Animal Models Of Acute Stroke Research Articles

Demonstration of magnetization transfer and relaxation normalized pH-specific pulse-amide proton transfer imaging in an animal model of acute stroke.

pH-weighted amide proton transfer (APT) MRI is promising to serve as a new surrogate metabolic imaging biomarker for refined ischemic tissue demarcation. APT MRI with pulse-RF irradiation (pulse-APT) is an alternative to the routine continuous wave (CW-) APT MRI that overcomes the RF duty cycle limit. Our study aimed to generalize the recently developed pH-specific magnetization transfer and relaxation-normalized APT (MRAPT) analysis to pulse-APT MRI in acute stroke imaging. Multiparametric MRI, including CW- and pulse-APT MRI scans, were performed following middle cerebral artery occlusion in rats. We calculated pH-sensitive MTRasym and pH-specific MRAPT contrast between the ipsilateral diffusion lesion and contralateral normal area. An inversion pulse of 10 to 15 ms maximizes the pH-sensitive MRI contrast for pulse-APT MRI. The contrast-to-noise ratio of pH-specific MRAPT effect between the contralateral normal area and ischemic lesion from both methods are comparable (3.25 ± 0.65 vs. 3.59 ± 0.40, P > .05). pH determined from both methods were in good agreement, with their difference within 0.1. Pulse-APT MRI provides highly pH-specific mapping for acute stroke imaging.

Abstract WP255: Omega-3 Fatty Acids as a Treatment for Experimental Ischaemic Stroke: A Systematic Review and Meta-analysis

Introduction: The number of stroke patients arriving at hospital within a therapeutic timeframe is increasing, enabling earlier and more successful intervention with thrombolysis and thrombectomy. Despite promising animal data, no neuroprotectants have translated into clinical practice. Brain tissue contains a high amount of polyunsaturated fatty acids, particularly docosahexaenoic acid (DHA), an omega-3 fatty acid essential for normal brain growth and cognitive function. As DHA plays a critical role in neuronal survival and synaptic function, and is also a potent modulator of brain inflammation, it is a strong candidate for a successful neuroprotectant in stroke. Aims: We therefore aimed to summarise the current evidence for omega-3 fatty acids as a treatment for experimental acute ischaemic stroke. Methods: A systematic literature review of papers reporting omega-3 administration in animal models of acute stroke was conducted using the CAMARADES systematic review facility (SyRF). 1173 titles were screened, 168 abstracts reviewed and data extracted from 15 studies. Data were extracted manually, and collated, organised and analysed within CAMARADES. Measures of study quality were recorded, reflecting current STAIR recommendations for pre-clinical studies. Pre-defined endpoints extracted included mortality, infarct volume and neurobehavioural score. Results: DHA reduced infarct volume with an effect size of 48.5%, (95% CI 32.2 - 65.5) compared to control treatments. Neurobehavioural score was improved by 34.8%,( 95% CI 21.8 - 47.7) in DHA treated animals. There was a decrease in mortality of 61% for DHA treated animals (OR 0.39, 95% CI 0.21-0.77(12 studies, no heterogeneity)). All studies used male animals, and no studies co-administered alteplase. Composition of omega-3 preparations was a source of significant heterogeneity (P<0.05). Post hoc analysis showed laboratory group was also a significant source of heterogeneity. Conclusions: Current evidence suggests that DHA administration significantly improves outcome and decreases mortality in animal models of acute ischaemic stroke, providing support for further translational studies.

PH imaging reveals worsened tissue acidification in diffusion kurtosis lesion than the kurtosis/diffusion lesion mismatch in an animal model of acute stroke

Diffusion weighted imaging (DWI) has been commonly used in acute stroke examination, yet a portion of DWI lesion may be salvageable. Recently, it has been shown that diffusion kurtosis imaging (DKI) defines the most severely damaged DWI lesion that does not renormalize following early reperfusion. We postulated that the diffusion and kurtosis lesion mismatch experience heterogeneous hemodynamic and/or metabolic injury. We investigated tissue perfusion, pH, diffusion, kurtosis and relaxation from regions of the contralateral normal area, diffusion lesion, kurtosis lesion and their mismatch in an animal model of acute stroke. Our study revealed significant kurtosis and diffusion lesion volume mismatch (19.7 ± 10.7%, P < 0.01). Although there was no significant difference in perfusion and diffusion between the kurtosis lesion and kurtosis/diffusion lesion mismatch, we showed lower pH in the kurtosis lesion (pH = 6.64 ± 0.12) from that of the kurtosis/diffusion lesion mismatch (6.84 ± 0.11, P < 0.05). Moreover, pH in the kurtosis lesion and kurtosis/diffusion mismatch agreed well with literature values for regions of ischemic core and penumbra, respectively. Our work documented initial evidence that DKI may reveal the heterogeneous metabolic derangement within the commonly used DWI lesion.

