title: Efficacy, dosage, and duration of action of branched chain amino Acid therapy for traumatic brain injury.
abstract: Traumatic brain injury (TBI) results in long-lasting cognitive impairments for which there is currently no accepted treatment. A well-established mouse model of mild to moderate TBI, lateral fluid percussion injury (FPI), shows changes in network excitability in the hippocampus including a decrease in net synaptic efficacy in area CA1 and an increase in net synaptic efficacy in dentate gyrus. Previous studies identified a novel therapy consisting of branched chain amino acids (BCAAs), which restored normal mouse hippocampal responses and ameliorated cognitive impairment following FPI. However, the optimal BCAA dose and length of treatment needed to improve cognitive recovery is unknown. In the current study, mice underwent FPI then consumed 100 mM BCAA supplemented water ad libitum for 2, 3, 4, 5, and 10 days. BCAA therapy ameliorated cognitive impairment at 5 and 10 days duration. Neither BCAA supplementation at 50 mM nor BCAAs when dosed 5 days on then 5 days off was sufficient to ameliorate cognitive impairment. These results suggest that brain injury causes alterations in hippocampal function, which underlie and contribute to hippocampal cognitive impairment, which are reversible with at least 5 days of BCAA treatment, and that sustaining this effect is dependent on continuous treatment. Our findings have profound implications for the clinical investigation of TBI therapy.
authors: Division of Neurology, Children's Hospital of Philadelphia , Philadelphia, PA , USA.
authors: Jaclynn A
authors: JA
authors: Elkind
authors: Sleep Disorders Laboratory, Division of Hospital and Specialty Medicine, Veterans Affairs Portland Healthcare System , Portland, OR , USA ; Department of Medicine, Oregon Health & Science University , Portland, OR , USA ; Department of Behavioral Neuroscience, Oregon Health & Science University , Portland, OR , USA.
authors: Miranda M
authors: MM
authors: Lim
authors: Division of Neurology, Children's Hospital of Philadelphia , Philadelphia, PA , USA.
authors: Brian N
authors: BN
authors: Johnson
authors: Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA , USA.
authors: Chris P
authors: CP
authors: Palmer
authors: Division of Neurology, Children's Hospital of Philadelphia , Philadelphia, PA , USA.
authors: Brendan J
authors: BJ
authors: Putnam
authors: Division of Neurology, Children's Hospital of Philadelphia , Philadelphia, PA , USA ; Department of Anesthesia and Critical Care, Children's Hospital of Philadelphia , Philadelphia, PA , USA.
authors: Matthew P
authors: MP
authors: Kirschen
authors: Division of Neurology, Children's Hospital of Philadelphia , Philadelphia, PA , USA ; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA , USA.
authors: Akiva S
authors: AS
authors: Cohen
keywords: branched chain amino acids; fear conditioning; hippocampus; network excitability; traumatic brain injury