Doxycycline attenuates l-DOPA-induced dyskinesia through an anti-inflammatory effect in a hemiparkinsonian mouse model

Abstract

The pharmacological manipulation of neuroinflammation appears to be a promising strategy to alleviate l-DOPA-induced dyskinesia (LID) in Parkinson’s disease (PD). Doxycycline (Doxy), a semisynthetic brain-penetrant tetracycline antibiotic having interesting anti-inflammatory properties, we addressed the possibility that this compound could resolve LID in l-DOPA-treated C57BL/6 mice presenting either moderate or intermediate lesions of the mesostriatal dopaminergic pathway generated by intrastriatal injections of 6-OHDA. Doxy, when given subcutaneously before l-DOPA at doses of 20 mg kg−1 and 40 mg kg−1, led to significant LID reduction in mice with moderate and intermediate dopaminergic lesions, respectively. Importantly, Doxy did not reduce locomotor activity improved by l-DOPA. To address the molecular mechanism of Doxy, we sacrificed mice with mild lesions 1) to perform the immunodetection of tyrosine hydroxylase (TH) and Fos-B and 2) to evaluate a panel of inflammation markers in the striatum, such as cyclooxygenase-2 and its downstream product Prostaglandin E2 along with the cytokines TNF-α, IL-1β and IL-6. TH-immunodetection revealed that vehicle and Doxy-treated mice had similar striatal lesions, excluding that LID improvement by Doxy could result from neurorestorative effects. Importantly, LID inhibition by Doxy was associated with decreased Fos-B and COX-2 expression and reduced levels of PGE2, TNF-α, and IL-1β in the dorsolateral striatum of dyskinetic mice. We conclude 1) that Doxy has the potential to prevent LID regardless of the intensity of dopaminergic lesioning and 2) that the anti-inflammatory effects of Doxy probably account for LID attenuation. Overall, the present results further indicate that Doxy might represent an attractive and alternative treatment for LID in PD.

Alpha Synuclein: Neurodegeneration and Inflammation

“…In a recent study by Dos Santos Pereira et al (2022) [ 272 ] Doxy affected L-DOPA-induced dyskinesia (LID) in mice with dopaminergic impairment induced by intrastriatal injection of 6OHDA. In this model, Doxy given before L-Dopa significantly attenuated LID, and the effect was associated with a reduction in inflammatory markers in the striatum.…”

Microbiota-mediated effects of Parkinson’s disease medications on Parkinsonian non-motor symptoms in male transgenic mice

“…Vancomycin pre-treatment in an MPTP mouse model of PD was found to improve motor function potentially through microbiota alterations and the suppression of inflammation ( 55 ) and a similar mechanism may be in play here. Doxycycline followed by LD treatment of a 6-OHDA PD mouse model resulted in reduced L-DOPA-induced dyskinesia—without affecting LD-induced motor improvements—potentially by suppressing inflammation ( 56 ). Although our study used a different antibiotic treatment and PD mouse model, we also observed a reduction in TNF-alpha expression, as well as some mild motor improvements, due to Abx treatment.…”

Neuroinflammation and Dyskinesia: A Possible Causative Relationship?

“…As described above, treatment with MPEP (a metabotropic glutamate receptor 5 antagonist) reduced the onset of LIDs in de novo MPTP-lesioned monkeys through decrease of inflammatory reaction by means of IBA1, GFAP, and CD68 in the basal ganglia without effects in the nucleus accumbens and motor cortex M1 [88]. An alternative treatment for LIDs in PD could be the use of doxycycline (doxy), a semisynthetic tetracycline antibiotic with anti-inflammatory characteristics able to pass the BBB [124]. Doxycycline triggered the reduction of LIDs in L-DOPA-treated dyskinetic mice by decreasing Fos-B and COX-2 expression and lowering PGE 2 , TNF-α, and IL-1β levels in the dorsolateral striatum [124,125].…”

“…An alternative treatment for LIDs in PD could be the use of doxycycline (doxy), a semisynthetic tetracycline antibiotic with anti-inflammatory characteristics able to pass the BBB [124]. Doxycycline triggered the reduction of LIDs in L-DOPA-treated dyskinetic mice by decreasing Fos-B and COX-2 expression and lowering PGE 2 , TNF-α, and IL-1β levels in the dorsolateral striatum [124,125].…”