Validation of fast diffusion kurtosis MRI for imaging acute ischemia in a rodent model of stroke.

Diffusion-weighted imaging (DWI) captures ischemic tissue that is likely to infarct, and has become one of the most widely used acute stroke imaging techniques. Diffusion kurtosis imaging (DKI) has lately been postulated as a complementary MRI method to stratify the heterogeneously damaged DWI lesion. However, the conventional DKI acquisition time is relatively long, limiting its use in the acute stroke setting. Recently, a fast kurtosis mapping method has been demonstrated in fixed brains and control subjects. The fast DKI approach provides mean diffusion and kurtosis measurements under substantially reduced scan time, making it amenable to acute stroke imaging. Because it is not practical to obtain and compare different means of DKI to test whether the fast DKI method can reliably detect diffusion and kurtosis lesions in acute stroke patients, our study investigated its diagnostic value using an animal model of acute stroke, a critical step before fast DKI acquisition can be routinely applied in the acute stroke setting. We found significant correlation, per voxel, between the diffusion and kurtosis coefficients measured using the fast and conventional DKI protocols. In acute stroke rats, the two DKI methods yielded diffusion and kurtosis lesions that were in good agreement. Importantly, substantial kurtosis-diffusion lesion mismatch was observed using the conventional (26 ± 13%, P < 0.01) and fast DKI methods (23 ± 8%, P < 0.01). In addition, regression analysis showed that the kurtosis-diffusion lesion mismatches obtained using conventional and fast DKI methods were substantially correlated (R(2) = 0.57, P = 0.02). Our results confirmed that the recently proposed fast DKI method is capable of capturing heterogeneous diffusion and kurtosis lesions in acute ischemic stroke, and thus is suitable for translational applications in the acute stroke clinical setting.

Neuroprotective agents in ischemic stroke: past failures and future opportunities

Tissue plasminogen activator is the only US FDA-approved therapy for acute ischemic stroke treatment. There is a need for other therapies such as neuroprotective agents that can be used in acute ischemic stroke patients. Many neuroprotective agents have been shown to be promising after testing in animal models of acute stroke, but when tested in patients, efficacy signals are not consistent or safety challenges have been noted. This review article will discuss different neuroprotective agents, including free-radical scavengers and antioxidants, NMDA-receptor antagonists, inflammatory cascade inhibitors and different ion channel blockers/modulators that have been tested in acute ischemic stroke. The review will also address the key reasons for their failure in clinical trials and provide recommendations to improve translation of basic science research into day-to-day clinical practice.

The role of citicoline in neuroprotection and neurorepair in ischemic stroke.

Advances in acute stroke therapy resulting from thrombolytic treatment, endovascular procedures, and stroke units have improved significantly stroke survival and prognosis; however, for the large majority of patients lacking access to advanced therapies stroke mortality and residual morbidity remain high and many patients become incapacitated by motor and cognitive deficits, with loss of independence in activities of daily living. Therefore, over the past several years, research has been directed to limit the brain lesions produced by acute ischemia (neuroprotection) and to increase the recovery, plasticity and neuroregenerative processes that complement rehabilitation and enhance the possibility of recovery and return to normal functions (neurorepair). Citicoline has therapeutic effects at several stages of the ischemic cascade in acute ischemic stroke and has demonstrated efficiency in a multiplicity of animal models of acute stroke. Long-term treatment with citicoline is safe and effective, improving post-stroke cognitive decline and enhancing patients’ functional recovery. Prolonged citicoline administration at optimal doses has been demonstrated to be remarkably well tolerated and to enhance endogenous mechanisms of neurogenesis and neurorepair contributing to physical therapy and rehabilitation.

The Influence of Stroke Risk Factors and Comorbidities on Assessment of Stroke Therapies in Humans and Animals

The main driving force behind the assessment of novel pharmacological agents in animal models of stroke is to deliver new drugs to treat the human disease rather than to increase knowledge of stroke pathophysiology. There are numerous animal models of the ischaemic process and it appears that the same processes operate in humans. Yet, despite these similarities, the drugs that appear effective in animal models have not worked in clinical trials. To date, tissue plasminogen activator is the only drug that has been successfully used at the bedside in hyperacute stroke management. Several reasons have been put forth to explain this, but the failure to consider comorbidities and risk factors common in older people is an important one. In this article, we review the impact of the risk factors most studied in animal models of acute stroke and highlight the parallels with human stroke, and, where possible, their influence on evaluation of therapeutic strategies.

