Expanding the therapeutic potential of neuro(active)steroids: a promising strategy for hyperdopaminergic behavioral phenotypes.

Imbalances in dopamine activity significantly contribute to the pathophysiology of several neuropsychiatric disorders, including addiction, ADHD, schizophrenia, impulse control disorders, and Parkinson's Disease. Neuro(active)steroids, comprising endogenous steroids that finely modulate neuronal activity, are considered crucial regulators of brain function and behavior, with implications in various physiological processes and pathological conditions. Specifically, subclasses of Neuro(active)steroids belonging to the 5α reductase pathway are prominently involved in brain disorders characterized by dopaminergic signaling imbalances. This review highlights the neuromodulatory effects of Neuro(active)steroids on the dopamine system and related aberrant behavioral phenotypes. We critically appraise the role of pregnenolone, progesterone, and allopregnanolone on dopamine signaling. Additionally, we discuss the impact of pharmacological interventions targeting 5α reductase activity in neuropsychiatric conditions characterized by excessive activation of the dopaminergic system, ranging from psychotic (endo)phenotypes and motor complications to decision-making problems and addiction.

Pregnenolone for the treatment of L-DOPA-induced dyskinesia in Parkinson's disease.

Growing preclinical and clinical evidence highlights neurosteroid pathway imbalances in Parkinson's Disease (PD) and L-DOPA-induced dyskinesias (LIDs). We recently reported that 5α-reductase (5AR) inhibitors dampen dyskinesias in parkinsonian rats; however, unraveling which specific neurosteroid mediates this effect is critical to optimize a targeted therapy. Among the 5AR-related neurosteroids, striatal pregnenolone has been shown to be increased in response to 5AR blockade and decreased after 6-OHDA lesions in the rat PD model. Moreover, this neurosteroid rescued psychotic-like phenotypes by exerting marked antidopaminergic activity. In light of this evidence, we investigated whether pregnenolone might dampen the appearance of LIDs in parkinsonian drug-naïve rats. We tested 3 escalating doses of pregnenolone (6, 18, 36 mg/kg) in 6-OHDA-lesioned male rats and compared the behavioral, neurochemical, and molecular outcomes with those induced by the 5AR inhibitor dutasteride, as positive control. The results showed that pregnenolone dose-dependently countered LIDs without affecting L-DOPA-induced motor improvements. Post-mortem analyses revealed that pregnenolone significantly prevented the increase of validated striatal markers of dyskinesias, such as phospho-Thr-34 DARPP-32 and phospho-ERK1/2, as well as D1-D3 receptor co-immunoprecipitation in a fashion similar to dutasteride. Moreover, the antidyskinetic effect of pregnenolone was paralleled by reduced striatal levels of BDNF, a well-established factor associated with the development of LIDs. In support of a direct pregnenolone effect, LC/MS-MS analyses revealed that striatal pregnenolone levels strikingly increased after the exogenous administration, with no significant alterations in downstream metabolites. All these data suggest pregnenolone as a key player in the antidyskinetic properties of 5AR inhibitors and highlight this neurosteroid as an interesting novel tool to target LIDs in PD.

Serotonin/dopamine interaction in the induction and maintenance of L-DOPA-induced dyskinesia: An update.

Ample evidence suggests that the serotonergic system plays a major role in several aspects of Parkinson's disease. In this review, we focus on the interplay between dopamine and serotonin in the appearance of L-DOPA-induced dyskinesia (LID), the most troublesome side effect of L-DOPA therapy. Indeed, while this drug exerts significant amelioration of motor symptoms during the first few years of treatment, eventually, most of patients experience dyskinesias, which limit the use of L-DOPA in advanced stages of disease. Here, we present the mechanisms underlying LID and the role of serotonin neurons, review preclinical and clinical data, and discuss possible therapeutic strategies.

BDNF Overexpression Increases Striatal D3 Receptor Level at Striatal Neurons and Exacerbates D1-Receptor Agonist-Induced Dyskinesia.

BACKGROUND: We recently showed that striatal overexpression of brain derived neurotrophic factor (BDNF) by adeno-associated viral (AAV) vector exacerbated L-DOPA-induced dyskinesia (LID) in 6-OHDA-lesioned rats. An extensive sprouting of striatal serotonergic terminals accompanied this effect, accounting for the increased susceptibility to LID. OBJECTIVE: We set to investigate whether the BDNF effect was restricted to LID, or extended to dyskinesia induced by direct D1 receptor agonists. METHODS: Unilaterally 6-OHDA-lesioned rats received a striatal injection of an AAV vector to induce BDNF or GFP overexpression. Eight weeks later, animals received daily treatments with a low dose of SKF82958 (0.02 mg/kg s.c.) and development of dyskinesia was evaluated. At the end of the experiment, D1 and D3 receptors expression levels and D1 receptor-dependent signaling pathways were measured in the striatum. RESULTS: BDNF overexpression induced significant worsening of dyskinesia induced by SKF82958 compared to the GFP group and increased the expression of D3 receptor at striatal level, even in absence of pharmacological treatment; by contrast, D1 receptor levels were not affected. In BDNF-overexpressing striata, SKF82958 administration resulted in increased levels of D1-D3 receptors co-immunoprecipitation and increased phosphorylation levels of Thr34 DARPP-32 and ERK1/2. CONCLUSION: Here we provide evidence for a functional link between BDNF, D3 receptors and D1-D3 receptor close interaction in the augmented susceptibility to dyskinesia in 6-OHDA-lesioned rats. We suggest that D1-D3 receptors interaction may be instrumental in driving the molecular alterations underlying the appearance of dyskinesia; its disruption may be a therapeutic strategy for treating dyskinesia in PD patients.

Community-based exercise for upper limb paresis: a controlled trial with telerehabilitation.

BACKGROUND: Arm paresis remains a major impairment after stroke despite the best conventional rehabilitation. Randomized, controlled trials of intensive exercise programs have demonstrated improvements in arm function for patients with chronic stroke. However, the gains achieved have been relatively modest for the large investments in patient and therapist time. OBJECTIVE: To evaluate the safety, acceptance, adherence, and effectiveness of a community-based exercise program for upper limb paresis in patients with chronic stroke and the effects of telerehabilitation monitoring in kiosks distributed through the community. METHODS: Longitudinal cohort with geographic control group. The experimental group received devices needed for a home exercise program based on the Carr and Shepherd "Motor Learning Program" and were instructed to practice the exercises at least twice a week at the kiosk and at least 3 more days a week at home. The control group received usual care. RESULTS: Compared with the control group, patients in the experimental group demonstrated significant gains in arm function as measured by the Wolf Motor Function Test, 9-Hole Peg Test, Motricity Index, and Nottingham Extended Activities of Daily Living Questionnaire. The intervention received high satisfaction ratings and produced no adverse events. Only 30% of the subjects attended kiosks regularly. Outcomes for this group did not differ significantly from those who only practiced at home. CONCLUSIONS: Home- and community-based exercise for arm paresis is safe and effective. Telerehabilitation interventions will need additional enhancements to improve effectiveness. The optimal upper extremity exercise prescription poststroke remains to be established.