Gambogic amide, a selective TrkA agonist, does not improve outcomes from traumatic brain injury in mice

ABSTRACT

Objectives: There is evidence that treatment with nerve growth factor (NGF) may reduce neuroinflammation and apoptosis after a traumatic brain injury (TBI). NGF is thought to exert its effects via binding to either TrkA or p75 neurotrophin receptors. This study aimed to investigate the effects of a selective TrkA agonist, gambogic amide (GA), on TBI pathology and outcomes in mice following lateral fluid percussion injury.

Methods: Male C57BL/6 mice were given either a TBI or sham injury, and then received subcutaneous injections of either 2 mg/kg of GA or vehicle at 1, 24, and 48 h post-injury. Following behavioural studies, mice were euthanized at 72 h post-injury for analysis of neuroinflammatory, apoptotic, and neurite outgrowth markers.

Results: Behavioural testing revealed that GA did not mitigate motor deficits after TBI. TBI caused an increase in cortical and hippocampal expression of several markers of neuroinflammation and apoptosis compared to sham groups. GA treatment did not attenuate these increases in expression, possibly contributed to by our finding of TrkA receptor down-regulation post-TBI.

Conclusions: These findings suggest that GA treatment may not be suitable for attenuating TBI pathology and improving outcomes.

KEYWORDS:

• Nerve growth factor
• neuroinflammation
• neurite growth
• synaptogenesis
• apoptosis
• behaviour

Funding

This work was supported by funding to SJM through the Understanding Disease RFA of La Trobe University and to SRS from the Australian National Health and Medical Research Council. No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the content of this article.

Declaration of interest statement

The authors report no declarations of interest.

Additional information

Funding

This work was supported by funding to SJM through the Understanding Disease RFA of La Trobe University and to SRS from the Australian National Health and Medical Research Council. No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the content of this article.

Notes on contributors

Maddison R Johnstone

MRJ, BLG, SRS and SJM conceptualized and designed the experiments. SRS, MRJ, SJM and MS conducted the injury methods and administered treatments. MRJ and MS completed behavioural testing. MRJ, RDB, SJM, JEC, CJT and MS completed post-mortem analysis. All authors contributed to the data interpretation and preparation of the manuscript.