A journey through cannabidiol in Parkinson's disease.

Parkinson's disease is a chronic neurodegenerative disorder with no known cure characterized by motor symptoms such as tremors, rigidity, bradykinesia (slowness of movement), and postural instability. Non-motor symptoms like cognitive impairment, mood disturbances, and sleep disorders often accompany the disease. Pharmacological treatments for these symptoms are limited and frequently induce significant adverse reactions, underscoring the necessity for appropriate treatment options. Cannabidiol is a phytocannabinoid devoid of the euphoric and cognitive effects of tetrahydrocannabinol. The study of cannabidiol's pharmacological effects has increased exponentially in recent years. Preclinical and preliminary clinical studies suggest that cannabidiol holds therapeutic potential for alleviating symptoms of Parkinson's disease, offering neuroprotective, anti-inflammatory, and antioxidant properties. However, knowledge of cannabidiol neuromolecular mechanisms is limited, and its pharmacology, which appears complex, has not yet been fully elucidated. By examining the evidence, this review aims to provide and synthesize scientifically proven evidence for the potential use of cannabidiol as a novel treatment option for Parkinson's disease. We focus on studies that administrated cannabidiol alone. The results of preclinical trials using cannabidiol in models of Parkinson's disease are encouraging. Nevertheless, drawing firm conclusions on the therapeutic efficacy of cannabidiol for patients is challenging. Cannabidiol doses, formulations, outcome measures, and methodologies vary considerably across studies. Though, cannabidiol holds promise as a novel therapeutic option for managing both motor and non-motor symptoms of Parkinson's disease, offering hope for improved quality of life for affected individuals.

Novel Proline Transporter Inhibitor (LQFM215) Presents Antipsychotic Effect in Ketamine Model of Schizophrenia.

The glutamatergic hypothesis of schizophrenia suggests a correlation between NMDA receptor hypofunction and negative psychotic symptoms. It has been observed that the expression of the proline transporter (PROT) in the central nervous system (CNS) is associated with glutamatergic neurotransmission, as L-proline has the capacity to activate and modulate AMPA and NMDA receptors. In this study, we aimed to investigate whether inhibition of proline transporters could enhance glutamatergic neurotransmission and potentially exhibit antipsychotic effects in an experimental schizophrenia model. Using molecular dynamics analysis in silico, we validated an innovative PROT inhibitor, LQFM215. We quantified the cytotoxicity of LQFM215 in the Lund human mesencephalic cell line (LUHMES). Subsequently, we employed the ketamine-induced psychosis model to evaluate the antipsychotic potential of the inhibitor, employing behavioral tests including open-field, three-chamber interaction, and prepulse inhibition (PPI). Our results demonstrate that LQFM215, at pharmacologically active concentrations, exhibited negligible neurotoxicity when astrocytes were co-cultured with neurons. In the ketamine-induced psychosis model, LQFM215 effectively reduced hyperlocomotion and enhanced social interaction in a three-chamber social approach task across all administered doses. Moreover, the compound successfully prevented the ketamine-induced disruption of sensorimotor gating in the PPI test at all tested doses. Overall, these findings suggest that PROT inhibition could serve as a potential therapeutic target for managing symptoms of schizophrenia model.

Behavioral effects induced by the cannabidiol analogs HU-502 and HU-556.

Cannabidiol is a phytocannabinoid that lacks the psychotomimetic properties of Δ9-tetrahydrocannabinol (THC), the main psychoactive Cannabis sativa component. Cannabidiol has several potential therapeutic properties, including anxiolytic, antidepressant, and antipsychotic; however, cannabidiol has low oral bioavailability, which can limit its clinical use. Here, we investigated if two cannabidiol analogs, HU-502 and HU-556, would be more potent than cannabidiol in behavioral tests predictive of anxiolytic, antidepressant, and antipsychotic effects. Different doses (0.01-3 mg/kg; intraperitoneally) of HU-556 and HU-502 were tested in male Swiss mice submitted to the elevated plus maze (EPM), forced swimming test (FST), and amphetamine-induced-prepulse inhibition (PPI) disruption and hyperlocomotion. Cannabidiol is effective in these tests at a dose range of 15-60 mg/kg in mice. We also investigated if higher doses of HU-556 (3 and 10 mg/kg) and HU-502 (10 mg/kg) produced the cannabinoid tetrad (hypolocomotion, catalepsy, hypothermia, and analgesia), which is induced by THC-like compounds. HU-556 (0.1 and 1 mg/kg) increased the percentage of open arm entries (but not time) in the EPM, decreased immobility time in the FST, and attenuated amphetamine-induced PPI disruption. HU-502 (1 and 3 mg/kg) decreased amphetamine-induced hyperlocomotion and PPI impairment. HU-556, at high doses, caused catalepsy and hypolocomotion, while HU-502 did not. These findings suggest that similar to cannabidiol, HU-556 could induce anxiolytic, antidepressant, and antipsychotic-like effects and that HU-502 has antipsychotic properties. These effects were found at a dose range devoid of cannabinoid tetrad effects.

