Pre-clinical Systematic Reviews

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New from Journal of Neurochemistry

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Pre-clinical systematic review

Sean P. Murphy and Anne N. Murphy

The ever-expanding volume of original articles creates difficulty for even the most resolute to remain current and to readily assimilate topics outside one’s expertise. Narrative scientific reviews are, therefore, invaluable resources and the Journal is pleased to continue to publish these popular and discerning compilations on a regular basis. By nature, and given the compiler’s particular expertise and viewpoint, narrative reviews highlight and interpret subsets of the literature. In contrast, systematic review and meta-analysis are powerful analytical tools typically used to analyze the effects of a drug or treatment, and offer the most objective evidence regarding efficacy. Such reviews are more familiar in the analysis of clinical data, serving to point out voids and weaknesses in current knowledge and helping to shape further trials. By comparison, such reviews of pre-clinical animal data appear only infrequently and yet these could inform the planning and improve the likelihood of success of future clinical trials, and are clearly an integral part of the drug development process. Pre-clinical systematic reviews also identify where there is a need for further ‘basic’ research, preclude unnecessary study replication, and can contribute to both ‘reduction’ and ‘refinement’ in animal experimentation. Hopefully, the systematic reviews of pre-clinical data in this issue exemplify these benefits and will encourage their future submission to the Journal.

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wAdministration of thiazolidinediones for neuroprotection in ischemic stroke: a pre-clinical systematic review

Amanda T. White and Anne N. Murphy

Department of Pharmacology, University of California San Diego, San Diego, California, USA

Thiazolidinediones (TZDs) may prevent or attenuate CNS injury arising from an ischemic event. We performed metaanalysis of experimental studies in which a TZD (either rosiglitazone or pioglitazone) was administered in a rodent model of focal or global cerebral ischemia. Infarct volume was the primary endpoint for analysis of drug efficacy, and neurological outcome was also assessed. We identified 31 studies through the use of PubMed and Embase, 22 of which met our pre-specified inclusion criteria and were analyzed with the Cochrane Review Manager software. Treatment with TZDs decreased infarct volume and improved neurological outcome regardless of study quality, dose timing, or ischemia model (transient or permanent). Rosiglitazone and pioglitazone were similarly effective in reducing infarct volume and protecting neurologic function. Importantly, the collective data suggest that pre-treatment with a TZD is not required for neuroprotection, although additional studies are clearly needed to define the breadth of the therapeutic window. The data warrant further studies into the potential acute use of TZDs for ischemic stroke therapy in the general population.

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wBenefits of histone deacetylase inhibitors for acute brain injury: a systematic review of animal studies

Claire L. Gibson* and Sean P. Murphy

*School of Psychology, University of Leicester, Leicester, UKDepartment of Neurological Surgery, University of Washington School of Medicine, Seattle, Washington, USA

Drugs that inhibit histone deacetylase (HDAC) activities have enormous potential as neuroprotective agents. We performed a systematic review of controlled animal studies that administered known inhibitors of the zinc-dependent HDACs before and/or after acute cerebral injury and assessed anatomic/functional outcomes. Relevant studies were found bysearching PubMed, Embase and Web of Science. From more than 100 identified publications, those data meeting specific criteria were analyzed using the Cochrane Review Managersoftware. A beneficial effect of administering HDAC inhibitors was seen in studies involving cerebral ischemia or nonischemic models of acute cerebral injury. Specific studies assessed efficacy when drug was administered up to 14 days prior to, and 14 days following, the onset of cerebral injury. This systematic review provides objective evidence of a neuroprotective role for drugs that inhibit HDACs and highlights particular areas that require further experimental investigation.

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wAre current disease-modifying therapeutics in multiple sclerosis justified on the basis of studies in experimental autoimmune encephalomyelitis?

Nasr Farooqi, Bruno Gran and Cris S. Constantinescu

Division of Clinical Neurology, University of Nottingham, Queen’s Medical Centre, Nottingham, UK

The precise aetio-pathology of multiple sclerosis remains elusive. However, important recent advances have beenmadeand several therapies have been licensed for clinical use. Many of these were developed, validated or tested in the animal model, experimental autoimmune encephalomyelitis (EAE). This systematic review aims to assess whether the current disease modifying treatments and those that are the closest to the clinic are justified on the basis of the results of EAE studies. We discuss some aspects of the utility and caveats of EAE as a model for multiple sclerosis drug development.

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wExperimental models of vascular dementia and vascular cognitive impairment: a systematic review

Nadim S. Jiwa, Peter Garrard and Atticus H. Hainsworth

Clinical Neuroscience, Division of Clinical Sciences, St George’s University of London, London, UK

Vascular cognitive impairment (VCI) encompasses vascular dementia and is the second most common cause of dementing illness after Alzheimer’s disease. The main causes of VCI are: cerebral small vessel disease; multi-infarct dementia; strategic infarct (i.e. located in a functionally-critical brain area); haemorrhage/microbleed; angiopathy (including cerebral amyloid angiopathy); severe hypoperfusion (e.g. cardiac arrhythmia); and hereditary vasculopathy (e.g. cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, CADASIL). In this systematic analysis, we aimed to relate cognitive and neuropathological features of experimental models to clinical VCI. We extracted data from 107 studies covering 16 models. These included: brief global ischaemic insults (in rats, mice or gerbils); chronic global hypoperfusion (rats, mice, gerbils); chronic hypertension (in primates or stroke-prone, spontaneously-hypertensive rats); multiple ischaemic lesions because of intra-vascular emboli (in rodents, rabbits or primates); strategic ischaemic lesions (in rats or minipigs); generalised vasculopathies, because of mutant Notch3, hyperhomocysteinaemia, experimental diabetes mellitus or lack of cerebral vasodilator M5 receptors (rats or mice). Most cognitive testing showed deficits in working and reference memory. The lesions observed were microinfarcts, diffuse white matter lesions, hippocampal neuronal death, focal ischaemic lesions and micro-haemorrhages. The most-used model was bilateral carotid artery occlusion in rats, leading to chronic hypoperfusion and white matter injury.

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