The brain is a highly complex organ comprised of a large number of cells and molecules, each with its own unique function. Diseases that affect the central nervous system (CNS), such as brain injury or stroke, not only kill vulnerable neurons, but often severely disrupt cell-cell signaling in the surviving cells (Guo et al., 2018; George and Steinberg, 2015). Discovering therapeutics to halt the domino effect that includes loss of cells and often portions of the brain, such as those observed in stroke patients, has been a slow process. One of the challenges in researching stroke and developing therapeutics, like many other types of human diseases/conditions, is mimicking the cellular interactions in an in vivo platform.
Including aged mice in these types of studies presents several advantages over other models, in that they can be genetically modified to examine the molecular pathophysiology. Furthermore, aged mice are a vital model as stroke generally affects the elderly. Aged C57BL/6J mice—both males and females—up to 78 weeks of age which is equivalent to about 56 human years, are available from JAX for use in studies, such as those for stroke.
A stroke is the result of a sudden disruption in the blood supply to the brain. Various mechanisms, including excitotoxicity, free radical release, protein misfolding, and inflammatory changes can cause neural injury or death. White matter injury, in conjunction with astrocyte death or injury, also contributes to cerebral damage, which can manifest as a loss of speech, motor function, and/or memory (Marin and Carmichael, 2018; George and Steinberg, 2015; Balkaya et al., 2013). This catastrophic event for both patients and families is the fourth largest cause of death in the US and the leading medical cause of disability worldwide (Ritzel et al., 2018; Fluri et al., 2015). From drug development and research perspectives, utilizing an in vivo model that mimics a targeted feature is more likely to yield translationally-relevant data.
A recent study by Bastian and colleagues (Bastian et al., 2018) examined whether protein kinase inhibition would protect white matter function and structure, and therefore serve as a therapeutic target for stroke patients and other neurodegenerative conditions. The authors used JAX aged C57BL/6J male mice at 12 and 20 months.
As white matter becomes increasingly susceptible to injury with age, the authors examined the optic nerves from 12 and 20 month old C57BL/6J mice. Following oxygen glucose deprivation in these mice, the authors observed that compound action potentials exhibited minimal recovery. However, inhibiting CK2 kinase prevented a complete loss of compound action potential during oxygen glucose deprivation and improved the compound action potential area recovery during post-oxygen glucose deprivation.
To investigate whether inhibition of CDK5 and AKT promoted axon function in optic nerves of 12-month-old mice, the authors administered roscovitine or MK-2206, inhibitors of AKT, at pre, during, and post-oxygen glucose deprivation. They observed that roscovitine given prior to oxygen glucose deprivation improved compound action potential area, whereas MK-2206 treatment preserved compound action potential area during oxygen glucose deprivation and promoted axonal recovery following oxygen glucose deprivation. These observation indicate that CK2 inhibition improves axon function recovery following an ischemic episode, and CDK5 and AKT are effector molecules that mediate these protective effects.
In the study by Bastian and colleagues, they investigated the use of kinase inhibitors to treat ischemic stroke-related neuronal injuries. Using aged mice, which is an appropriate model for conducting stroke research, they observed post-ischemic protection following administration of their therapeutic. As the authors note, this therapeutic may result in successful translation into clinical trials.
For nearly 90 years, JAX—a pioneer in mouse model research—has been empowering the global biomedical community with a comprehensive and innovative range of mouse models of human disease and preclinical research services. For researchers, utilizing the most appropriate model platform can be the difference between reaching a milestone and starting a study from the beginning—with a new target. JAX is committed to providing access to mouse models, such as aged C57BL/6J, to advance scientific discovery.
Visit the JAX aged B6 page to learn more about including this invaluable mouse model in your next study.
Balkaya, M., et al. (2013). "Assessing post-stroke behavior in mouse models of focal ischemia." J Cereb Blood Flow Metab 33(3): 330-338.
Bastian, C., et al. (2018). "CK2 inhibition confers functional protection to young and aging axons against ischemia by differentially regulating the CDK5 and AKT signaling pathways." Neurobiol Dis.
Fluri, F., et al. (2015). "Animal models of ischemic stroke and their application in clinical research." Drug Des Devel Ther 9: 3445-3454.
George PM, Steinberg GK., 2015. Novel Stroke Therapeutics: Unraveling Stroke Pathophysiology and Its Impact on Clinical Treatments. Neuron 87(2): 297-309. [PMID: 26182415]
Guo D, Deng W, Xing C., et al., 2018. Effects of aging, hypertension and diabetes on the mouse brain and heart vasculomes. Neurobiol Dis. Jul. DOI: 10.1016/j.nbd.2018.07.021. [PMID: 30031157]
Marin MA, Carmichael ST., 2018. Stroke in CNS White Matter: Models and Mechanisms. Neurosci Lett. Aug. DOI: 10.1016/j.neulet.2018.07.039. [PMID: 30098384]
Ritzel RM, Lai YJ, Crapser JD., et al., 2018. Aging alters the immunological response to ischemic stroke. Acta Neuropathol. May. DOI: 10.1007/s00401-018-1859-2. [PMID: 29752550]