Search

Despite advances in understanding the pathophysiology of Huntington's disease (HD), there are currently no effective pharmacological agents available to treat core symptoms or to stop or prevent the progression of this hereditary neurodegenerative disorder. Pridopidine, a novel small molecule compound, has demonstrated potential for both symptomatic treatment and disease modifying effects in HD. While pridopidine failed to achieve its primary efficacy outcomes (Modified motor score) in two trials (MermaiHD and HART) there were consistent effects on secondary outcomes (TMS). In the most recent study (PrideHD) pridiopidine did not differ from placebo on TMS, possibly due to a large enduring placebo effect. This review describes the process, based on in vivo systems response profiling, by which pridopidine was discovered and discusses its pharmacological profile, aiming to provide a model for the system-level effects and a rationale for the use of pridopidine in patients affected by HD. Considering the effects on brain neurochemistry, gene expression and behaviour in vivo, pridopidine displays a unique effect profile. A hallmark feature in the behavioural pharmacology of pridopidine is its state-dependent inhibition or activation of dopamine-dependent psychomotor functions. Such effects are paralleled by strengthening of synaptic connectivity in cortico-striatal pathways suggesting pridopidine has potential to modify phenotypic expression as well as progression of HD. The preclinical pharmacological profile is discussed with respect to the clinical results for pridopidine and proposals are made for further investigation, including preclinical and clinical studies addressing disease progression and effects at different stages of HD. [ABSTRACT FROM AUTHOR]

Background: The efficacy of the dopaminergic stabilizer, pridopidine, in reducing the voluntary and involuntary motor symptoms of Huntington's disease (HD) is under clinical evaluation. Tetrabenazine is currently the only approved treatment for chorea, an involuntary motor symptom of HD; both compounds influence monoaminergic neurotransmission. Objective: To investigate pharmacological interactions between pridopidine and tetrabenazine. Methods: Drug-interaction experiments, supplemented by dose-response data, examined the effects of these compounds on locomotor activity, on striatal levels of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC), and on levels of activity-regulated cytoskeleton-associated (Arc) gene expression in the striatum and frontal cortex of male Sprague-Dawley rats. Haloperidol, a classical dopamine D2 receptor antagonist, was also tested for comparison. Results: Monitoring for 1 hour after co-administration of tetrabenazine 0.64 mg/kg and pridopidine 32 mg/kg revealed a reduction in locomotor activity, measured as distance travelled, in the tetrabenazine treated group, down to 61% vs. vehicle controls (p < 0.001). This was significantly alleviated by pridopidine (distance travelled reached 137% vs. tetrabenazine controls, p < 0.01). In contrast, co-administration of haloperidol 0.12 mg/kg and tetrabenazine produced increased inhibition of locomotor activity over the same period (p < 0.01, 41% vs. tetrabenazine). Co-administration of pridopidine, 10.5 mg/kg or 32 mg/kg, with tetrabenazine counteracted significantly (p < 0.05) and dose-dependently the decrease in frontal cortex Arc levels induced by tetrabenazine 0.64 mg/kg (Arc mRNA reached 193% vs. tetrabenazine mean at 32 mg/kg); this counteraction was not seen with haloperidol. Tetrabenazine retained its characteristic neurochemical effects of increased striatal DOPAC and reduced striatal dopamine when co-administered with pridopidine. Conclusions: Pridopidine alleviates tetrabenazine-induced behavioural inhibition in rats. This effect may be associated with pridopidine-induced changes in cortical activity and may justify clinical evaluation of pridopidine/tetrabenazine combination therapy. [ABSTRACT FROM AUTHOR]

Abstract: Early destruction of the ventral hippocampus from postnatal day 7 (P7) has been shown to induce behavioral alterations in post-pubertal rats, similar to those observed in models for schizophrenia. Using a single injection of tetanus toxin into the ventral hippocampus at P1, we tested the consequences of an early neonatal activity deprivation (&#60;P7) on behavioral and neurochemical parameters of pre- and post-pubertal rats. We found no significant differences in either behavioral or biochemical pattern, indicating that an early neonate neural activity blockade does not induce behavioral alterations in pre- and post-puberty rats. [Copyright &y& Elsevier]