Dalfampridine Improves Sensorimotor Function in Rats With Chronic Deficits After Middle Cerebral Artery Occlusion

Abstract

Background and Purpose-Stroke survivors often have permanent deficits that are only partially addressed by physical therapy. This study evaluated the effects of dalfampridine, a potassium channel blocker, on persistent sensorimotor deficits in rats with treatment initiated 4 or 8 weeks after stroke. Methods-Rats underwent permanent middle cerebral artery occlusion. Sensorimotor function was measured using limbplacing and body-swing symmetry tests, which normally show a partial recovery from initial deficits that plateaus ≈4 weeks after permanent middle cerebral artery occlusion. Dalfampridine was administered starting at 4 or 8 weeks after permanent middle cerebral artery occlusion in 2 blinded, vehicle-controlled studies. Plasma samples were collected and brain tissue was processed for histologic assessment. Results-Dalfampridine treatment (0.5-2.0 mg/kg) improved forelimb-and hindlimb-placing responses and body-swing symmetry in a reversible and dose-dependent manner. Plasma dalfampridine concentrations correlated with dose. Brain infarct volumes showed no differences between treatment groups. Conclusions-Dalfampridine improves sensorimotor function in the rat permanent middle cerebral artery occlusion model.Dalfampridine extended-release tablets (prolonged release fampridine outside the United States) are used to improve walking in patients with multiple sclerosis, and these preclinical data provide a strong rationale for examining the potential of dalfampridine to treat chronic stable deficits in stroke patients.

The Epigenetics of Stroke Recovery and Rehabilitation: From Polycomb to Histone Deacetylases

“…Repression of potassium channels not only leads to decreased consumption of adenosine triphosphate (ATP) (via decreased dependence and utilization of the Na + /K + ATPase to maintain potassium gradients), but can also lead to prolonged action potentials and increased conduction velocity. Indeed, potassium channel blockers, such as dalfampridine (trade name Ampyra) and tetraethylammonium, have been shown not only to protect neurons from apoptosis, but also enhance recovery following stroke in animals [21,22]. Besides potassium channels, BMI-1/polycomb complex proteins appear to be important in repressing genes involved in senescence in cortical neurons, thereby de-repressing antioxidant and prosurvival genes, and enhancing survival [23].…”

Clinically Relevant Levels of 4-Aminopyridine Strengthen Physiological Responses in Intact Motor Circuits in Rats, Especially After Pyramidal Tract Injury

“…In most of the injuries to the nervous system, including stroke, some of the neural circuits that have potential to take over the function of the injured ones are preserved. The increased motor cortex and spinal cord excitability observed with 4-AP should be corroborated by studies examining improvements in motor skill at the same dose, in addition to the improvement in reflexive behaviors already tested 6 . Many other studies demonstrate a strong link between increased excitability of spared motor circuits and motor recovery after CNS injury 38,39 .…”

“…This mechanism suggests that 4-AP can be effective in neurological disorders of axonal injuries and is supported by preclinical and clinical studies demonstrating efficacy in stroke 6,7 . In rats with permanent middle cerebral artery occlusion 6 , administration of 4-AP improved sensorimotor function, even at drug levels similar to those observed in the MS clinical trials. This positive preclinical study led to clinical trials of the sustained-release formulation of 4-AP (dalfampridine) in people with stroke.…”

“…Blood was immediately centrifuged at 10,000 rpm for 5 minutes at 4°C and the plasma was transferred and stored at −20°C. 4-AP plasma concentrations were measured using liquid chromatography and tandem mass spectrometry by Covance, Inc (Madison, WI) using standard controls 6 .…”

Structure-activity relationship studies of three novel 4-aminopyridine K+ channel blockers

“…This aberrant redistribution of K + channels impairs conduction of action potentials, which leads to neurological deficits 3,10-14 . 4-aminopyridine (4AP) is a selective blocker of K v channels [15][16][17][18][19][20][21] used clinically to improve neurological conduction in people with multiple sclerosis (MS) [22][23][24][25][26] and other demyelinating diseases 27,28 . Mechanistically, 4AP blocks the exposed K + channels and therefore enhances conduction 16,17,19,20,[29][30][31][32] .…”