDO activation in STZ-associated depressive-like behavior is mediated by proinflammatory cytokine-dependent mechanisms. Our study not only extends the evidence that IDO has a critical role in mediating inflammation-induced depression but also supports the notion that neuroinflammation and the kynurenine pathway are important targets of novel therapeutic drugs for depression. In addition, our study provides new insights into the neurobiological mechanisms underlying ICV-STZ and indicates that this model could be employed in the preclinical research of depression.

BDNF protects pancreatic ß cells (RIN5F) against cytotoxic action of alloxan, streptozotocin, doxorubicin and benzo(a)pyrene in vitro.

OBJECTIVE: The study was conducted to observe whether brain-derived neurotrophic factor (BDNF) has cytoprotective actions against alloxan (AL), streptozotocin (STZ), doxorubicin (DB) and benzo(a)pyrene (BP) compounds in vitro that may account for its beneficial action in diabetes mellitus. MATERIALS AND METHODS: This in vitro study was performed using rat insulinoma (RIN5F) cells. Possible cytoprotective action of BDNF (using pre-treatment, simultaneous and post-treatment schedules of RIN5F cells with BDNF) against the four chemicals tested was evaluated using MTT and apoptosis assays. Possible mechanism of cytoprotective action of BDNF was assessed by measuring BCl2/IKB-ß/Pdx mRNA transcripts and anti-oxidant levels in RIN5F cells. Effect of alloxan, STZ, doxorubicin and BP on the production of BDNF by RIN5F cells was also studied. RESULTS: Results of the present study revealed that BDNF in the doses (100ng>50ng>10ng/ml) has significant cytoprotection (P<0.001, P<0.01) on cytotoxic action of AL, STZ, DB and BP against rat insulinoma RIN5F (5×10(4) cells/100µl) cells in vitro. It was observed that AL, STZ, DB and BP inhibited BDNF production significantly (P<0.001) in a dose-dependent manner by RIN5F cells (0.5×10(6) cells/500µl) in vitro, while BDNF not only prevented apoptosis induced by these four chemicals but also significantly increased (P<0.001) BCl2/IKB-ß/Pdx mRNA transcripts and restored anti-oxidant levels (P<0.01) in RIN5F cells to normal. DISCUSSION: These results suggest that BDNF has potent cytoprotective actions, restores anti-oxidant defenses to normal and thus, prevents apoptosis and preserves insulin secreting capacity of ß cells. In addition, BDNF enhanced viability of RIN 5F in vitro. Thus, BDNF not only has anti-diabetic actions but also preserves pancreatic ß cells integrity and enhances their viability. These results imply that BDNF functions as an endogenous cytoprotective molecule that may explain its beneficial actions in some neurological conditions as well.

Octaphlorethol A, a novel phenolic compound isolated from Ishige foliacea, protects against streptozotocin-induced pancreatic ß cell damage by reducing oxidative stress and apoptosis.

Pancreatic ß cells are extremely sensitive to oxidative stress, which probably has an important role in ß cell damage in diabetes. The protective effect of octaphlorethol A (OPA), a novel phenolic compound isolated from Ishige foliacea, against streptozotocin (STZ)-induced pancreatic ß cell damage was investigated using a rat insulinoma cell line (RINm5F pancreatic ß cells). Pretreatment with OPA decreased the death of STZ-treated pancreatic ß cells at concentrations of 12.5 µg/ml or 50 µg/ml, and reduced the generation of thiobarbituric acid reactive substances and intracellular reactive oxygen species in a dose-dependent manner in STZ-treated pancreatic ß cells. In addition, the OPA pretreatment increased the activities of antioxidant enzymes such as catalase, superoxide dismutase, and glutathione peroxidase in STZ-treated pancreatic ß cells. Moreover, OPA treatment elevated the level of insulin, which was reduced by STZ treatment, and protected pancreatic ß cells against damage under STZ-treated conditions. These effects were mediated by suppressing apoptosis and were associated with increased anti-apoptotic Bcl-xL expression and reduced pro-apoptotic Bax and cleaved caspase-3 expression. These findings indicate that OPA may be useful as a potential pharmaceutical agent to protect against pancreatic ß cell damage caused by oxidative stress associated with diabetes.

