Treatment of severe apathy with methylphenidate

Journal of Pharmacy and Pharmacology, 2009

Objectives 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. Methods 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. Key findings 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. Conclusions 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.

2011

Oligomeric β-amyloid (Aβ) has recently been linked to synaptic plasticity deficits, which play a major role in progressive cognitive decline in Alzheimer's disease (AD). Here we present evidence that chronic oral administration of carvedilol, a nonselective β-adrenergic receptor blocker, significantly attenuates brain oligomeric Aβ content and cognitive deterioration in two independent AD mouse models. We found that carvedilol treatment significantly improved neuronal transmission, and that this improvement was associated with the maintenance of number of the less stable "learning" thin spines in the brains of AD mice. Our novel observation that carvedilol interferes with the neuropathologic, biochemical and electrophysiological mechanisms underlying cognitive deterioration in AD supports the potential development of carvedilol as a treatment for AD.

Journal of Applied Pharmaceutical Science

The use of β-adrenoceptor blocking agents (β-blockers) in the clinical treatment of cardiovascular disorders and glaucoma are associated with enhancedvigilance, attention, reward, learning and memory. The present study was designed to explore the possible role of Carvedilol, an adrenergic antagonist in ameliorating scopolamineinduced neurotoxicity in rats. Mice were divided into control and treatment groups. Control mice for each test received 10 ml normal saline/kg while the treatment groups (n = 6) received Carvedilol (2.5, 5 and 10 mg/kg orally) and1 mg scopolamine/kg intraperitoneally). One hour after sildenafil and thirty minutes after scopolamine administration orally and intraperitoneally respectively, the animals were assessed for 5 minutes on elevated plus maze, Y-maze and open-field. The parametersmeasured on the EPM were memory acquisition and memory retention latencies with and without scopolamine while spontaneous alternation behaviour was measured in Ymaze. The effect of Carvedilol on locomotion was assessed in mice using open field.Carvedilol significantly (p<0.001) shortened memory acquisition and retrieval latencies in mice with scopolamine-induced cognitive deficit. Carvedilol produced significant (p<0.0001) increase in spontaneous alternation behaviour in both memory intact and memory deficit models. Carvedilol however, had no effect on locomotor activity of mice. The results suggest that Carvedilol enhanced memory acquisition and retrieval in cognitive deficit and cognitive intactmice.It also improved short term memory as indicated by increase in spontaneous alternation behaviour in mice.Carvedilol may therefore be useful in management of dementing disorders such as Alzheimer's disease.

Pharmacological reports : PR

3-nitropropionic acid (3-NP)-induced neurotoxicity causes a cellular energy deficit and oxidative stress via an irreversible inhibition of the mitochondrial enzyme succinate dehydrogenase (SDH). Systemic administration of 3-NP causes motor and cognitive deficits, particularly those associated with excessive free radical generation. Recently, carvedilol has been implicated as a neuroprotectant in the treatment of various neurological disorders. The present study was designed to investigate the neuroprotective effects of carvedilol against 3-NP-induced cognitive impairment and oxidative damage in rats. Intraperitoneal administration of 3-NP (20 mg/kg for 4 days) caused significant body weight reduction, impaired motor function (locomotor activity, movement pattern), induced vacuous chewing movements, led to poor retention of memory in the Morris water maze, and elevated plus maze task paradigms. Chronic treatment with carvedilol (1 and 2 mg/kg, po), once daily for a period of 8 days b...

Journal of Alzheimer's disease : JAD, 2010

In this study, we examined acute effects of carvedilol, a nonselective alpha/beta-adrenergic receptor blocker, on neuronal transmission and long-term potentiation (LTP) in six month-old TgCRND8 mice and their wild-type age-matched controls. Field excitatory postsynaptic potentials were recorded in the CA1 region of the hippocampus from carvedilol- or vehicle dimethyl sulfoxide-treated slices, and differences in basal synaptic transmission and LTP were assessed. Carvedilol treatment produced a significant increase in basal synaptic transmission and LTP in TgCRND8 mice, as compared to their vehicle-treated slices, in which basal neuronal transmission and LTP decreased. Interestingly, carvedilol significantly suppressed spontaneous seizure activity in TgCRND8 mice as measured by the number of slices showing epileptic discharges as well as the number of spikes within these and the amplitude of the second spike, measured at baseline and end of recording. In contrast, vehicle-treated slic...

