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Efficacy, dosage, and duration of action of branched chain amino Acid therapy for traumatic brain injury.

Elkind JA, Lim MM, Johnson BN, Palmer CP, Putnam BJ, Kirschen MP, Cohen AS - Front Neurol (2015)

Bottom Line: However, the optimal BCAA dose and length of treatment needed to improve cognitive recovery is unknown.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Neurology, Children's Hospital of Philadelphia , Philadelphia, PA , USA.

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.

No MeSH data available.


Related in: MedlinePlus

Time course of BCAA treatment required to restore conditioned fear response. (A) BCAA supplemented water (100 mM, black bars) or plain water (open bars) were offered ad libitum to brain-injured mice for 2, 3, 4, 5, or 10 days. Conditioned fear responses, as measured by the percentage of observations in which the animal demonstrated freezing behavior, were recorded for each animal. All animals in all treatment groups demonstrated at least some freezing, and the average level of freezing was calculated for each group. Freezing was restored to normal levels at the 5- and 10-day time points (*P < 0.05). Conditioned fear responses in naïve animals were not significantly different from conditioned fear responses in either the 5- or 10-day BCAA treated groups. (B) Water containing BCAAs (0.26 g/kg) or untreated water was administered via oral gavage once daily for 3 or 5 days. Significant improvement in freezing behavior was observed following five consecutive days of gavage BCAA treatment (*P < 0.05), but not after 3 days of treatment, and 5-day gavage results were not significantly different from the 5-day supplemented water results. Abbreviations: FPI, fluid percussion injury; BCAAs, branched chain amino acids.
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Figure 2: Time course of BCAA treatment required to restore conditioned fear response. (A) BCAA supplemented water (100 mM, black bars) or plain water (open bars) were offered ad libitum to brain-injured mice for 2, 3, 4, 5, or 10 days. Conditioned fear responses, as measured by the percentage of observations in which the animal demonstrated freezing behavior, were recorded for each animal. All animals in all treatment groups demonstrated at least some freezing, and the average level of freezing was calculated for each group. Freezing was restored to normal levels at the 5- and 10-day time points (*P < 0.05). Conditioned fear responses in naïve animals were not significantly different from conditioned fear responses in either the 5- or 10-day BCAA treated groups. (B) Water containing BCAAs (0.26 g/kg) or untreated water was administered via oral gavage once daily for 3 or 5 days. Significant improvement in freezing behavior was observed following five consecutive days of gavage BCAA treatment (*P < 0.05), but not after 3 days of treatment, and 5-day gavage results were not significantly different from the 5-day supplemented water results. Abbreviations: FPI, fluid percussion injury; BCAAs, branched chain amino acids.

Mentions: In the time course experiments, mice consumed BCAA supplemented drinking water or untreated water ad libitum for 2, 3, 4, 5, or 10 consecutive days before undergoing CFR testing (Figure 1A). All animals tested demonstrated freezing. Freezing in individual animals ranged from 6.7% (measured 2 days after injury, in the untreated group) to 68.3% (measured 10 days after injury, in the 10-day BCAA treated group). As a group, injured mice that received BCAA treatment showed a significantly greater freezing response on average compared to untreated FPI mice when treatment was delivered for 5 or 10 consecutive days (Figure 2A; F = 18.12, P < 0.0001, two-way ANOVA; *P < 0.05, Bonferroni post hoc tests; untreated n’s, 2 through 10 days: 4, 8, 7, 16, 12; treated n’s, 2 through 10 days: 8, 7, 8, 15, 5). Although BCAA treatment also increased freezing in mice treated for 2, 3, and 4 days, those improvements were not statistically significant. These results suggest that BCAA supplementation improves cognitive recovery if consumed for at least five consecutive days after injury.


Efficacy, dosage, and duration of action of branched chain amino Acid therapy for traumatic brain injury.

Elkind JA, Lim MM, Johnson BN, Palmer CP, Putnam BJ, Kirschen MP, Cohen AS - Front Neurol (2015)

Time course of BCAA treatment required to restore conditioned fear response. (A) BCAA supplemented water (100 mM, black bars) or plain water (open bars) were offered ad libitum to brain-injured mice for 2, 3, 4, 5, or 10 days. Conditioned fear responses, as measured by the percentage of observations in which the animal demonstrated freezing behavior, were recorded for each animal. All animals in all treatment groups demonstrated at least some freezing, and the average level of freezing was calculated for each group. Freezing was restored to normal levels at the 5- and 10-day time points (*P < 0.05). Conditioned fear responses in naïve animals were not significantly different from conditioned fear responses in either the 5- or 10-day BCAA treated groups. (B) Water containing BCAAs (0.26 g/kg) or untreated water was administered via oral gavage once daily for 3 or 5 days. Significant improvement in freezing behavior was observed following five consecutive days of gavage BCAA treatment (*P < 0.05), but not after 3 days of treatment, and 5-day gavage results were not significantly different from the 5-day supplemented water results. Abbreviations: FPI, fluid percussion injury; BCAAs, branched chain amino acids.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4378292&req=5

Figure 2: Time course of BCAA treatment required to restore conditioned fear response. (A) BCAA supplemented water (100 mM, black bars) or plain water (open bars) were offered ad libitum to brain-injured mice for 2, 3, 4, 5, or 10 days. Conditioned fear responses, as measured by the percentage of observations in which the animal demonstrated freezing behavior, were recorded for each animal. All animals in all treatment groups demonstrated at least some freezing, and the average level of freezing was calculated for each group. Freezing was restored to normal levels at the 5- and 10-day time points (*P < 0.05). Conditioned fear responses in naïve animals were not significantly different from conditioned fear responses in either the 5- or 10-day BCAA treated groups. (B) Water containing BCAAs (0.26 g/kg) or untreated water was administered via oral gavage once daily for 3 or 5 days. Significant improvement in freezing behavior was observed following five consecutive days of gavage BCAA treatment (*P < 0.05), but not after 3 days of treatment, and 5-day gavage results were not significantly different from the 5-day supplemented water results. Abbreviations: FPI, fluid percussion injury; BCAAs, branched chain amino acids.
Mentions: In the time course experiments, mice consumed BCAA supplemented drinking water or untreated water ad libitum for 2, 3, 4, 5, or 10 consecutive days before undergoing CFR testing (Figure 1A). All animals tested demonstrated freezing. Freezing in individual animals ranged from 6.7% (measured 2 days after injury, in the untreated group) to 68.3% (measured 10 days after injury, in the 10-day BCAA treated group). As a group, injured mice that received BCAA treatment showed a significantly greater freezing response on average compared to untreated FPI mice when treatment was delivered for 5 or 10 consecutive days (Figure 2A; F = 18.12, P < 0.0001, two-way ANOVA; *P < 0.05, Bonferroni post hoc tests; untreated n’s, 2 through 10 days: 4, 8, 7, 16, 12; treated n’s, 2 through 10 days: 8, 7, 8, 15, 5). Although BCAA treatment also increased freezing in mice treated for 2, 3, and 4 days, those improvements were not statistically significant. These results suggest that BCAA supplementation improves cognitive recovery if consumed for at least five consecutive days after injury.

Bottom Line: However, the optimal BCAA dose and length of treatment needed to improve cognitive recovery is unknown.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Neurology, Children's Hospital of Philadelphia , Philadelphia, PA , USA.

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.

No MeSH data available.


Related in: MedlinePlus