Thalidomide attenuates learning and memory deficits induced by intracerebroventricular administration of streptozotocin in rats.

Neuroinflammatory responses caused by amyloid ß (Aß) peptide deposits are involved in the pathogenesis of Alzheimer's disease (AD). Thalidomide has a significant anti-inflammatory effect by inhibiting TNF-α, which plays role in Aß neurotoxicity. We investigated the effect of thalidomide on AD-like cognitive deficits caused by intracerebroventricular injection of streptozotocin (STZ). Intraperitoneal thalidomide was administered 1 h before the first dose of STZ and continued for 21 days. Learning and memory behavior was evaluated on days 17, 18 and 19, and the rats were sacrificed on day 21 to examine histopathological changes. STZ injection caused a significant decrease in the mean escape latency in passive avoidance and decreased improvement of performance in Morris water maze tests. Histopathological changes were examined using hematoxylin-eosin and Bielschowsky staining. Brain sections of STZ treated rats showed increased neurodegeneration and disturbed linear arrangement of cells in the cortical area compared to controls. Thalidomide treatment attenuated significantly STZ induced cognitive impairment and histopathological changes. Thalidomide appears to provide neuroprotection from the memory deficits and neuronal damage induced by STZ.

The protective effect of a mix of Lactarius deterrimus and Castanea sativa extracts on streptozotocin-induced oxidative stress and pancreatic ß-cell death.

Pancreatic ß-cell death or dysfunction mediated by oxidative stress underlies the development and progression of diabetes mellitus. In the present study, we tested extracts from the edible mushroom Lactarius deterrimus and the chestnut Castanea sativa, as well as their mixture (MIX Ld/Cs), for potential beneficial effects on streptozotocin (STZ)-induced pancreatic ß-cell death. Analysis of chelating effects, reducing power and radical-scavenging assays revealed strong antioxidant effects of the C. sativa extract and MIX Ld/Cs, while the L. deterrimus extract displayed a weak to moderate effect. The antioxidative effect of the chestnut extract corresponds with the high content of phenolics and flavonoids identified by HPLC analysis. In contrast, the mushroom extract contains relatively small amounts of phenols and flavonoids. However, both extracts, and especially their combination MIX Ld/Cs, increased cell viability after the STZ treatment as a result of a significant reduction of DNA damage and improved redox status. The chestnut extract and MIX Ld/Cs significantly lowered the STZ-induced increases in superoxide dismutase and catalase activities, while the mushroom extract had no impact on the activities of these antioxidant enzymes. However, the L. deterrimus extract exhibited good NO-scavenging activity. Different mechanisms that underlie antioxidant effects of the mushroom and chestnut extracts were discussed. When combined as in the MIX Ld/Cs, the extracts exhibited diverse but synergistic actions that ultimately exerted beneficial and protective effects against STZ-induced pancreatic ß-cell death.

Berberine, an isoquinoline alkaloid, inhibits streptozotocin-induced apoptosis in mouse pancreatic islets through down-regulating Bax/Bcl-2 gene expression ratio.

Diabetes may cause apoptosis in pancreatic islets. Berberine is an isoquinoline alkaloid used for its pharmacological functions including anti-inflammation. However, the berberine effect on pancreatic islets is still not clear. This study is aimed at clarifying the protective mechanism in berberine against islet cell apoptosis. This study established in vitro experimental models using streptozotocin (STZ)-treated primary pancreatic islet cells from ICR mice to unravel the protective mechanism of berberine on islets. The Bax/Bcl-2 (pro-/anti-apoptotic) genes expression in the islets was determined using real-time quantitative polymerase chain reaction assay. The results showed that berberine administration at one time or before STZ-stimulation significantly (P<0.05) down-regulated the Bax/Bcl-2 genes expression ratio, compared to those in STZ-treatment alone group. Our results suggest that berberine's anti-apoptotic effect on pancreatic primary islets is through down-regulating the Bax/Bcl-2 genes expression ratio in both concurrent and preventive manners.

Thyroid hormone T3 counteracts STZ induced diabetes in mouse.

