Alpha-Linolenic Acid Treatment Reduces the Contusion and Prevents the Development of Anxiety-Like Behavior Induced by a Mild Traumatic Brain Injury in Rats.

Key Findings

Traumatic brain injury (TBI) is a major public health concern in the USA and results in more than five million deaths per year across the globe.  Most patients recover fully from mild TBI (mTBI); however, for a significant fraction (10–15%), there are persistent cognitive, behavioral, and emotional sequelae. This group confirmed that administration of a single intravenous ALA injection (500 nmol/kg) significantly increased NF-κB levels in hippocampal nuclear extracts up to 24 h after injection. ALA deficiency in the diet may increase one’s risk for certain neurodegenerative disorders. In this study, a CCI model of mild TBI was used to determine the therapeutic efficacy of ALA on the impact injury, the number of GABAergic interneurons and inhibitory tonus in the BLA and on anxiety-like behavior. The current study shows that CCI results in a significant contusion (lesion) volume 10 and 30 days after CCI in the absence of treatment.  Administration of ALA by subcutaneous injection at 30 min, 3 and 7 days after CCI results in a significant reduction in contusion (lesion) volume. TBI triggers a neuroinflammatory response that involves activation of microglia and astrocytes leading to the release and synthesis of pro-inflammatory cytokines. The results suggest that ALA prevents the significant reduction in the GABAergic synaptic transmission. Administration of ALA after CCI prevented the loss of inhibitory interneurons, the reduction in GABAergic synaptic transmission and the anxiety-like behavior 30 days after CCI.  ALA is a nutraceutical with pleiotropic properties and a natural product that should be further developed as a therapy to reduce brain injuries and prevent the long-term difficult to treat anxiety disorders that develop after TBI.

ABSTRACT

Approximately, 1.7 million Americans suffer a TBI annually and TBI is a major cause of death and disability. The majority of the TBI cases are of the mild type and while most patients recover completely from mild TBI (mTBI) about 10% result in persistent symptoms and some result in lifelong disability. Anxiety disorders are the second most common diagnosis post-TBI. Of note, TBI-induced anxiety disorders are difficult to treat and remain a chronic condition suggesting that new therapies are needed. Previous work from our laboratory demonstrated that a mild TBI induced an anxiety-like phenotype, a key feature of the human condition, associated with loss of GABAergic interneurons and hyperexcitability in the basolateral amygdala (BLA) in rodents 7 and 30 days after a controlled cortical impact (CCI) injury. We now confirm that animals display significantly increased anxiety-like behavior 30 days after CCI. The anxiety-like behavior was associated with a significant loss of GABAergic interneurons and significant reductions in the frequency and amplitude of spontaneous and miniature GABA_A-receptor-mediated inhibitory postsynaptic currents (IPSCs) in the BLA. Significantly, subchronic treatment with alpha-linolenic acid (ALA) after CCI prevents the development of anxiety-like behavior, the loss of GABAergic interneurons, hyperexcitability in the BLA and reduces the impact injury. Taken together, administration of ALA after CCI is a potent therapy against the neuropathology and pathophysiological effects of mTBI in the BLA.