Non-selective membrane channel blockers for mTBI

Blast induced traumatic brain injury (TBI) is a common injury in modern warfare. Estimates are that from 12
to 23 percent of Veterans who served in the conflicts in Iraq, Afghanistan and other theaters of operation during
OEF, OIF and New Dawn suffered a TBI during deployment with blast exposure being the predominant
mechanism of injury and mild injuries (mTBI) being most common. Blast related mTBI has been linked to a
variety of chronic cognitive and chronic mental health disorders in Veterans including post-traumatic stress
disorder (PTSD), depression and risk for suicide. Supportive care remains the mainstay of treatment.
Pharmacological options are limited and do not correct the underlying cause of brain dysfunction.
For more than a decade the Elder lab have been studying a rat model of repetitive low-level blast exposure.
Rats exposed to three 74.5 kPa exposures delivered one per day over three days develop a delayed blast-
induced behavioral phenotype, which includes chronic cognitive changes and post-traumatic stress disorder
(PTSD)-related traits. These rats thus provide a clinically relevant model of the chronic neurobehavioral
syndromes seen in veterans. Inflammation has long been implicated in the pathophysiology of blast injury. In the
rat model being studied in the Elder lab, blast exposure is associated with chronic perivascular astroglial injury
and chronic perivascular inflammation. Recent RNA transcriptomics has identified an inflammatory signature in
brain following blast, which develops over the time frame during which the chronic behavioral phenotype
appears.
Boldine has anti-inflammatory and anti-oxidant properties, and has been shown to exert beneficial effects in
experimental models associated with increased pro-inflammatory signaling. These effects of boldine have been
attributed in part to its ability to block connexin (Cx) hemichannels (HC) which are membrane pores that bind
CxHC on adjacent cells to form gap junctions or exist as HC on the cell surface. CxHC can be either open or
closed. Open CxHC trigger pro-inflammatory signaling cascades including activation of inflammasomes and of
NF-kB.
The overall goal of the present study is to address the unmet need for new therapies for the chronic cognitive
and neuropsychiatric complications of blast-related mTBI by determining whether boldine can improve behavior
in rats following low-level blast exposure and block development of the inflammatory signature seen in brain
following blast injury. These goals will be achieved using the Elder lab’s rat model of blast exposure through two
specific aims: (1) To determine whether orally administered boldine can prevent the appearance of PTSD-related
traits and cognitive impairments in blast-exposed rats. (2) To test if orally administered boldine reverses the
inflammatory signature in brain following blast exposure. We posit that boldine will reduce chronic perivascular
inflammation and the molecular inflammatory signature that follows blast overpressure injury. If this prediction is
correct, we anticipate an accelerated path to translation of boldine – an ingredient in a USDA-approved nutritional
supplement – for use in relieving neuropsychiatric symptoms of Veterans.

Grant Number: 5I21RX004886-02
NIH Institute/Center: VA
Principal Investigator: CHRISTOPHER CARDOZO