Effect of chronic treatment of Carvedilol on oxidative stress in an intracerebroventricular streptozotocin induced model of dementia in rats

Pharmacology Division, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study, Panjab University, Chandigarh, India.
The Journal of pharmacy and pharmacology 12/2009; 61(12):1665-72. DOI: 10.1211/jpp/61.12.0012
Source: PubMed


Oxidative stress is emerging as an important issue in the pathogenesis of dementia. This study was conducted to investigate the possible neuroprotective effects of carvedilol against streptozotocin induced behavioural alterations and oxidative damage in rats.
An intracerbroventricular cannula was implanted in the lateral ventricles of male Wistar rats. Various behavioural (locomotor activity, Morris water maze task) and biochemical parameters (lipid peroxidation, nitrate concentration, catalase, acetylcholinesterase, reduced glutathione and protein) were assessed.
Intracerebroventricular administration of streptozotocin caused a significant memory deficit as evaluated in the Morris water maze task paradigms, and caused marked oxidative damage as indicated by significant increases in malondialdehyde and nitrite levels, and depletion of superoxide dismutase, catalase and reduced glutathione levels. It also caused a significant increase in acetylcholinesterase activity. Chronic administration of carvedilol (1 and 2 mg/kg, i.p.) for a period of 25 days starting 4 days before streptozotocin administration resulted in an improvement in memory retention, and attenuation of oxidative damage and acetylcholinesterase activity.
This study demonstrates the effectiveness of carvedilol in preventing cognitive deficits as well as the oxidative stress caused by intracerbroventicular administration of streptozotocin in rats. Carvedilol may have potential in the treatment of neurodegenerative diseases.

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Available from: Atish Prakash, May 07, 2014
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    • "For example, icv-STZ treated animals display spatial [11], [20], working, episodic [21], and reference memory alterations [7]. Currently, the icv-STZ model is widely used to evaluate neuroprotective properties of various compounds such as anti-inflammatory drugs (cyclooxygenase inhibitors [22], Jun N-terminal kinase inhibitors [23], antioxidants (curcumin [24], S-allyl cysteine [25], selenium [26]), acetylcholinesterase inhibitors (donepezil, tacrine [21], [27], [28]), antidiabetic drugs (pioglitazone, [29]), cholesterol-lowering drugs (statins [30], [31] and others like adrenergic alpha and beta receptors antagonists (carvedilol [32]), protease inhibitors [33] or type-1 phosphodiesterase inhibitors (vinpocetine [13]). "
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    ABSTRACT: Cerebral aging is often associated with the occurrence of neurodegenerative diseases leading to dementia. Animal models are critical to elucidate mechanisms associated to dementia and to evaluate neuroprotective drugs. Rats that received intracerebroventricular injection of streptozotocin (icv-STZ) have been reported as a model of dementia. In these animals, this drug induces oxidative stress and brain glucose metabolism impairments associated to insulin signal transduction failure. These mechanisms are reported to be involved in the pathogenesis of Alzheimer's disease and other dementia. Icv-STZ rats also display memory impairments. However, little is known about the precise location of the lesions induced by STZ administration. In this context, the present study characterized the cerebral lesions induced by two-doses of icv-STZ by using high-field magnetic resonance imaging to easily and longitudinally detect cerebral abnormalities and by using immunohistochemistry to evaluate neuronal loss and neuroinflammation (astrocytosis and microgliosis). We showed that, at high doses, icv-STZ induces severe and acute neurodegenerative lesions in the septum and corpus callosum. The lesions are associated with an inflammation process. They are less severe and more progressive at low doses. The relevance of high and low doses of icv-STZ to mimic dementia and evaluate new drugs is discussed in the final part of this article.
    PLoS ONE 09/2012; 7(9):e46196. DOI:10.1371/journal.pone.0046196 · 3.23 Impact Factor
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    • "Carvedilol is a racemic third-generation beta blocker with both enantioselective pharmacokinetic and pharmacodynamic properties (Keating et al., 2006; Bartsch et al., 1990; Prakash et al., 2009). It also shows pleiotropic effects, including antioxidant activity, inhibition of apoptosis, anti-inflammatory action and mitochondrial protection (Ruffolo et al., 1990). "
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    ABSTRACT: Cardiovascular effects and pharmacokinetics of carvedilol were assessed in fructose-fed rats using pharmacokinetic-pharmacodynamic (PK-PD) modeling. Male Sprague-Dowley rats were randomly assigned to receive tap water (C rats) or fructose solution (10% w/v) (F rats) during 6 weeks. Effects of carvedilol (1-3 mg/kg i.v.) on blood pressure, heart rate and blood pressure variability were recorded. Carvedilol plasma pharmacokinetics was studied by traditional blood sampling. Relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by PK-PD modeling. Vascular sympatholytic activity of carvedilol was assessed by estimation of drug effects on low frequency blood pressure variability using spectral analysis. A greater volume of distribution and clearance of S-carvedilol compared to R-enantiomer was found in both experimental groups. Although PK-PD properties of S-carvedilol chronotropic effect were not altered in F rats, hypertensive rats showed greater efficacy to the carvedilol hypotensive response after administration of the higher dose. A similar potency of carvedilol to inhibit sympathetic vascular activity was found in F rats. Carvedilol showed enantioselective pharmacokinetic properties with increased distribution in F rats compared with normotensive animals. An enhanced hypotensive activity of carvedilol was found in F rats compared with C rats, which is not related to enhance sympatholytic activity.
    Xenobiotica 09/2011; 42(2):206-19. DOI:10.3109/00498254.2011.604746 · 2.20 Impact Factor
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    • "of memory retention (evaluated in the Morris water maze task paradigms) and in attenuation of oxidative damage in the streptozotocin induced model of dementia in rats (Prakash & Kumar, 2009). Carvedilol may have a potential in the treatment of neurodegenerative diseases. "
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    ABSTRACT: New effective strategies and new highly effective neuroprotective agents are being searched for the therapy of human stroke and cerebral ischemia. The compound SMe1EC2 is a new derivative of stobadine, with enhanced antioxidant properties compared to the maternal drug. Carvedilol, a non-selective beta-blocker, possesses besides its cardioprotective and vasculoprotective properties also an antioxidant effect. We compared the effect of carvedilol and SMe1EC2, antioxidants with a similar chemical structure, in two experimental models of oxidative stress in young and adult rat brain tissue. SMe1EC2 was found to improve the resistance of hippocampal neurons to ischemia in vitro in young and even in 18-month-old rats and inhibited formation of protein carbonyl groups induced by the Fe(2+)/ascorbic acid pro-oxidative system in brain cortex homogenates of young rats. Carvedilol exerted a protective effect only in the hippocampus of 2-month-old rats and that at the concentration 10-times higher than did SMe1EC2. The inhibitory effect of carvedilol on protein carbonyl formation induced by the pro-oxidative system was not proved in the cortex of either young or adult rats. An increased baseline level of the content of protein carbonyl groups in the adult versus young rat brain cortex confirmed age-related changes in neuronal tissue and may be due to increased production of reactive oxygen species and low antioxidant defense mechanisms in the adult rat brain. The results revealed the new pyridoindole SMe1EC2 to be more effective than carvedilol in neuroprotection of rat brain tissue in both experimental models involving oxidative stress.
    Interdisciplinary toxicology 12/2010; 3(4):122-6. DOI:10.2478/v10102-010-0051-x
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