The Cannabigerol Derivative VCE-003.2 Exerts Therapeutic Effects in 6-Hydroxydopamine-Lesioned Mice: Comparison with The Classic Dopaminergic Replacement Therapy

Abstract

(1) Background: A cannabigerol aminoquinone derivative, so-called VCE-003.2, has been found to behave as a neuroprotective agent (administered both i.p. and orally) in different experimental models of Parkinson's disease (PD) in mice. These effects were exerted through mechanisms that involved the activation of a regulatory site within the peroxisome proliferator-activated receptor-γ (PPAR-γ). (2) Methods: We are now interested in comparing such neuroprotective potential of VCE-003.2, orally administered, with the effect of the classic dopaminergic replacement therapy with L-DOPA/benserazide in similar conditions, using 6-hydroxydopamine-lesioned mice. (3) Results: The oral administration of VCE-003.2 during 14 days at the dose of 20 mg/kg improved, as expected, the neurological status (measured in motor tests) in these mice. This correlated with a preservation of TH-labelled neurons in the substantia nigra. By contrast, the treatment with L-DOPA/benserazide (during 7 days at 2 mg/kg) was significantly less active in these experimental conditions, in concordance with their profile as a mere symptom-alleviating agent. (4) Conclusions: Our results confirmed again the therapeutic profile of VCE-003.2 in experimental PD and revealed a different and more relevant effect, as a disease modifier, compared to the classic symptom-alleviating L-DOPA treatment. This reinforces the interest in VCE-003.2 for a future clinical development in this disease.

Keywords: 6-OHDA-lesioned mice; L-DOPA/benserazide; PPAR-γ; Parkinson’s disease; VCE-003.2; cannabinoids.

Figure 1

Response in the cylinder rearing and pole tests of 6-OHDA-lesioned mice treated with VCE-003.2 (at an oral dose of 20 mg/kg), L-DOPA/benserazide (at an i.p. dose of 2 mg/kg) or vehicle (sesame oil or 0.9% saline, respectively), and the corresponding controls. Data corresponded to 24 h after the last dose of VCE-003.2 (2 weeks of daily treatment) or L-DOPA (1 week of daily treatment). Values are mean ± SD and were analyzed by one-way ANOVA followed by the Tukey test (** p < 0.01, *** p < 0.005 versus vehicle-treated sham mice; ## p < 0.01 versus vehicle-treated 6-OHDA-lesioned mice).

Figure 2

TH immunoreactivity levels (expressed as % over the contralateral non-lesioned side) in the substantia nigra of 6-OHDA-lesioned mice treated with VCE-003.2 (at an oral dose of 20 mg/kg), L-DOPA/benserazide (at an i.p. dose of 2 mg/kg) or vehicle (sesame oil or 0.9% saline, respectively), and the corresponding controls. The figure also includes representative microphotographs of ipsi-lateral lesioned and contralateral non-lesioned sides for each experimental group (scale bar = 200 µm). Data corresponded to 24 h after the last dose of VCE-003.2 (2 weeks of daily treatment) or L-DOPA (1 week of daily treatment). Values are mean ± SD, and were analyzed by one-way ANOVA followed by the Tukey test (** p < 0.01, *** p < 0.005 versus vehicle-treated sham mice; # p < 0.05 versus vehicle-treated 6-OHDA-lesioned mice).

Figure 3

GFAP immunoreactivity levels (expressed as % over the contralateral non-lesioned side) in the substantia nigra of 6-OHDA-lesioned mice treated with VCE-003.2 (at an oral dose of 20 mg/kg), L-DOPA/benserazide (at an i.p. dose of 2 mg/kg) or vehicle (sesame oil or 0.9% saline, respectively), and the corresponding controls. Data corresponded to 24 h after the last dose of VCE-003.2 (2 weeks of daily treatment) or L-DOPA (1 week of daily treatment). Values are mean ± SD and were analyzed by one-way ANOVA followed by the Tukey test.

Figure 4

Cd68 immunoreactivity levels (expressed as % over the contralateral non-lesioned side) in the substantia nigra of 6-OHDA-lesioned mice treated with VCE-003.2 (at an oral dose of 20 mg/kg), L-DOPA/benserazide (at an i.p. dose of 2 mg/kg) or vehicle (sesame oil or 0.9% saline, respectively), and the corresponding controls. Data corresponded to 24 h after the last dose of VCE-003.2 (2 weeks of daily treatment) or L-DOPA (1 week of daily treatment). Values are mean ± SD and were analyzed by one-way ANOVA followed by the Tukey test.