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Safety and efficacy evaluation of carnosine, an endogenous neuroprotective agent for ischemic stroke.

ABSTRACT: An urgent need exists to develop therapies for stroke that have high efficacy, long therapeutic time windows, and acceptable toxicity. We undertook preclinical investigations of a novel therapeutic approach involving supplementation with carnosine, an endogenous pleiotropic dipeptide.Efficacy and safety of carnosine treatment was evaluated in rat models of permanent or transient middle cerebral artery occlusion. Mechanistic studies used primary neuronal/astrocytic cultures and ex vivo brain homogenates.Intravenous treatment with carnosine exhibited robust cerebroprotection in a dose-dependent manner, with long clinically relevant therapeutic time windows of 6 hours and 9 hours in transient and permanent models, respectively. Histological outcomes and functional improvements including motor and sensory deficits were sustained on 14th day poststroke onset. In safety and tolerability assessments, carnosine did not exhibit any evidence of adverse effects or toxicity. Moreover, histological evaluation of organs, complete blood count, coagulation tests, and the serum chemistry did not reveal any abnormalities. In primary neuronal cell cultures and ex vivo brain homogenates, carnosine exhibited robust antiexcitotoxic, antioxidant, and mitochondria protecting activity.In both permanent and transient ischemic models, carnosine treatment exhibited significant cerebroprotection against histological and functional damage, with wide therapeutic and clinically relevant time windows. Carnosine was well tolerated and exhibited no toxicity. Mechanistic data show that it influences multiple deleterious processes. Taken together, our data suggest that this endogenous pleiotropic dipeptide is a strong candidate for further development as a stroke treatment.

SUBMITTER: Bae ON

PROVIDER: S-EPMC3678096 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Safety and efficacy evaluation of carnosine, an endogenous neuroprotective agent for ischemic stroke.

Bae Ok-Nam ON Serfozo Kelsey K Baek Seung-Hoon SH Lee Ki Yong KY Dorrance Anne A Rumbeiha Wilson W Fitzgerald Scott D SD Farooq Muhammad U MU Naravelta Bharath B Bhatt Archit A Majid Arshad A

Stroke 20121218 1

<h4>Background and purpose</h4>An urgent need exists to develop therapies for stroke that have high efficacy, long therapeutic time windows, and acceptable toxicity. We undertook preclinical investigations of a novel therapeutic approach involving supplementation with carnosine, an endogenous pleiotropic dipeptide.<h4>Methods</h4>Efficacy and safety of carnosine treatment was evaluated in rat models of permanent or transient middle cerebral artery occlusion. Mechanistic studies used primary neur ...[more]

PMID: 23250994

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Project description:BackgroundVinpocetine as a neuroprotective agent is effective in acute ischemic stroke in some randomized controlled trials (RCTs). Since the last systematic review has been published in 2008, which didn't find conclusive evidence favoring its use, two more RCTs have also been completed.MethodsRelevant electronic databases were searched with a suitable combination of Medical Subject Headings terms to detect publications describing RCTs exploring the safety and efficacy of vinpocetine in patients with acute ischemic stroke. The risk of bias was determined by using the Cochrane Collaboration's tool for assessing the risk of bias in RCTs after full-text review and relevant data extraction. Higgins and Thompson's I2 method was used to assess heterogeneity in studies. The presence of publication bias was assessed by Egger's test. We used a random effect model when I2 was more than 50% and a fixed-effect model for other parameters.ResultsFour placebo-controlled RCTs enrolling a total of 601 and 236 patients in vinpocetine and placebo groups, respectively, were included. The number of patients with death or significant disability was lower in the vinpocetine group than that in the placebo group at both 1 and 3 months (relative risk 0.80, 95% confidence interval [CI] 0.65-0.99 and relative risk 0.67, CI 0.48-0.92, p = 0.04 and 0.02, respectively). The degree of disability in participants at 1 month and 3 months was also lower in vinpocetine group than that in the placebo group (standardized mean difference (SMD) 0.49, 95% CI 0.03-0.95 and SMD 1.22, CI 0.23-2.24, p = 0.001 and 0.04, respectively). Change in mini-mental state examination score compared with baseline at trial enrolment was also better in the vinpocetine group than in the placebo group (pooled weighted mean difference 0.92, 95% CI 0.02-1.82, p = 0.04).ConclusionsVinpocetine has some promising efficacy in patients with ischemic stroke when used in the acute stage in reducing the disability, but presently there is not enough evidence to suggest that it also reduces case fatality. More double-blind, placebo-controlled RCTs of adequate sample size are needed before making recommendations for the routine administration of vinpocetine for all patients with acute ischemic stroke.

Project description:This is the first in vivo study to investigate the neuroprotective effects of krypton on focal cerebral ischemia. The aim of the study was to analyze the effect of 2 h of inhalation of a krypton-oxygen mixture (Kr 70%/O2 30%) on the recovery of neurological functions and the degree of brain damage in rats after photoinduced ischemic stroke (PIS) and to investigate the possible mechanisms responsible for this neuroprotection. Experiments were performed on male Wistar rats weighing 250-300 g (n = 32). Animals were randomized into four groups. Two groups (n = 20) underwent photoinduced ischemic stroke, followed by 2 h of inhalation of krypton-oxygen mixture consisting of Kr 70%/O2 30% or a nitrogen-oxygen breathing mixture consisting of N2 70%/O2 30%, followed by neurological examinations on days 3 and 7. The other two groups (n = 12) received only gas mixtures of the same concentration and exposure duration as in those in the PIS groups, then Western blot analysis of the potential molecular mechanisms was performed. The results of the study show that treatment with the krypton-oxygen mixture consisting of Kr 70%/O2 30% improves the neurological status on day 7 of observation, reduces the lesion volume according to the MRI examination and the number of Iba-1- and caspase-3-positive cells in the damaged area, promotes the activation of neoangiogenesis (an increase in the von Willebrand factor), and reduces the penumbra area and the number of NeuN-positive cells in it on day 14 of observation. Inhalation of the krypton-oxygen mixture also significantly increases the levels of phosphorylated AKT kinase (protein kinase B) and glycogen synthase kinase 3b (pGSK3b) and promotes the expression of transcription factor Nrf2, which was accompanied by the lowered expression of transcription factor NFkB (p50). Thus, we showed pronounced neuroprotection induced by krypton inhalation after stroke and identified the signaling pathways that may be responsible for restoring neurological functions and reducing damage.

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Safety and efficacy evaluation of carnosine, an endogenous neuroprotective agent for ischemic stroke.

Publications

Safety and efficacy evaluation of carnosine, an endogenous neuroprotective agent for ischemic stroke.

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