Gene Identified That May Provide Potential Therapy for Cerebral Cavernous Malformations

Researchers at University of California San Diego School of Medicine, with national collaborators, have identified a series of molecular clues to understanding the formation of cerebral cavernous malformations (CCMs). The study offers the first genome-wide analysis of the transcriptome of brain microvascular endothelial cells after KRIT1 inactivation. Findings were published September 28 in the Journal of Experimental Medicine.

“These mouse studies reveal a critical mechanism in the pathogenesis of cerebral cavernous malformations and point to the possibility of using angiogenesis inhibitors, such as TSP1 for potential therapy,” said Mark H. Ginsberg, MD, professor of medicine, UC San Diego School of Medicine.

CCMs are collections of enlarged and irregular blood vessels in the central nervous system (CNS), for which there is no drug therapy. The vessels are prone to leakage causing headaches, seizures, paralysis, hearing or vision loss, or bleeding in the brain. There are two forms of the condition: familial and sporadic, affecting 1 in 200 patients in the U.S. The current treatment for CCMs involves invasive surgery, however, surgery is not possible for all patients due to location of vascular lesions within the CNS.

The most common cause of familial cavernous malformations is mutations of KRIT1. The protein produced from this gene is found in the junctions connecting neighboring blood vessel cells. Loss of function mutations in KRIT1 result in weakened contacts between blood vessel cells and CNS vascular abnormalities as seen in CCMs.

“Inactivation of KRIT1 in endothelial cells causes a cascade of changes in the expression of genes that regulate cardiovascular development,” said Ginsberg. “What we learned is that reduced expression of a protein encoded by one of these genes, TSP1, contributes to the growth of CCMs. Loss of one or two copies of THBS1, the gene that encodes TSP1, makes a mouse model of the disease much worse. Conversely, administration of 3TSR, a fragment of TSP1, reduces lesions in this mouse model. This means that replacement of TSP1 by 3TSR or other angiogenesis inhibitors may be a preventative for CCMs or treatment of the disease.”

Antidepressant May Enhance Drug Delivery to the Brain

NIH rat study suggests amitriptyline temporarily inhibits the blood-brain barrier, allowing drugs to enter the brain.

New research from the National Institutes of Health found that pairing the antidepressant amitriptyline with drugs designed to treat central nervous system diseases, enhances drug delivery to the brain by inhibiting the blood-brain barrier in rats. The blood-brain barrier serves as a natural, protective boundary, preventing most drugs from entering the brain. The research, performed in rats, appeared online April 27 in the Journal of Cerebral Blood Flow and Metabolism.

Although researchers caution that more studies are needed to determine whether people will benefit from the discovery, the new finding has the potential to revolutionize treatment for a whole host of brain-centered conditions, including epilepsy, stroke, human amyotrophic lateral sclerosis (ALS), depression, and others. The results are so promising that a provisional patent application has been filed for methods of co-administration of amitriptyline with central nervous system drugs.

According to Ronald Cannon, Ph.D., staff scientist at NIH’s National Institute of Environmental Health Sciences (NIEHS), the biggest obstacle to efficiently delivering drugs to the brain is a protein pump called P-glycoprotein. Located along the inner lining of brain blood vessels, P-glycoprotein directs toxins and pharmaceuticals back into the body’s circulation before they pass into the brain.

To get an idea of how P-glycoprotein works, Cannon said to think of the protein as a hotel doorman, standing in front of a revolving door at a lobby entrance. A person who is not authorized to enter would get turned away, being ushered back around the revolving door and out into the street.

“For example, as good as vegetables are for us to eat, they have molecules that could be toxic if they slipped into the brain,” Cannon said. “They don’t get in, because of P-glycoprotein, but this same protector also keeps out helpful therapeutics.”

Cannon and his NIEHS colleagues initially found that amitriptyline significantly reduced P-glycoprotein’s pump activity in brain capillaries from wild-type rats. Later, they saw amitriptyline had the same effect in brain capillaries from genetically modified rats designed to mimic human ALS. In both rat models, amitriptyline turned off P-glycoprotein within 10-15 minutes. When amitriptyline was removed, P-glycoprotein pump activity returned to full-strength.

NIEHS postbaccalaureate fellow David Banks is lead author on the paper and described amitriptyline’s action on P-glycoprotein as rapid and reversible. It’s these advantages that make the therapy so appealing.

“Most inventions developed at the bench don’t make it to the clinic, but I’m hopeful that our findings will translate into better treatment options for doctors and their patients,” Banks said.

Cannon anticipates that administering amitriptyline along with a lower dose of an opioid could relieve pain and reduce the negative side effects, such as constipation and addiction, usually seen with higher doses of prescribed opioids.

“As our nation faces increases in Alzheimer’s disease, autism, and opioid abuse, we’re hopeful that this discovery will help address these serious health challenges,” said NIEHS Director Linda Birnbaum, Ph.D.