Novel Applications of FDA Approved Drugs in Neurologic Rehabilitation
| Novel Applications of FDA Approved Drugs in Neurologic Rehabilitation |  Rajiv Ratan, MD, PhD |  William Zev Rymer, MD, PhD - Moderator |
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| Clinically approved daidzein enhances cholesterol homeostasis via ApoE to promote stroke recovery in mice
Stroke is the leading cause of physiological disability in the world. Currently, no FDA approved pharmacological agents are available for stroke patients to enhance functional recovery. A previous study indicated that daidzein, a soy isoflavone, is a clinically approved agent that is neuroprotective in vitro and promotes axon growth in an animal model of optic nerve crush. In light of the fact that cholesterols play an essential role as lipid substrates in injury-induced synaptic remodeling, this talk will focus on the preclinical findings of daidzein’s effect on cholesterol homeostasis and functional recovery in chronic stroke. While daidzein treatment did not reduce stroke-induced injury size, it increased the expression of cholesterol homeostasis genes including apolipoprotein E, an abundant cholesterol transporter in CNS, and also enhanced motor/gait functions in stroke. The daidzein-induced functional benefits were absent in mice that lack ApoE (ApoE knock-out mice). With its apparent safety in humans, these preclinical findings suggest that early and chronic use of daidzein aimed at augmenting cholesterol homeostasis via ApoE may serve as a strategy to promote recovery in stroke patients. |
| Drugs for Motor Rehabilitation - a fine balancing act. Drugs that are used to control spasticity after spinal cord injury may improve motor function, such as walking, to reduce uncontrolled contractions that interfere with purposeful movements. However, anti-spastics that act on motoneurons and sensory pathways may dampen spinal cord excitability and reduce the efficacy of motor driving commands. On the other hand, facilitating motoneuron and sensory pathway excitability may enhance motor movements but at the expense of functional motor control. Thus, strategies that target the facilitation of spinal interneurons involved in driving motor behaviors, such as walking, may be more beneficial to promote motor function by facilitating excitatory networks and at the same time reducing spasticity by facilitating inhibitory networks. I will discuss the mechanisms of various drugs that activate receptors on motoneurons and sensory pathways and potential new therapies that more readily and specifically target spinal interneurons. |
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| Combined pharmacological and physical interventions following neurological injury
The use of serotonergic agents, such as selective serotonin reuptake inhibitors, to facilitate motor recovery following neurological injury has gained momentum in the past decade. Long-standing and recent studies suggest that SSRIs may enhance motor function, although other data suggest increased spasticity which may hamper recovery. Alternative data suggest serotonin antagonists may reduce spastic motor behaviors, although these agents can result in worsening of selected motor function. While pharmacological agents are typically tested in isolation, our data suggest that the benefits of these agents may depend on the dose of the agents, patient-specific impairments, and the use of these drugs when combined with rehabilitation. |
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| Repurposing Drugs to Repair the Brain
Exciting studies over the past decade have created momentum around the notion that drugs approved and intended for one clinical indication can be repurposed for other indications. The a priori assumption was that agents with the sanctions of safety from the FDA would move quickly along a translatational pipeline to impact patient care in the near term. However, initial excitement has been met with a number of challenging realities surrounding this approach. In this talk, I will try to inform and outline some of the approaches that have been engaged to repurpose drugs and how these different approaches offer distinct opportunities and pitfalls.
The hope is to provide direction and renewed excitement for those interested in repurposing agents for use in rehabilitation. |
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| Inflammatory suppression augments intermittent hypoxia-induced plasticity in individuals with spinal cord injury
The spinal cord possesses a robust capacity for neuronal plasticity, which could be harnessed to strengthen neural connections and enhance motor function in individuals with spinal cord injury (SCI). One unique approach to induce plasticity is exposure to low-dose acute intermittent hypoxia (AIH)–a treatment modality that constitutes brief periods of reduced oxygen levels, alternating with exposures to normal levels. AIH has been demonstrated to improve leg strength, and over-ground walking ability in persons with chronic, incomplete SCI. |
