Stroke


Background

Ischemic stroke is the third leading cause of mortality in the world with more than 2 million cases diagnosed every year (Garber 2007). By the year 2020, stroke is expected to be the fourth leading disease burden in the world (Gladstone, 2002). A stroke is characterized by an interruption in blood flow in the brain resulting in neuronal death and loss of brain function. Variability is imposed depending if the interruption is acute or slow, complete or partial, focal or global, and permanent or transient. Preclinical studies must be designed to reduce this variability. The only approved and validated treatment in the US is the intravenous administration of recombinant tissue plasminogen activator (rtPA) initiated within three hours of stroke onset. Administration of rtPA is intended to dissolve blood clots and restore cerebral perfusion in the ischemic tissue. However, there is a current need for neuroprotectant drugs to prevent brain damage beyond the initial blockage. Additionally, novel compounds which rapidly break down blood clots may also be efficacious in treating stroke.

Preclinical Models

Treatments for ischemic stroke continue to evolve and many companies and laboratories are exploring the opportunity to develop new therapies in the areas of thrombolysis and neurorestoration. Preclinical models for the study of new entities try to replicate the pathophysiology of the clinical situation. The most important equivalent of clinical stroke is the focal ischemia produced by middle cerebral artery occlusion (MCAO) in rats. Blood supplied by the middle cerebral artery perfuse the majority of the temporal lobe, parts of the frontal and parietal lobes, as well as the basal ganglia. MCAO results in consistent brain damage often observed as motor and behavioral impairments (Hossmann, 2008).

Preclinical Models

Model Description Length Endpoints
Tamura Model
The proximal right middle cerebral artery is occluded by microbipolar coagulation 28 days Infarct volume, limb placing, body swing test, additional behavioral tests
Permanent Filament Model
A silk filament is inserted into the right external carotid artery until reaching the internal carotid artery 28 days Infarct volume, limb placing, body swing test, additional behavioral tests
Transient Filament Model
The same procedure as the permanent filement model, but the filament is removed after 90 minutes 28 days Infarct volume, limb placing, body swing test, additional behavioral tests

 

Tamura Model

The Tamura model is the most sophisticated of the three models and survival rates are high. The occlusion is produced by electrocoagulation. This model requires craniotomy and does not use a suture as in the other two models. Infarct volume is measured via histology of the brain tissue. Additionally, several behavioral tests are conducted to assess motor coordination and cognitive impairment. These endpoints are clinically relevant as they demonstrate recovery of function and neuroprotection.

Control

Treated with Neuroprotectant

 

Assessment of Hindlimb Impairment

 

Permanent Filament Model

The permanent filament model uses a nylon suture occluder to prevent blood flow. This model is useful for testing compounds designed to prevent loss in brain tissue by neuroprotective mechanisms. As with all the stroke models, behavioral endpoints demonstrating loss and recovery of function in addition to the traditional histology endpoints of infarct volume.

Transient Filament Model

The transient filament model uses the same technique for occlusion of the middle cerebral artery as the permanent filament model, however the occluder is removed after 90 minutes. Since blood flow is eventually restored, this model has more similarity to clinical cases in which ischemia was treated. The tradeoff for this model though is that survival rates are typically lower than that of the permanent filament model. Behavioral endpoints demonstrating loss and recovery of function in addition to traditional histology endpoints of infarct volume are examined.

Publications

Jalal, F.Y., Böhlke, M., Maher, T.J.: Acetyl-L-carnitine reduces the infarct size and striatal glutamate outflow following focal cerebral ischemia in rats. Ann. N. Y. Acad. Sci. 1199:95-104, 2010.

Pino-Figueroa, A., Nguyen, D., Maher, T.J.: Neuroprotective effects of Lepidium meyenii (Maca). Ann. N. Y. Acad. Sci. 1199:77-85, 2010.

Sadasivan, S., Maher, T.J., Quang, L.S.: Gamma-hydroxybutyrate (GHB), gamma-butyrolactone (GBL), and 1,4-butanediol (1,4-BD) reduce the volume of cerebral infarction in rodent transient middle cerebral artery occlusion. Ann. N.Y. Acad. Sci. 1074:537-544, 2006.

Ally, A., Maher, T.J.: Endothelial NOS expression within the ventrolateral medulla can affect cardiovascular function during static exercise in stroked rats
Brain Research PMID: 18234158

Ally, A., Nauli, S.M., Maher, T.J.: Molecular changes in nNOS protein expression within the ventrolateral medulla following transient focal ischemia affect cardiovascular functions
Brain Research PMID: 16084499