Do-it-yourself brain repair following stroke

	Tweet

Stroke is a leading cause of long-term disability and death in the United States. A team of researchers - led by Gregory Bix, at Texas A&M College of Medicine, College Station - has identified a way to exploit one of the brain’s self-repair mechanisms to protect nerve cells and enhance brain repair in rodent models of stroke. The authors suggest that this approach could provide a nontoxic treatment for stroke.

The most common form of stroke (ischemic stroke) occurs when a blood vessel that brings oxygen and nutrients to the brain becomes clogged, for example with a blood clot, causing nerve cells in the affected area to die rapidly. In their study, Bix and colleagues detected in rodent models of stroke elevated levels of domain V, a naturally occurring fragment of the molecule perlecan, suggesting it might have a natural role in repairing the brain after a stroke. When administered in these models 24 hours after stroke, perlecan domain V protected nerve cells from death and promoted blood vessel growth, a key component of brain repair. The authors therefore suggest that perlecan domain V could provide a therapy that improves stroke outcome by protecting nerve cells and enhancing brain repair.

###

Ischemic stroke, a condition resulting from occlusion of brain vasculature, manifests as an ischemic core of rapid cell death, surrounded by a vulnerable penumbral region. Within the penumbra, reparative revascularization (angiogenesis) and neuronal repopulation (neurogenesis) occur in close proximity, facilitating mutually supportive neuron–endothelial cell crosstalk. Additionally, angiogenic blood vessels serve as a physical scaffold for neurons to migrate toward the ischemic core. Collectively, this neurovascular coupling represents a means of post-stroke repair ripe for therapeutic exploitation. Indeed, recent experimental therapies such as pharmaceuticals, stem cells, and growth factors have attempted to capitalize on neurovascular repair concepts to promote stroke recovery. However, pharmaceutical and growth factor therapies raise questions of potentially serious systemic side effects, drug interactions, and contra-indications. Similarly, cell-based therapies raise important safety issues, including the potential for cancerous transformation.

Additionally, many factors that prevent cell death also inhibit repair, or vice versa, depending upon when they are administered after stroke. For example, NMDA receptor antagonists and protease inhibitors are both neuroprotective and detrimental to repair. VEGF further disrupts blood-brain barrier stability, promotes brain edema, and enhances hemorrhagic transformation and brain infarct size if administered acutely, but is neuroprotective and enhances angiogenesis and neurogenesis when given chronically. Thus, there is a clear need for a stroke therapy that is both neuroprotective and promotes brain repair. This need is underscored by the fact that the one FDA-approved stroke therapy, TPA, has a narrow therapeutic window of 3–4.5 hours after ischemic stroke onset.

We hypothesized that neuroprotection and brain repair might both be enhanced by treatment with a factor generated endogenously by injury and the reparative process itself. We further reasoned that the vascular extracellular matrix, a biologic interface between vascular and other brain tissue that is actively proteolyzed during both the initial injury and subsequent repair response (10), was a logical place to look for factors with therapeutic potential. In particular, the vascular extracellular matrix proteoglycan component perlecan undergoes greater acute (within 1–2 hours of stroke onset) and chronic (up to 7 days) proteolysis after stroke (in the non-human primate) than any other extracellular matrix component studied. Furthermore, perlecan is required for brain angiogenesis. Interestingly, perlecan also contains the antiangiogenic C-terminal protein fragment domain V (DV, also known as endorepellin; ref. 13), which is activated by proteolysis from full-length perlecan. However, DV has not been studied in the brain due to the absence of its previously identified antiangiogenic receptor from angiogenic brain endothelial cells. In this study, using two different stroke models in mice and rats, we have demonstrated a stable and long-lasting increase in brain DV concentrations following stroke injury. We further demonstrate that this endogenous DV could play a role in the brain’s response to stroke, inasmuch as DV-deficient mice experience larger infarcts than their WT counterparts. Additionally, we have demonstrated that DV administered systemically 24 hours after stroke (a) is well tolerated; (b) reaches stroke core and peri-infarct vasculature; (c) is neuroprotective; (d) significantly improves post-stroke functional motor recovery to pre-stroke function via a previously unidentified DV receptor; (e) “rescues” the worsened stroke severity of DV-deficient mice; and (f) unexpectedly enhances brain angiogenesis. This latter result underscores substantial differences between brain and non-brain angiogenesis. Collectively, our results suggest that DV is a distinct, nontoxic, multi-functional stroke treatment.

TITLE: Perlecan domain V is neuroprotective and proangiogenic following ischemic stroke in rodents

AUTHOR CONTACT:
Gregory J. Bix
Texas A&M College of Medicine, College Station, Texas, USA.
Phone: 979.862.7613; Fax: 979.847.9481; E-mail: .

Full article
###

Contact: Karen Honey

734-546-5242
Journal of Clinical Investigation

RELATED STORIES:
Statins Prevent Stroke Recurrences… But Can They Improve Stroke Outcome?   No link seen between stressful events, stroke   Weekend Strokes May Receive More Aggressive Treatment   Promising new compound for treating stroke   Drinking shows little effect on stroke outcome   Heart Surgeries Trigger Strokes, Seizures   Coffee may cut women’s stroke risk   Stroke Survivors Improve Balance with Tai Chi   Smoking doubles stroke risk in younger women   Drinking coffee, having sex are triggers that raise rupture risks for brain aneurysm   Women More Likely to Experience Non-Traditional Stroke Symptoms   Less hemorrhaging after stroke, but not fewer deaths

Comments

[ + Post Your Own ]

Now you're in the public comment zone. What follows is not Armenian Medical Network's stuff; it comes from other people and we don't vouch for it. A reminder: By using this Web site you agree to accept our Terms of Service. Click here to read the Rules of Engagement.

There are no comments for this entry yet. [ + Comment here + ]