Enhancing Post-Stroke Rehabilitation and Preventing Exo-Focal Dopaminergic Degeneration in Rats—A Role for Substance P

Dopaminergic signaling is a prerequisite for motor learning. Delayed degeneration of dopaminergic neurons after stroke is linked to motor learning deficits impairing motor rehabilitation. This study investigates safety and efficacy of substance P (SP) treatment on post-stroke rehabilitation, as this neuropeptide combines neuroprotective and plasticity-promoting properties. Male Sprague Dawley rats received a photothrombotic stroke within the primary motor cortex (M1) after which a previously acquired skilled reaching task was rehabilitated. Rats were treated with intraperitoneal saline (control group, n = 7) or SP-injections (250 µg/kg) 30 min before (SP-pre; n = 7) or 16 h (SP-post; n = 6) after rehabilitation training. Dopaminergic neurodegeneration, microglial activation and substance P-immunoreactivity (IR) were analyzed immunohistochemically. Systemic SP significantly facilitated motor rehabilitation. This effect was more pronounced in SP-pre compared to SP-post animals. SP prevented dopaminergic cell loss after stroke, particularly in the SP-pre condition. Despite its proinflammatory propensity, SP administration did not increase stroke volumes, post-stroke deficits or activation of microglia in the midbrain. Finally, SP administration prevented ipsilesional hypertrophy of striatal SPergic innervation, particularly in the SP-post condition. Mechanistically, SP-pre likely involved plasticity-promoting effects in the early phase of rehabilitation, whereas preservation of dopaminergic signaling may have ameliorated rehabilitative success in both SP groups during later stages of training. Our results demonstrate the facilitating effect of SP treatment on motor rehabilitation after stroke, especially if administered prior to training. SP furthermore prevented delayed dopaminergic degeneration and preserved physiological endogenous SPergic innervation.