Pridopidine: Overview of Pharmacology and Rationale for its Use in Huntington's Disease

Abstract

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.

Keywords: Huntington’s disease; dopamine; dopamine D2 receptors; indirect pathway; motor control; prefrontal cortex; pridopidine; stabilizer; striatum.

Fig.1

Pridopidine is able to enhance or inhibit dopamine-dependent functions. Graphic illustration of psycho-motor stabilization: In vivo pharmacological studies have consistently demonstrated state dependent behavioral effects of pridopidine; reducing psychomotor activity in hyperactive states, and enhancing activity in hypoactive states. This is proposed to translate to stabilization of both hyper- and hypokinetic motor disturbances in HD; to some extent overlapping with observations of disturbed dopamine transmission over the course of the disease [40].

Fig.2

Proposed in vivo mode of action of pridopidine in manifest HD. A schematic overview of the organization of the basal ganglia, involving the direct and indirect pathway, and the proposed in vivo effects of pridopidine. The left panel shows the direct and indirect pathway in the state of manifest HD. Dashed lines represent reduced transmission, thick lines increased transmission. In manifest HD, output in both striatal pathways is attenuated, and cortico-striatal connectivity is impaired [53, 55]. The right panel illustrates the suggested mode of action for pridopidine: (1) Pridopidine normalizes the aberrant function in the indirect pathway, by blocking DA D2 receptors, which results in attenuation of involuntary movements. (2) Pridopidine improves voluntary movements by stimulating the direct pathway via activation of the DA D1 receptor. (3) Pridopidine strengthens the prefrontal cortex, which indirectly stimulates both the direct and indirect pathways. The schemes shown represent the changes in late stage, symptomatic HD, and the tentative impact of pridopidine. At earlier stages of HD an increase in cortico-striatal glutamate transmission has been suggested (not shown). D1, dopamine D1 receptors; D2, dopamine D2 receptors; GPe, globus pallidus pars externa; SNc, substantia nigra pars compacta; VTA, ventral tegmental area; GPi, globus pallidus pars interna.