This study intended to demonstrate that the thyroid hormone T3 counteracts the onset of a Streptozotocin (STZ) induced diabetes in wild type mice. To test our hypothesis diabetes has been induced in Balb/c male mice by multiple low dose Streptozotocin injection; and a group of mice was contemporaneously injected with T3. After 48 h mice were tested for glucose tolerance test, insulin serum levels and then sacrificed. Whole pancreata were utilized for morphological and biochemical analyses, while protein extracts and RNA were utilized for expression analyses of specific molecules. The results showed that islets from T3 treated mice were comparable to age- and sex-matched control, untreated mice in number, shape, dimension, consistency, ultrastructure, insulin and glucagon levels, Tunel positivity and caspases activation, while all the cited parameters and molecules were altered by STZ alone. The T3-induced pro survival effect was associated with a strong increase in phosphorylated Akt. Moreover, T3 administration prevented the STZ-dependent alterations in glucose blood level, both during fasting and after glucose challenge, as well as in insulin serum level. In conclusion we demonstrated that T3 could act as a protective factor against STZ induced diabetes.

Protective effect of cyclo(his-pro) on streptozotocin-induced cytotoxicity and apoptosis in vitro.

Cyclo(His-Pro) (CHP) is a naturally occurring, cyclic dipeptide structurally related to thyrotropin-releasing hormone (TRH). CHP was efficiently obtained from soybean meal by hydrolysis with flavourzyme and alcalase. In this study, the effects of CHP on streptozotocin (STZ)-induced beta-cell dysfunction and apoptosis were investigated in rat insulinoma cells (RINm5F) secreting insulin. When the RINm5F cells were treated with 2mM STZ, insulin secretion decreased to approximately 54% that of control cells. However, CHP treatment restored the insulin-secreting activity of RINm5F cells to approximately 71% that of the untreated control cells. Moreover, CHP significantly protected the cells from STZ-mediated cytotoxicity via reduction of nitric oxide (NO) production (2.3-fold) and lipid peroxidation (1.9-fold), which were induced by STZ. Moreover, CHP treatment also attenuated STZ-induced apoptotic events, such as activation of caspase-3, poly(ADP-ribose) polymerase (PARP) cleavage, and DNA fragmentation in RINm5F cells, indicating that CHP could protect the cells from apoptotic cell death induced by oxidative stress of STZ by increasing the expression of an anti-apoptotic protein, Bcl-2. These results suggest that CHP could be a candidate material for a protective and therapeutic agent against STZ-mediated cytotoxicity and apoptosis.

Streptozotocin induced activation of oxidative stress responsive splenic cell signaling pathways: protective role of arjunolic acid.

Present study investigates the beneficial role of arjunolic acid (AA) against the alteration in the cytokine levels and simultaneous activation of oxidative stress responsive signaling pathways in spleen under hyperglycemic condition. Diabetes was induced by injection of streptozotocin (STZ) (at a dose of 70 mg/kg body weight, injected in the tail vain). STZ administration elevated the levels of IL-2 as well as IFN-gamma and attenuated the level of TNF-alpha in the sera of diabetic animals. In addition, hyperglycemia is also associated with the increased production of intracellular reactive intermediates resulting with the elevation in lipid peroxidation, protein carbonylation and reduction in intracellular antioxidant defense. Investigating the oxidative stress responsive cell signaling pathways, increased expressions (immunoreactive concentrations) of phosphorylated p65 as well as its inhibitor protein phospho IkappaBalpha and phosphorylated mitogen activated protein kinases (MAPKs) have been observed in diabetic spleen tissue. Studies on isolated splenocytes revealed that hyperglycemia caused disruption of mitochondrial membrane potential, elevation in the concentration of cytosolic cytochrome c as well as activation of caspase 3 leading to apoptotic cell death. Histological examination revealed that diabetic induction depleted the white pulp scoring which is in agreement with the reduced immunological response. Treatment with AA prevented the hyperglycemia and its associated pathogenesis in spleen tissue. Results suggest that AA might act as an anti-diabetic and immunomodulatory agent against hyperglycemia.

Dihydroavenanthramide D protects pancreatic beta-cells from cytokine and streptozotocin toxicity.

