Research suggests better treatment combo for strokes
Louisiana State University Health Sciences Center
Nicolas
Bazan, MD, PhD, Boyd Professor, Professor of Neurology and Director of the
Neuroscience Center of Excellence at LSU Health New Orleans School of Medicine,
and Ludmila Belayev, MD, LSU Health New Orleans Professor of Neuroscience,
Neurology, and Neurosurgery, discovered this novel therapeutic strategy for
ischemic stroke using an experimental model.
During an ischemic stroke, signals are produced from arriving blood white cells and primary brain immune cells called microglia that cause neuroinflammation leading to a buildup of chemicals that harm the brain.
Platelet-activating factor (PAF) accumulates, and inhibition of this process plays a critical role in neuronal survival. Dr. Bazan's earlier studies also showed that in addition to its anti-inflammatory properties, DHA, an essential omega-3 fatty acid, stimulates the production of Neuroprotectin D1 (NPD1), a molecule that protects brain cells and promotes their survival.
One complicating factor in developing
neuroprotective strategies for stroke are the multiple routes and events that
occur in the brain during a stroke, which has been approached mainly by
monotherapeutic agents that were mostly unsuccessful.
Because no single therapy has proven effective in treating the complexity of stroke, the team aimed at two different events -- blocking pro-inflammatory platelet-activating factor receptors (PAF-R) and activating cell-survival pathways.
They found that treatment with LAU-0901, a synthetic molecule discovered in the Bazan lab that blocks pro-inflammatory platelet-activating factor, plus aspirin-triggered NPD1 (AT-NPD1) reduced the size of the damaged area in the brain, initiated repair mechanisms, and remarkably improved behavioral recovery.
Total
lesion volumes were reduced with LAU‑0901 plus NPD1 by 62% and LAU‑0901 plus AT‑NPD1
by 90%. Combinatory treatment with LAU‑0901 plus AT‑NPD1 improved the
behavioral score up to 54% on day three. LAU‑0901 and LAU‑0901 plus DHA
decreased the production of 12‑hydroxyeicosatetraenoic acid, a pro‑inflammatory
mediator.
"The biological activity of LAU-0901 and AT-NPD1 is due to specific activation or modulation of signaling pathways associated with the immune system, inflammation, cell survival, and cell-cell interactions," notes Dr. Bazan.
"These
findings provide a major conceptual advance of broad therapeutic relevance for
cell survival, brain function and, particularly, stroke and neurodegenerative
diseases."
"We
discovered that these novel molecules promote neuronal cell survival with
important anti-inflammatory activity," explains Dr. Belayev. "This
combinatorial therapy may hold promise for future therapeutic development
against ischemic stroke."
According to the Centers for Disease Control and Prevention, someone in the United States has a stroke every 40 seconds. Every 4 minutes, someone dies of stroke. Every year, more than 795,000 people in the United States have a stroke. About 87% of all strokes are ischemic strokes, in which blood flow to the brain is blocked.
Stroke-related costs in the United States came to nearly $46 billion between
2014 and 2015. This total includes the cost of health care services, medicines
to treat stroke, and missed days of work. Stroke is a leading cause of serious
long-term disability. Stroke reduces mobility in more than half of stroke
survivors age 65 and over.
Other
LSU Health authors include Drs. Pranab K. Mukherjee, Eric J. Knott and Reinaldo
B. Oria, along with Larissa Khoutorova and graduate students Madigan M. Reid
and Cassia R. Roque. Dr. Andre Obenaus, Lawrence Nguyen, and Jeong Bin Lee from
the University of California Irvine School of Medicine, and Dr. Nicos A.
Petasis of the University of Southern California, are also co-authors.
This
research was supported by grants from the National Institute of Neurological
Disorders and Stroke of the National Institutes of Health and Brazilian CAPES.