Traumatic brain injury (TBI) is a significant health problem in the United States. The Centers for Disease Control and Prevention (CDC) estimates that 1.7 million people sustain traumatic brain injury in the United States each year; 52,000 die; 275,000 are hospitalized; and 1.4 million, nearly 80%, are treated and released from an emergency department. TBI is a contributing factor to a third of all injury-related deaths in the United States. An estimated 5.3 Americans live with a permanent TBI-related disability. Americans at highest risk for TBI include very young children aged 0-4 years, older adolescent children aged 15 to 19 years, older adults aged 65 years and older, and military personnel, particularly soldiers deployed to Iraq and Afghanistan. TBI accounted for 12% of the war related medical evacuations to the Walter Reed Army Medical Center in 2002-2006. The most frequent causes of TBI in non-military personnel are car accidents followed by sports injury. Bicycling and football account for the largest numbers of TBI in persons less than 19 years of age.
TBI is particularly devastating in children as the developing brain is more physiologically vulnerable; children who sustain injury early in development have not yet learned skills to help regulate their behavior and emotions, and prolonged symptoms impair essential developmental experiences in school, with family and with friends. Although “moderate” (GCS score 8-12) or “complicated mild” (those with GCS score 13-15 and positive neuroimaging findings) injuries comprise less than 10% of the total TBI population, these children are at much greater risk for having prolonged cognitive symptoms that impair their day to day functioning. Of the children with complicated mild or moderate TBI prospectively enrolled in the Children’s Health After Trauma (CHAT) study, 20-25% had sustained impairment of executive function and working memory lasting 3-12 months after injury. Children with impaired executive function have difficulty carrying out goal-directed behavior such as planning and sequencing multistep actions, inhibiting inappropriate behavior, and sustaining effort for extended periods of time. Impairment of executive function is a consequence of injury to frontal cortex which is a frequent site of injury in TBI.
Several years ago, Dr. Kris Ruttan and colleagues showed that executive function in monkeys can be improved by treatment with a phosphodiesterase 4 (PDE4) inhibitor. The compound that was used in the study, rolipram, was developed in the 1980’s for treatment of depression and was later found to have strong benefit in multiple tests of learning and memory in animals. Executive function can be evaluated in monkeys using the Object Reaching (OR) task. The OR task assesses executive function and its components such as attention, response inhibition and planning which involve frontal cortex. Monkeys are trained to reach for a food reward, such as raisin, from a transparent plastic box that is open on one side. In the simple version of the task, the raisin is placed in the opening and the open side of the box is pointed towards the monkey. First reach accuracy is 75%. Rotating the box so that the opening is pointed towards the side does not lessen first reach accuracy if the raisin is placed on the open edge. However, if the raisin is placed deep against the back of the rotated box, first reach accuracy falls to 10%. Monkeys find it difficult to restrain their first impulse to reach directly towards the raisin when it is visible through the transparent side and instead reach around to the open side. Remarkably, Ruttan and colleagues found that rolipram increases first reach accuracy in the difficult form of the task from 10% back to 75%. This is a dramatic improvement in executive function. While most TBI patients sustaining a mild concussion recover within 30 days, a significant number of TBI patients show sustained impairment of executive function and other aspects of learning and memory. Such patients may benefit from treatment with a compound such as rolipram.
PDE4 inhibitors may also benefit patients with TBI-related disability or even patients sustaining a focal stroke. The brain is remarkably plastic, and even after damage to one brain region, other brain regions are sometimes able to compensate by “re-learning” and taking over the function of the region that has been damaged. This type of re-learning can be improved by rolipram. In a study by Dr. Erin MacDonald and colleagues, rats were trained to reach through a slot to retrieve a food pellet. Although the rats could use either forepaw to retrieve the food pellet, animals generally preferred to use one paw more than the other. The investigators then caused a focal stroke in the region of the rat motor cortex that controlled the function of the preferred paw. Prior to the stroke, rats correctly reached and retrieved the food pellet about 50% of the time. After the stroke, rats made fewer reaches and were successful only 20% of the time. With motor rehabilitation, retrained rats could regain about 80% of function, whereas rats treated with rolipram each day, rehabilitated more quickly and attained a level of performance similar to their pre-stroke performance. This is an exciting result as it implies that modulation of the PDE4 pathway increases the speed of rehabilitation from focal stroke as well as the level of recovery.
Rolipram was not studied further in human clinical trials as the compound causes vomiting and nausea. Second generation PDE4 allosteric inhibitors, in contrast, have a much wider window of tolerability with equally strong efficacy in animal tests of learning and memory. Thus, such compounds show promise for the treatment of sustained impairment of executive and cognitive function in TBI patients, and may also facilitate rehabilitation in patients with TBI-related disability or stroke.
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