Evidence for improved motor function by ceftriaxone despite striatal tyrosine hydroxylase loss following nigrostriatal lesion




Meadows, Samantha
Kasanga, Ella
Cantu, Mark
Bishop, Chris
Salvatore, Michael


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Purpose: The beta-lactam antibiotic, ceftriaxone, attenuates tyrosine hydroxylase (TH) loss in striatum in rodent Parkinson’s disease (PD) models when given early after nigrostriatal lesion. This protection may be related to the well-known properties of ceftriaxone to increase expression of the glutamate transporter, GLT-1, which increases glutamate uptake. Ser19 TH phosphorylation, which is modulated by glutamate and Ca2+-influx, increases in proportion to TH loss following nigrostriatal lesion and may predispose TH to premature degradation via the ubiquitin-proteasome pathway. Here we evaluated if ceftriaxone could partially restore striatal TH loss, concomitant with a decrease in motor impairment, when administered 1 week after lesion induction. Methods: The ability of ceftriaxone to decrease motor impairment was evaluated after evidence of motor impairment by evaluation of forepaw adjustment steps (FAS) and open-field locomotor activity. Ceftriaxone (200 mg/kg, i.p.) was given intermittently on days 7-13, 21-27, and 35-38 post-lesion. Motor function 7 days after lesion induction was used as a baseline to evaluate if ceftriaxone could reduce motor impairment out to 40 days post-lesion. Results: There was a significant increase in FAS taken, with an overall 45% increase in mean FAS post-lesion compared to the day 7 baseline. Locomotor activity (ambulatory count and total distance) increased at the end of the study (38 days post-lesion) against the day 7 baseline following ceftriaxone. [greater than] 90% striatal TH protein loss was evident regardless of whether the rats received ceftriaxone or saline injection. However, in the substantia nigra, there was a significant increase in TH expression in the side contralateral to lesion in the ceftriaxone group. Conclusion: Taken together, these results suggest that ceftriaxone-mediated protection against locomotor decline, after the establishment of a nigrostriatal lesion, may be independent of any preservation or possible restoration of striatal TH.