Distinct sex-dependent behavioral responses induced by two positive allosteric modulators of alpha 5 subunit-containing GABAA receptors.

Dysregulation of GABAergic neurotransmission has long been implicated in several psychiatric disorders, including schizophrenia, depression, and anxiety disorders. Alpha 5 subunit-containing GABAA receptors (α5-GABAAR), which are expressed mainly by pyramidal neurons in the hippocampus, have been proposed as a potential target to treat these psychiatric disorders. Here, we evaluated the effects produced by GL-II-73 and SH-053-2'F-R-CH3 (1, 5, and 10 mg/kg), two positive allosteric modulators of α5-GABAAR in behavioral tests sensitive to drugs with anxiolytic, antidepressant, and antipsychotic properties in male and female C57BL/6 mice. In both males and females, GL-II-73 produced an anxiolytic-like effect in the elevated plus-maze (EPM) and novelty-suppressed feeding and a rapid and sustained antidepressant-like effect in the forced swim test. GL-II-73 also induced antipsychotic-like effects in males indicated by attenuating MK-801-induced hyperlocomotion and prepulse inhibition (PPI) disruption. However, GL-II-73 per se increased locomotor activity and impaired fear memory extinction in males and females and PPI in males. On the other hand, SH-053-2'F-R-CH3 induced anxiolytic-like effects in the EPM and facilitated fear memory extinction in males. Contrary to GL-II-73, SH-053-2'F-R-CH3 attenuated MK-801-induced hyperlocomotion and PPI disruption in females but not in males. Neither of these drugs induced rewarding effects or impaired motor coordination. These findings suggest that GL-II-73 and SH-053-2'F-R-CH3 cause distinct sex-dependent behavioral responses and support continued preclinical research on the potential of positive allosteric modulators of α5-GABAAR for the treatment of psychiatric disorders.

HU-910, a CB2 receptor agonist, reverses behavioral changes in pharmacological rodent models for schizophrenia.

Despite attenuating the positive symptoms, drugs currently used to treat schizophrenia frequently do not improve the negative symptoms and cognitive impairments. In addition, they show low tolerability, which has been associated with high rates of treatment discontinuation. Recent evidence suggests that the endocannabinoid system may be a target for schizophrenia treatment. The CB2 receptor modulates dopaminergic neurotransmission, which is abnormally enhanced in schizophrenia patients. Here, we aimed to evaluate whether HU-910, a selective CB2 receptor agonist, would reverse schizophrenia-related behavioral changes observed after the acute injections of amphetamine or the N-methyl-d-aspartate receptor (NMDAR) antagonist MK-801. We also investigated the effects of HU-910 in the memory impairment caused by repeated MK-801 administration. Finally, we tested whether HU-910 would produce the cannabinoid tetrad (catalepsy, hypolocomotion, hypothermia, and antinociception). In male C57BL/6 mice, the acute treatment with HU-910 (30 mg/kg) prevented the hyperlocomotion induced by acute MK-801. This effect was blocked by the CB2 receptor antagonist AM630 (1 mg/kg). On the contrary, HU-910 did not prevent the increased locomotor activity caused by acute amphetamine. The acute treatment with HU-910 (3, 10, and 30 mg/kg) also attenuated the impairments in the prepulse inhibition test induced by acute MK-801 and amphetamine. The repeated treatment with HU-910 attenuated the cognitive impairment caused by chronic administration of MK-801 in the novel object recognition test. Furthermore, HU-910 did not produce the cannabinoid tetrad. These results indicate that HU-910 produced antipsychotic-like effects and support further research on the potential therapeutic properties of this compound to treat schizophrenia.

