Reduction of LID markers in the striatum of rats expressing LID after the acute administration of doxycycline
FosB-expressing neurons appear in the brain of patients with PD (Lindgren et al., 2011; Tekumalla et al. 2001) and accumulation of FosB has been linked to the development of dyskinetic behavior in animal models (Anderson et al. 1999). Treatment with doxycycline decreased FosB up-regulation in the dopamine-depleted striatum of rats expressing LID.
Doxycycline treatment decreased COX-2 immunoreactivity in the dopamine-depleted striatum induced by L-DOPA treatment. Bortolanza et al., (2015b) and Berke et al. (1998) previously described the increase in COX-2 in the LID striata. COX-2 expression was also up-regulated in SNc dopaminergic neurons in both patients with PD and experimental PD models (Braak et al., 2008; de Meira Santos Lima et al., 2006; Knott et al., 2000; Teismann et al., 2003). The evidence for a direct role of COX-2 in PD and LID is still unclear (Bartels and Leenders, 2007).
In the striatum of parkinsonian rats presenting LID, it was found that GFAP and OX-42 immunoreactivity increased, along with the presence of reactive astrocytes and microglia, respectively (Bortolanza et al., 2015a, b; Lanza et al., 2019; Ramirez-Garcia et al., 2015). The pattern of neuroinflammatory-glial activation seen in our study was at least partially a consequence of the L-DOPA treatment in the lesioned animals. The glial activation identified was attenuated by treatment with doxycycline. Postmortem analyses of patients with PD have indicated the presence of reactive astrocytes and microglia (Ben Haim et al., 2015), which produce and release a variety of pro- and anti-inflammatory substances (Block et al., 2007; Liu et al., 2017; Röhl et al. 2007; Sidoryk-Wegrzynowicz et al., 2011; Wolf et al. 2017).
Taken together, FosB, COX-2, GFAP, and OX42 expression reduction as demonstrated by doxycycline treatment, is proposed to be part of a feasible therapeutic strategy for LID, and may well be appropriate for the treatment of PD patients.