Stroke, 1992

Background and Purpose: Free radical generation mediates part of the ischemic neuronal damage caused by the excitatory amino acid glutamate. Carvedilol, a novel multiple-action antihypertensive agent, has been shown to scavenge free radicals and inhibit lipid peroxidation in swine heart and rat brain homogenates. Therefore, we studied the neuroprotective effect of carvedilol on cultured cerebellar neurons and on CA1 hippocampal neurons of gerbils exposed to brain ischemia. Methods: Neuroprotective mechanisms were studied using an in vitro ischemia model of cultured rat cerebellar granule cell neurons exposed to either glutamate or oxygen free radical-generating systems. Prevention of lipid peroxidation by carvedilol was studied by measuring the formation of thiobarbituric acid-reactive substance. Gerbil CA1 neuron survival was examined by direct neuronal count 7 days after 6 minutes of global ischemia with reperfusion. Results: Carvedilol protected cultured neurons in a dose-dependent manner against glutamate-mediated excitotoxicity (inhibitory concentration [IC S0 ] = 1.1 fiM) as well as against a 20-minute oxidative challenge (IC5o=5 /tM). The IC 50 against the oxidative challenge was lowered to 1.3 fiM by growing neurons for 24 hours in the presence of carvedilol. At 10 ftM carvedilol inhibited lipid peroxidation 50% and 73% (n=4, p< 0.001) in neurons exposed to two different free radical-generating systems. Neuroprotection of 52% («=22, p=0.009 versus vehicle) of gerbil CA1 hippocampal neurons was achieved by pretreatment and posttreatment with subcutaneous injection of 3 nig/kg carvedilol twice a day for 4 and 3 days, respectively. Conclusions: Carvedilol provided neuroprotection in both in vitro and in vivo models of neuroinjury, where oxygen radicals are likely to play an important role. Therefore, carvedilol may reduce the risk of cerebral ischemia and stroke by virtue of both its antihypertensive action and its antioxidative properties.

Neuroscience Letters, 1992

Carvedilol's potent antioxidant activity could explain its protective action in brain ischemia, but may not apply to glutamate-induced excitotoxicity in cultured cerebellar granule cells, since glutamate neurotoxicity was not associated with the formation of lipid peroxidative products. Rather, carvedilol diminished the N-methyl-D-aspartate (NMDA)/glycine-induced increase in intracellular calcium ([Ca2+]i), lowering [Ca2+], by a maximum of 66 _+ 5% (n = 8) with a 50% inhibitory concentration of 0.8 HM. Prior addition of 5/~M dihydropyridines did not shift the dose response of carvedilol, but did significantly lower the NMDA/glycine-stimulated response to 64% of untreated (n-8, P-0.014). Inclusion of 5/IM carvedilol before the additions of NMDA/glycine prevented 85% of the increase in [Ca2÷]~. Furthermore, carvedilol displaced 3[H]MK-801 binding to rat brain cortical membranes with a Kj of 29.4 _+ 2.2¢tM (n = 6) and no selectivity for the glutamate or glycine binding sites. These data therefore suggest that, in addition to its antihypertensive and anti-lipid peroxidative functions, carvedilol has neuroprotective activity as a calcium channel blocker and as a non-competitive inhibitor at the NMDA receptor.

Annals of the New York Academy of Sciences, 2006

Journal of Diabetes Research

Diabetic neuropathy serves as a major complication for diabetic patients across the world. The use of effective treatment is integral for reducing the health complications for diabetic patients. This study has evaluated the carvedilol potential neuroprotective effect on diabetic neuropathy. An in vitro model of diabetic neuropathy was used, including dorsal root ganglia (DRG) that were cultured from male adult mice C57BL. These were incubated for about twenty-four hours in high glucose (HG) media (45 mM). Some cells were incubated with carvedilol (10 μM). Neuronal viability, neuronal morphology, and activating transcription factor 3 (AFT3) were measured. The cell viability was decreased, along with neuronal length, soma area, and soma perimeter with HG media. Also, there was an overexpression of ATF3, which is a neuronal stress response marker. The pretreatment with carvedilol increased the viability of DRG as compared to HG-treated cells. Also, it significantly protected the DRG fr...

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