R215Dose-response study of Ceftriaxone on GLT-1 expression in rats

Réanimation / Urgences
Neuroscience
D. Bouvier 1, F. Bernard 1, A. Jacquens 2, V. Bevilacqua 2, V. Degos 2, S. Marchand 3, G. Page 3, C. Dahyot-Fizelier 1.
1Centre Hospitalier Universitaire - Poitiers (France), 2Groupe Hospitalier Pitié-Salpétrière - Paris (France), 3Inserm U1070 - Poitiers (France)

Conflits d'intérêt

Aucun


Position du problème et objectif(s) de l’étude

Acute brain injury is responsible for excitotoxicity through excessive glutamate release. Glutamate Transporter 1 (GLT-1) is the major transporter of glutamate in the central nervous system. Its expression is modulated by an antibiotic, Ceftriaxone (CTX), conferring a neuroprotective effect. No studies have investigated the dose- response of CTX on GLT-1 expression. Our objective was to evaluate the response to GLT-1 expression of several doses of CTX at different injection times.


Matériel et méthodes

Two therapeutic doses of CTX (Ceftriaxone 1g, Mylan), 30 and 100mg/kg/day, and a supra-therapeutic one (300mg/kg/day) were tested. Sprague-Dawley adults rats received 1 or 3 days of CTX intra-venous injection. The expression of GLT-1 mRNA was determined in the right frontal cortex by RT-qPCR (n=6 rats per dose and time points). Data were analyzed by a non-parametric Mann-Whitney test. Pharmacokinetics of CTX in plasma and cerebrospinal fluid (CSF) were investigated for 100mg/kg dose at 8 times of injection (30min, 1h, 2h, 3h, 4h, 5h, 24h, 72h) in n=5 rats per time. Analysis of CTX concentration in plasma and CSF was performed by HPLC-UV.


Résultats & Discussion

CTX increased expression of GLT-1 mRNA at 100 and 300mg/kg/day after 3 days of injection comparatively to sham (p=0.019 and p=0.029), without difference after 1 day. We did not observe any difference between sham and rats receiving 30mg/kg/day CTX. These results demonstrated a time-effect of CTX on GLT-1 mRNA expression, without dose-effect between 100 and 300mg/kg/day. Increasing rat number may be needed to obtain a significant difference for 30mg/kg/day dose. PK analyses confirmed the small diffusion of CTX in CSF with an AUClcr/AUCplasma ratio at 10%. Quantification of PK parameters for 30 and 300mg/kg/day doses are needed to create a pharmacokinetic-pharmacodynamic model.


Conclusion

The dose-response of CTX on GLT-1 mRNA expression is time-dependent. Three injection days are needed to significally increase GLT-1 mRNA expression. Potential dose-effect could allow to identify a minimal efficient dose to systematically use CTX as neuroprotective agent. This experiment may be repeated in an acute brain injury model.


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