Authors :
Presenting Author: Mushajiang Xierzhati, MS – Boston Children's Hospital
Mustafa Hameed, MD – Boston Children's Hospital
Yongho Choe, BA – Boston Children's Hospital
Zijie Jin, MS – Boston Children's Hospital
Justin Chao, Undergraduate – Boston Children's Hospital
Alexander Rotenberg, MD, PhD – Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Rationale:
Severe traumatic brain injury (TBI) is commonly followed by post-traumatic epilepsy (PTE), which usually occurs weeks to months after the initial trauma. The acute post-TBI phase is marked by glutamate-mediated excitotoxicity, leading to continued neuronal damage and death, which contributes post-TBI epileptogenesis. These effects are exacerbated by the post-traumatic downregulation of glutamate transporter 1 (GLT-1), which is responsible for 95% of glutamate clearance in the mammalian brain. We previously identified that short-term therapy with ceftriaxone (CRO), an injectable beta-lactam antibiotic, promotes GLT-1 expression and reduces neuronal death and seizures in a rat PTE model. Our finding raises prospects for PTE prevention by beta lactam treatment. However, CRO benefits do not last beyond therapy discontinuation, and long-term CRO administration (as long-term administration of any antibiotic) is impractical due to gut flora disturbance, risks of generating antibiotic-resistant superinfection, and other complications. The atypical non-bactericidal beta-lactam clavulanic acid (CLAV) also increases GLT-1 expression and protects against glutamate-mediated damage in animal models of addiction and neuropathic pain. This well-tolerated, orally available non-antibiotic drug can potentially serve as a mainstay of prolonged (weeks to months after injury) GLT-1 upregulation strategies for sustained neuroprotection and epilepsy prevention, without the risks associated with CRO.
Methods:
Adult male CD1 mice (n=6) received severe CCI (controlled cortical Impact) via a craniotomy over the motor cortex and received either 25mg/kg CLAV (n=6) or vehicle (VEH; n=6), intraperitoneally (IP) daily for 7 days post-CCI. A sham group (n=6) received all surgical procedures except CCI, and did not receive IP injections. Brain tissue was harvested one week after injury, and GLT-1 expression in perilesional tissue was measured by immunoblotting. Results:
We identified a 35.3% reduction in cortical perilesional GLT-1 expression following injury (CCI: 64.7± 2.2%; SHAM: 100 ± 3.1%; paired t-test; p< 0.01). CLAV treatment led to a 20.0% increase in perilesional GLT-1 protein expression (VEH: 100 ± 3.6%; CLAV: 120 ± 4.9 %; unpaired t-test; p< 0.01).