Effects of Doxycycline in Swiss Mice Predictive Models of Schizophrenia.

Schizophrenia patients show very complex symptoms in several psychopathological domains. Some of these symptoms remain poorly treated. Therefore, continued effort is needed to find novel pharmacological strategies for improving schizophrenia symptoms. Recently, minocycline, a second-generation tetracycline, has been suggested as an adjunctive treatment for schizophrenia. The antipsychotic-like effect of doxycycline, a minocycline analog, was investigated here. We found that both minocycline and doxycycline prevented amphetamine-induced prepulse inhibition (PPI) disruption. However, neither of them blocked MK801-induced effects, albeit doxycycline had a modest impact against ketamine-induced effects. Neither c-Fos nor nNOS expression, which was evaluated in limbic regions, were modified after acute or sub-chronic treatment with doxycycline. Therefore, apomorphine inducing either PPI disruption and climbing behavior was not prevented by doxycycline. This result discards a direct blockade of D2-like receptors, also suggested by the lack of doxycycline cataleptic-induced effect. Contrasting, doxycycline prevented SKF 38393-induced effects, suggesting a preferential doxycycline action at D1-like rather than D2-like receptors. However, doxycycline did not bind to the orthosteric sites of D1, D2, D3, D4, 5-HT2A, 5-HT1A, and A2A receptors suggesting no direct modulation of these receptors. Our data corroborate the antipsychotic-like effect of doxycycline. However, these effects are probably not mediated by doxycycline direct interaction with classical receptors enrolled in the antipsychotic effect.

The role of striatum and prefrontal cortex in the prevention of amphetamine-induced schizophrenia-like effects mediated by nitric oxide compounds.

Pharmacological manipulation of nitric oxide (NO) has been suggested as a promising treatment for schizophrenia symptoms. A single infusion of sodium nitroprusside, a NO donor with short half-life, was found to improve schizophrenia symptoms. However, an increasing number of preclinical studies have demonstrated the potential beneficial effects of both NO donors and inhibitors. We investigated the potential synergistic effect of sub-effective doses of the NO donor sodium nitroprusside or the NO inhibitor 7-Nitroindazole (7NI) combined with clozapine, a standard atypical antipsychotic, on counteracting amphetamine or MK-801-induced psychosis-like behaviors. The impact of sodium nitroprusside and 7NI on cAMP regulation in the prefrontal cortex and striatum was also evaluated. Confirming previous results, we found that both NO donors and inhibitors prevented amphetamine-induced effects (prepulse inhibition [PPI] disruption and hyperlocomotion). In addition, we observed a synergistic effect of sodium nitroprusside and clozapine on antagonizing the disruptive effects of amphetamine, but not MK-801, in the PPI test. The sub-effective dose of 7NI tested did not prevent amphetamine or MK-induced PPI effects when combined with clozapine. Interestingly, cAMP levels were significantly decreased in the prefrontal cortex after treatment with sodium nitroprusside. In the striatum, both sodium nitroprusside and 7NI blocked the amphetamine-induced increase of cAMP. Our data corroborate previous findings on the dopaminergic mechanisms involved in the action of sodium nitroprusside. It is likely that the differential effects of sodium nitroprusside are related to its ability to modify cAMP levels in the prefrontal cortex.

Correction: Fluorinated Cannabidiol Derivatives: Enhancement of Activity in Mice Models Predictive of Anxiolytic, Antidepressant and Antipsychotic Effects.

[This corrects the article DOI: 10.1371/journal.pone.0158779.].

Fluorinated Cannabidiol Derivatives: Enhancement of Activity in Mice Models Predictive of Anxiolytic, Antidepressant and Antipsychotic Effects.

Cannabidiol (CBD) is a major Cannabis sativa constituent, which does not cause the typical marijuana psychoactivity. However, it has been shown to be active in a numerous pharmacological assays, including mice tests for anxiety, obsessive-compulsive disorder, depression and schizophrenia. In human trials the doses of CBD needed to achieve effects in anxiety and schizophrenia are high. We report now the synthesis of 3 fluorinated CBD derivatives, one of which, 4'-F-CBD (HUF-101) (1), is considerably more potent than CBD in behavioral assays in mice predictive of anxiolytic, antidepressant, antipsychotic and anti-compulsive activity. Similar to CBD, the anti-compulsive effects of HUF-101 depend on cannabinoid receptors.