Preclinical Drug Evaluation for Combination Therapy in Acute Stroke Using Systematic Review, Meta-Analysis, and Subsequent Experimental Testing

There is some evidence that in animal models of acute ischaemic stroke, combinations of neuroprotective agents might be more efficacious than the same agents administered alone. Hence, we developed pragmatic, empirical criteria based on therapeutic target, cost, availability, efficacy, administration, and safety to select drugs for testing in combination in animal models of acute stroke. Magnesium sulphate, melatonin, and minocycline were chosen from a library of neuroprotective agents, and were tested in a more 'realistic' model favoured by the STAIR (Stroke Therapy Academic Industry Roundtable). Outcome was assessed with infarct volume, neurologic score, and two newly developed scales measuring general health and physiologic homeostasis. Owing to the failure to achieve neuroprotection in aged, hypertensive animals with drug delivery at 3 hours, the bar was lowered in successive experiments to determine whether neuroprotection could be achieved under conditions more conducive to recovery. Testing in younger animals showed more favourable homeostasis and general health scores than did testing in older animals, but infarct volume and neurologic scores did not differ with age, and treatment efficacy was again not shown. Testing with shorter occlusions resulted in smaller infarct volumes; nevertheless, treatment efficacy was still not observed. It was concluded that this combination, in these stroke models, was not effective.

Quantitative Temporal Profiles of Penumbra and Infarction During Permanent Middle Cerebral Artery Occlusion in Rats

The basic premise of neuroprotection in acute stroke is the presence of salvageable tissue, but the spatiotemporal volume profiles of the penumbra and infarction remain poorly defined in preclinical animal models of acute stroke used to evaluate therapies for clinical application. Our aim was to define these profiles using magnetic resonance imaging (MRI) quantitative cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) for dual-parameter voxel analysis in the rat suture permanent middle cerebral artery occlusion (pMCAO) model. Eleven male Sprague Dawley rats were subjected to pMCAO with MRI measurements of quantitative CBF and ADC at baseline, over the first 4 h (n=9) and at 7, 14, and 21 days (n=4). Voxel analysis of CBF and ADC was used to characterize brain tissue ischemic transitions. Penumbra, core, and hyperemic infarction volumes were significantly elevated (P<0.05) and unchanged over the first 4 h of pMCAO while the total lesion volume progressively rose. At 7, 14, and 21 days, tissue compartment transitions reflected infarction, tissue cavitation, and selective ischemic neuronal necrosis. Anatomical distribution of penumbra and core revealed marked heterogeneity with penumbra scattered within core and penumbra persisting even after 4 h of permanent MCAO.

Neuroinflammation and Neuroprotective Strategies in Acute Ischaemic Stroke - from bench to bedside

Cerebrovascular disease is one of the commonest causes of disability and mortality worldwide. Over the past two decades, a tremendous amount of research has been undertaken into developing effective therapeutic strategies for the treatment of acute stroke. Unfortunately, many neuroprotective agents that have shown successful results in treating animal models of acute stroke have failed to translate into clinical treatments. Only tissue-plasminogen activator (t-PA) is currently licensed for use in the treatment of acute ischaemic stroke. One of the important pathophysiological mechanisms involved during the acute phase of stroke is neuroinflammation. This review article will discuss the molecular aspects of neuroinflammation in acute ischaemic stroke and potential therapeutic strategies as part of translational medicine research.

Combination of hyperbaric oxygenation and selective JNK-inhibition by D-JNK-I-1 as a potent neuroprotective strategy in a focal ischaemia/reperfusion injury model in rats

Background: In pervious studies, hyperbaric oxygenation (HBO) was proven as a potent neuroprotective treatment in animal models of acute stroke by reducing apoptotic cell death. Furthermore, c-Jun N-terminal kinase (JNK) is activated in ischaemic neurons downstream of the activated glutamate receptors and thus mediating neuronal cell death. The highly specific peptide JNK-inhibitor D-JNK-I-1 (XG-102) has been shown to be neuroprotective in acute stroke in mammals, acting by intracellular inhibition of JNK-kinase. We thus hypothesized that combination of both treatments might enhance the neuroprotective effect of each regimen. Infarct volumetry and clinical outcome were the primary endpoints.

Minocycline May Improve Outcomes After Acute Stroke

The venerable antibiotic, minocycline, has anti-inflammatory effects that have led to its use for treatment of inflammatory arthritis and some other illnesses not thought to have infectious etiologies. In animal models of acute stroke, minocycline has improved outcomes. The presumed mechanisms of …

The 2006 International Stroke Conference Orlando, Florida February 15-18, 2006

The 2006 International Stroke Conference Orlando, Florida February 15-18, 2006

Neuroprotection for Ischemic Stroke Using Hypothermia

The development of animal models of acute stroke has allowed the evaluation of mild and moderate hypothermia as a therapeutic modality in this clinical setting. Studies have demonstrated that animals subjected to hypothermia up to 3 hours after the primary central nervous system insult have reduced mortality and neuronal injury, and improved neurological outcome. These results warranted the evaluation of hypothermia in clinical trials. Even though hypothermia has potent neuroprotective effects in animal models of ischemic stroke, there are only a few clinical studies of therapeutic hypothermia in humans. Because of the small number of patients in the studies and the absence of matched controls, clinical studies are considered pilot studies for feasibility and safety. Thus, therapeutic hypothermia for ischemic stroke remains a promising but fiercely debated therapeutic modality. This review summarizes the animal model studies that have led to clinical trials in acute ischemic stroke. The existing techniques for inducing brain cooling, the mechanisms of neuroprotection, the complications of therapeutic hypothermia, and the future perspective of the field are also discussed.

