Objective: To evaluate the effects of doxycycline on the outcomes of 6-OHDA-induced Parkinson’s disease in Sapajus apella monkeys.

Background: Doxycycline (doxy) has been reported as a potential neuroprotective treatment for PD as it appears to inhibit dopaminergic neurodegeneration and reduce levodopa-induced dyskinesia in humans [1]. However, there is still limited evidence of its effects in preclinical settings. This study aims to analyze, for the first time, the neuroprotective effects of doxy in a nonhuman primate (NHP) model.

Method: Six Sapajus apella monkeys underwent stereotaxic microinjections of 6-OHDA in the substantia nigra and caudate nucleus. 6-OHDA was administered at concentrations of 4, 10, and 40 mg/ml to replicate different stages of PD (PD, n=3), with three subjects pre-treated with doxy (150 mg/day/30 d) and then injected with 6-OHDA at 40 mg/ml (DOXY, n=3). Forelimb motor performances were bilaterally assessed before and after the intervention using the Staircase [2] and Pipe tests [3]. Statistical analysis was conducted using ANOVA (p<0.05, Tukey post-test).

Results: Various concentrations of 6-OHDA induced impairments in motor performance as detected by Staircase and Pipe tests, including hand grip coordination (loss of treats p<0.001), and all parameters in the Pipe (p<0.05). Doxy reduced impairment in hand grip coordination for the nondominant limb in Staircase (p<0.001). However, other Staircase parameters exhibited differences between groups with conflicting results, possibly reflecting non-motor features of PD (cognitive or psychological). Pipe revealed impairments in all parameters both before and after the intervention for both groups (p<0.05), with concentration-dependent effects on types of hand grip and number of finger insertions (p<0.001). Doxy reduced motor impairment for all Pipe parameters compared to PD (p<0.001).

Conclusion: Doxy reduced the motor impairment induced by 6-OHDA in NPHs. Different concentrations of 6-OHDA induced symptoms in a dose-response pattern, suggesting it can serve as a model for different stages of PD. Doxy’s effects reduced motor impairment even when compared to lower concentrations of 6-OHDA-induced PD. Pipe test demonstrated high sensitivity to motor fluctuations induced by PD in NHPs, as it is less influenced by cognitive and emotional factors and primarily relies on fine motor coordination skills. Histological evaluations will be conducted to validate these findings.

References: [1] Santos-Lobato, Bruno Lopes, et al. “Doxycycline to treat levodopa-induced dyskinesias in Parkinson’s disease: a preliminary study.” Arquivos de Neuro-Psiquiatria 81 (2023): 460-468.
[2] Marshall, Jonathan WB, and Rosalind M. Ridley. “Assessment of cognitive and motor deficits in a marmoset model of stroke.” ILAR journal 44.2 (2003): 153-160.
[3] Murchison, M. A. “PVC-pipe food puzzle for singly caged primates.” Laboratory Primate Newsletter 30.3 (1991): 12-14.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/evaluation-of-neuroprotective-effects-of-doxycycline-in-a-primate-model-of-pd/