Perfil antipsicótico do canabidiol / Antipsychotic profile of cannabidiol

O canabidiol, fitocanabinóide presente na planta Cannabis sativa é desprovido dos efeitos psicotomiméticos característicos do principal composto da Cannabis, o ∆9-tetraidrocanabinol, mais conhecido como delta 9-THC. Um conjunto crescente de evidências sugere que o canabidiol apresente potencial terapêutico para o tratamento dos sintomas de distúrbios psiquiátricos, como a depressão, a ansiedade e as psicoses. A observação em humanos, mas também em modelos animais experimentais da capacidade do canabidiol de antagonizar os efeitos psicotomiméticos do delta 9-THC constitui uma importante evidência de seu potencial para utilização clínica. Embora os efeitos farmacológicos do canabidiol tenham sido investigados em diferentes sistemas biológicos in vitro e in vivo, seu mecanismo de ação ainda não é claro. O delta 9-THC ativa os receptores canabinóides do tipo CB1 e CB2, contudo o canabidiol apresenta uma baixa afinidade por esses receptores. Adicionalmente, o canabidiol em apresentado boa tolerabilidade em testes com humanos, tornando-o alvo de grande interesse da comunidade científica. O objetivo dessa revisão é apresentar, de forma breve, algumas das principais evidências experimentais e clínicas do provável perfil antipsicótico do canabidiol...

Cannabidiol an important phytocannabinoid present in the Cannabis sativa opposing to the major plant compound D9-tetrahydrocannabinol, known as delta-9-THC, is devoid of the psychotomimetic effects. Growing set of evidence suggest that cannabidiol may be used for the treatment of the symptoms of psychiatric disorders such as depression, anxiety and psychosis. The first evidence of the cannabidiol therapeutic potential was the observation of its ability to antagonize delta-9-THC effects either on human and experimental animal models. Pharmacological effects of CBD has been investigated in different biological systems, in vitro and in vivo, however, the mechanisms responsible for their therapeutic potential are still unclear. delta-9-THC effects results from activation of the cannabinoid receptors CB1 and CB2, however, the cannabidiol has low affinity for these receptors. The good tolerability of cannabidiolin human trials makes this compound an interesting target of the scientific community. The aim of this paper is to present concisely some experimental and clinical evidence about the cannabidiol antipsychotic profile...

Critical role of nitric oxide in the modulation of prepulse inhibition in Swiss mice.

RATIONALE: Nitric oxide (NO) modulates the dopamine uptake and release processes and appears to be implicated in dopamine-related pathologies, such as schizophrenia. However, it is unclear whether there is excess or deficient NO synthesis in schizophrenia pathophysiology. Analyses of the intracellular pathways downstream of NO system activation have identified the cyclic nucleotide cyclic guanosine monophosphate (cGMP) as a possible target for drug development. Defects in the sensorimotor gating of the neural mechanism underlying the integration and processing of sensory information have been detected across species through prepulse inhibition (PPI). OBJECTIVES: The aim of this study was to investigate the effects of NO/cGMP increase on sensorimotor gating modulation during dopamine hyperfunction. METHODS: Mice were treated with NO donors and subjected to the PPI test. Treatment with the NO donor sodium nitroprusside was preceded by pretreatment with a soluble guanylate cyclase (sGC) inhibitor. Additionally, the mice were treated with NO donors and phosphodiesterases inhibitors prior to amphetamine treatment. RESULTS: Pretreatment with the NO donors enhanced the PPI response and attenuated the amphetamine-disruptive effects on the PPI. The sGC inhibitor did not modify the sodium nitroprusside effects. Additionally, the cGMP increase induced by a specific phosphodiesterase inhibitor did not modify the amphetamine-disruptive effect. CONCLUSIONS: This study provides the first demonstration that an increase in NO can improve the PPI response and block the amphetamine-disruptive effects on the PPI response. Our data are consistent with recent clinical results. However, these effects do not appear to be related to an increase in cGMP levels, and further investigation is thus required.