Growth Factor Treatment of Stroke

This review discusses the potential usefulness of several selected polypeptide growth factors as treatments for stroke. Distinctions between global vs. focal cerebral ischemia, permanent vs. temporary focal ischemia, and acute stroke vs. stroke recovery are first discussed. Potential routes of administration of growth factors are also considered. The growth factors basic fibroblast growth factor (bFGF), osteogenic protein-1 (OP-1), vascular endothelial growth factor (Veg-f), erythropoietin (EPO), and granulocyte colony stimulating factor (G-CSF) all show potential usefulness in animal models of acute stroke and stroke recovery. Two of these factors, bFGF and EPO, have reached human clinical trials for acute stroke, and the data are discussed. Future directions in this field are also discussed.

Glycine Antagonist (GV150526) in Acute Stroke: A Multicentre, Double-Blind Placebo-Controlled Phase II Trial

GV150526 is a novel glycine antagonist at the NMDA receptor complex. It is a potent neuroprotective agent in animal models of acute stroke including permanent middle cerebral artery occlusion in the rat. GV150526 was very well tolerated in early human studies. The purpose of this randomised, double-blind, multicentre, placebo-controlled trial was to assess the safety and population pharmacokinetics of GV150526 in patients with a clinical diagnosis of acute stroke. Exploratory assessment of efficacy, quality of life and resource utilisation was also undertaken. Upon clinical diagnosis of acute stroke within 12 h of onset of symptoms, patients were treated with a loading dose of 800 mg GV150526 (or placebo), followed by 5 maintenance doses of 400 mg GV150526 (or placebo) given every 12 h over 3 days. Following observation of asymptomatic hyperbilirubinaemia, the maintenance dose was reduced mid-study to 200 mg. CT/MRI scanning was not mandatory prior to treatment. The study treated 128 patients (38 with GV 800 mg/400 mg, 48 with GV 800 mg/200 mg and 42 with placebo). Fewer patients with mild stroke (NIH scores ≤5) were enrolled in the GV150526-treated groups than in the placebo group (placebo 38%, GV 800 mg/400 mg 18%, GV 800 mg/200 mg 15%). There was also an imbalance in the proportion of patients with haemorrhagic strokes (placebo 5%, GV 800 mg/400 mg 3%, GV 800 mg/200 mg 15%). Mortality at 1 month was unbalanced between treatment groups, being 10, 18 and 17% in the placebo, GV 800 mg/400 mg and GV 800 mg/200 mg groups, respectively (no significant difference). Similarly, adverse events, though consistent with an acute stroke population, appeared more often in the GV 800 mg/200 mg group. Functional outcomes at 1 month also showed imbalances, the percentage of patients with a Barthel Index score of ≧95 at 1 month being 52, 39 and 27% in the placebo, GV 800 mg/400 mg and GV 800 mg/200 mg groups, respectively. These results probably reflect a prognostically significant baseline difference between the groups rather than the effect of GV150526. GV150526 was generally well tolerated in patients with a clinical diagnosis of acute stroke and formal efficacy studies were considered justified.

Analytic Reviews : Potential New Therapies for Acute Ischemic Stroke

Evidence from animal models of acute stroke suggests ischemia may be reversible if blood flow is restored in the first few hours. Studies of human stroke using posi tron emission tomography demonstrate areas with re duced blood flow and relatively preserved metabolism, indicating potentially reversible ischemic brain. Resto ration of blood flow during this reversible phase should improve outcome after stroke. Many therapeutic strategies for treatment of acute ischemic stroke have been proposed, including increas ing collateral flow, removing vascular obstructions, and interfering with the intracellular cascade of events that lead to neuronal cell death. Hypervolemic hemodilution reduces viscosity and increases cerebral blood flow, and this may hopefully raise blood flow above the critical threshold of irreversible ischemia. Naloxone, calcium channel blockers, and glutamate antagonists alter blood flow and influence intracellular events during and after acute ischemia. Thrombolytic therapy restores blood flow by lysis of obstructing clot. These therapies show promise in preliminary studies, but additional ran domized controlled studies are needed.