Dihydroavenanthramide D (DHAvD) is a synthetic analog to naturally occurring avenanthramide, which is the active component of oat. Although its anti-inflammatory, antiatherosclerotic, and antioxidant effects have been reported, the effect of DHAvD on type 1 diabetes is unknown. Therefore, in this study, the effect of DHAvD on cytokine- or streptozotocin-induced beta-cell damage was investigated. Treatment of RINm5F insulinoma cells or isolated islets with IL-1beta and IFN-gamma induced beta-cell damage through a NF-kappaB-dependent signaling pathway. DHAvD-pretreated RINm5F cells or islets showed resistance to cytokine toxicity, namely suppressed nitric oxide (NO) production, reduced the inducible form of NO synthase expression, and decreased beta-cell destruction and the normal insulin secretion capacity. Furthermore, pretreatment with DHAvD blocked the development of type 1 diabetes in streptozotocin-treated mice. Prior injection with DHAvD maintained a normal range of plasma glucose and insulin, and retained immunoreactivity for insulin in the pancreas. These results suggest that DHAvD may be used to preserve functional beta-cell mass.

Chronic treatment with tocotrienol, an isoform of vitamin E, prevents intracerebroventricular streptozotocin-induced cognitive impairment and oxidative-nitrosative stress in rats.

Intracerebroventricular (ICV) streptozotocin (STZ) has been shown to cause cognitive impairment, which is associated with increased oxidative stress in the brain of rats. In the present study, we investigated the effect of both the isoforms of vitamin E, alpha-tocopherol and tocotrienol against ICV STZ-induced cognitive impairment and oxidative-nitrosative stress in rats. Adult male Wistar rats were injected with ICV STZ (3 mg/kg) bilaterally. The learning and memory behavior was assessed using Morris water maze and elevated plus maze. The rats were sacrificed on day 21 and parameters of oxidative stress, nitrite levels and acetylcholinesterase activity were measured in brain homogenate. alpha-Tocopherol as well as tocotrienol treated groups showed significantly less cognitive impairment in both the behavioral paradigms but the effect was more potent with tocotrienol. Both isoforms of vitamin E effectively attenuated the reduction in glutathione and catalase and reduced the malonaldehyde, nitrite as well as cholinesterase activity in the brains of ICV STZ rats in a dose dependent manner. The study demonstrates the effectiveness of vitamin E isoforms, of which tocotrienol being more potent in preventing the cognitive deficits caused by ICV STZ in rats and suggests its potential in the treatment of neurodegenerative diseases such as Alzheimer's disease.

Alpha(1) and alpha(2)-adrenoreceptor antagonists in streptozotocin- and vincristine-induced hyperalgesia.

The effect of alpha(1)- and alpha(2)-adrenoreceptor antagonists (prazosin and yohimbine, respectively) on streptozotocin (STZ)- and vincristine (VIN)-induced hyperalgesia in rats was studied. In two experimental models, yohimbine (1.0 mg/kg ip) completely abolished STZ and VIN-induced hyperalgesia. This effect was markedly prolonged in diabetic rats. Prazosin (0.3 mg/kg ip) attenuated and delayed development of STZ-induced hyperalgesia. In VIN-elicited neuropathy, the administration of prazosin not only delayed hyperalgesia but also produced antinociception. After cessation of drug administration, a significant decrease in nociceptive threshold was observed. The obtained results seem to indicate that both alpha(1)- and alpha(2)-adrenoreceptors are engaged in diabetic (STZ) and toxic (VIN) neuropathy.

Ozagrel reverses streptozotocin-induced constriction of arterioles in rat retina.

Retinal blood flow decreases early in the progression of diabetic retinopathy; however, the mediators and mechanisms responsible for this decrease have yet to be determined. In this study, diabetes was induced by streptozotocin in rats, and retinal blood flow was measured via intravital microscopy 1 or 3 weeks following the induction of hyperglycemia. Additionally, retinal arteriolar diameters and flow were measured prior to and following acute administration of the thromboxane synthase inhibitor ozagrel to investigate the potential role of thromboxane in the observed constriction. Minimal changes in the retinal diameters and flow were observed at 1 week of diabetes; however, at 3 weeks of diabetes, arteriolar constriction and decreases in blood flow were significant. Notably, the constriction occurred only in the arterioles that were in closer proximity to the venules draining the retina. Acute administration of ozagrel reversed the constriction of the closely venule-paired arterioles. In summary, the results suggest that thromboxane mediates localized, venule-dependent arteriolar constriction induced by streptozotocin-induced diabetes in rats.