title: Can 4-aminopyridine modulate dysfunctional gait networks in Parkinson's disease?
abstract: Gait dysfunction and postural instability represent a major therapeutic challenge in Parkinson's disease (PD). Gait disability in PD has been historically attributed to striato-nigral degeneration, however there is emerging evidence that multiple neurotransmitter deficits contribute to mobility impairment in PD. 4-aminopyridine (4-AP), a potent neurotransmitter modulator, has a wide range of favorable effects on gait in patients with neurological conditions including multiple sclerosis, spinal cord injury and cerebellar ataxia. In this Review we identify the neurobiological pathways involved in gait dysfunction in PD and discuss the mechanisms of action of 4-AP and its effect on gait related neuronal networks. The proposed mechanisms that may facilitate 4-AP favorable effect on gait in Parkinson's disease include 1) neurotransmitter release (dopamine, glutamate, acetylcholine and noradrenaline) 2) modulation of neuronal network oscillations and 3) increased cortical excitation. Recent clinical trials of 4-AP in neurological conditions associated with gait disorders will be highlighted and the importance of studying non-dopaminergic medications such as 4-AP in PD patients with gait impairment will be emphasized.
authors.affiliation: Department of Neurology, Movement Disorders Division, University of Miami Miller School of Medicine, Miami, FL 33136, USA. cluca@med.miami.edu
authors.forename: Corneliu C
authors.initials: CC
authors.lastname: Luca
authors.forename: Carlos
authors.initials: C
authors.lastname: Singer
mesh_terms: D015761:4-Aminopyridine / Q000627:therapeutic use*; D000818:Animals; D005684:Gait / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D009415:Nerve Net / Q000187:drug effects / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects; D010300:Parkinson Disease / Q000188:drug therapy* / Q000503:physiopathology; D026902:Potassium Channel Blockers / Q000627:therapeutic use*
chemical_list: D026902:Potassium Channel Blockers; D015761:4-Aminopyridine
keywords: 4-Aminopyridine; Basal ganglia; Gait dysfunction and postural instability; Neuronal networks; Non-dopaminergic treatment; Parkinson's disease