Traumatic brain injury (TBI), even when mild, frequently leaves individuals with persistent cognitive and behavioral impairment. In particular, chronic memory dysfunction often plagues patients who have suffered a brain injury and treatment of this condition remains difficult. Much of the memory dysfunction observed in the TBI population has been ascribed to defects in working memory (WM). WM, formerly called short-term memory, is the ability to store information for a brief time in order to guide behavior or decision-making. For instance, when you lack a pen and must focus to hold a 7-digit phone number you just heard in your mind, you are using your WM. Using the computer as an analogy, WM would be the RAM or random access memory in contrast to the long-term memory of the hard drive. Functional imaging has implicated the prefrontal cortex (PFC) as one area of the brain involved with WM. Although the pathophysiology of post-traumatic WM dysfunction remains unknown, there is growing evidence that damage to the PFC plays a role.
A recent study by Kobori et al from the University of Texas Medical School at Houston (Neuroscience 172: 293-302, 2011) has helped to elucidate the molecular mechanisms behind traumatic WM dysfunction. Building on the work of a TBI rodent model which showed an association between WM dysfunction and significant increases in PFC catecholamine levels, the researchers sought to investigate the role of norepinephrine signaling in traumatic WM dysfunction. Under anesthesia, a craniectomy was performed in rats and a TBI was modeled by using a controlled cortical impact device over a region of parietal association cortex. WM was measured with a modified version of the Morris water maze task. At day 14 post-injury, following the demonstration of WM deficits in injured rats, either an alpha-1 antagonist, an alpha-2a selective agonist, or a vehicle was injected. Thirty minutes after the injection, WM was tested. Vehicle-treated (control) rats and alpha-2a agonist-treated rats continued to show the same degree of WM dysfunction but alpha-1 antagonist treated rats demonstrated a statistically significant improvement in spatial WM.
Next, the scientists used real-time PCR to amplify mRNA from the medial PFC of injured rats on day 14 post-injury. They found that mRNA levels of the alpha-1A but not the alpha-1B or alpha-1D adrenergic receptor were significantly increased in the medial PFC as compared to sham-injured rats. Moreover, the group went on to show that TBI in this rat model increases phosphorylation of a transcription factor called CREB within the medial PFC and showed that TBI increases the binding of phospho-CREB to the promoter of the alpha-1A receptor gene. CREB is known to be phosphorylated by protein kinase A which is activated by cAMP. Using an inhibitor of protein kinase A, this group was able to show a significant reduction in alpha-1A mRNA levels. Thus, the combined results suggest that TBI leads to cAMP-dependent kinase phosphorylation of CREB, which then drives gene expression in the medial PFC to cause increased mRNA for the alpha-1A adrenergic receptor.
Given the association between a particular subtype of norepinephrine receptor and dysfunctional WM, the researchers went on to explore whether pharmacological manipulation of this receptor subtype could be used to mitigate WM deficits. Selective agonists and antagonists of adrenergic receptor subtypes have been used for years in humans to treat diseases such as hypertension, depression, and benign prostatic hypertrophy. One of these drugs, Prazosin, is an FDA-approved selective alpha-1 antagonist. Prazosin or vehicle was injected into injured rats on day 14 post-injury and WM performance was assessed 30 minutes, 24 hours, and 3 days post-injection. At 24 hours and 3 days post-infection, Prazosin-treated rats showed a statistically significant improvement in WM as compared to vehicle-treated controls.
Kobori and colleagues have made several important contributions to the neuroscience of brain trauma. First, they have linked WM dysfunction in an animal model of TBI with a particular neurotransmitter receptor, alpha-1A, and transcription factor, CREB. Moreover, they have linked increased transcription of alpha-1A in TBI to upstream increases in cAMP and have demonstrated that these molecular changes are occurring within the PFC, a region of brain previously associated with WM. This work has culminated in the production of a novel hypothetical model for TBI-induced WM deficits. This model offers several new targets for pharmacological intervention. Finally, they have demonstrated that WM dysfunction can be rapidly improved by using small molecules to block a part of this pathway. The speed of WM improvement is dramatic with statistical significance being reached at just 24 hours. This is exciting because it suggests that memory augmentation, perhaps contrary to popular belief, does not require prolonged brain repair and re-wiring. Moreover, the researchers were able to improve WM deficits with a small molecule that is already FDA-approved and in active clinical use.
It is interesting then to speculate if alpha-1 receptor antagonism may hold a therapeutic role for other forms of memory dysfunction such as age-related cognitive decline or neurodegenerative disease-related memory problems. It may turn out that patients currently taking alpha-1 blockers for hypertension experience less age-related memory problems. Obviously, one has to be wary about applying the results of any animal study to humans. However, the established safety and widespread availability of drugs that influence adrenergic receptors in clinical medicine will surely facilitate the first human trials of adrenergic pathway drugs for preventing memory dysfunction in TBI.
Nestor D. Tomycz
Robert M. Friedlander