Maraviroc to Augment Rehabilitation Outcomes After Stroke

Background

After stroke, the combination of progressive skills practice in an adequate dose, exercise for fitness, and reduced sedentary time will augment motor and cognitive outcomes. Sensorimotor and cognitive improvements after stroke often reach a general plateau by approximately 12 weeks after onset, however. Drugs that might enhance learning or neural repair, as well as other molecular and synaptic adaptations that occur during skills training and fitness exercise, might extend that recovery curve, although to date only fluoxetine has given any hint of this. Most trials have tested agents that modulate neurotransmitters. Several very recent preclinical experiments and observational studies in patients after stroke suggest that the commercially available medication, Maraviroc, may augment skills learning during rehabilitation training especially during the first three months after onset, by acting on unique molecular components for novel learning.

The C-C chemokine receptor 5 (CCR5) is a seven-transmembrane G protein-coupled receptor that mediates HIV virus cellular entry. Individuals who are homozygous for a 32 base pair deletion in the CCR5 gene (CCR5D32), and subsequently do not express functional CCR5, are highly protected from infection with R5 HIV-1. The receptor is expressed in microglia, astrocytes and neurons in many regions of the brain. Dr. Alcino Silva at UCLA postulates that this receptor is involved in learning and memory. In a series of elegant experiments, he showed 1) CCR5 deficiency results in enhancements in hippocampal learning and memory and in experience-dependent sensory plasticity; and 2) CCR5 overexpression leads to learning and memory deficits. Decreasing the function of CCR5 increases MAPK/CREB signaling, long-term potentiation, hippocampus-dependent memory, and neocortical experience-dependent plasticity. Ligand binding to CCR5 is known to modulate several parallel signaling cascades implicated in learning and memory, including the suppression of adenyl cyclase, as well as the activation of the PI3K/AKT and P44/42 MAPK signaling. These findings support the application of brain permeable CCR5 antagonists, not only as a combination drug in antiretroviral therapy, but also as a treatment for cognitive deficits caused by HIV. In addition, the studies suggest that the receptor is a novel target to augment learning and memory in those with cognitive and motor deficits in relation to training.

Several preclinical models of stroke and traumatic brain injury from Drs. ST Carmichael, Alcino Silva, and Esty Shohami suggest that the FDA-approved CCR5 reversible co-receptor antagonist, Maraviroc, may lead to better motor outcomes when combined with training, presumably due to enhanced learning. Stroke induces CCR5 expression in neurons in the first month after onset in a mouse model (Carmichael). Knockdown of CCR5 in the motor cortex of adult mice improves recovery after stroke (Carmichael and Silva et al). Maraviroc also improves motor recovery in this model. An Israeli post stroke observational trial (TABASCO, Einor Ben Assayag, et al.) enabled a test of the effects of a naturally occurring loss of function mutation in CCR5 (CCR5 delta32). About 15% of the Ashkenazi Jewish population carries the deletion (CCR5 rs333 - 32). This group in TABASCO had better outcomes for walking speed and the Berg Balance Scale. A Washington University observational study that included some subjects with this deletion also looked positive for better outcomes, but was more equivocal, based on differences in stroke type. Neither gene association study has been published yet.

Maraviroc is the only CCR5 antagonist currently approved by the United States Food and Drug Administration, the European Commission, Health Canada. Maraviroc (Selzentry, Pfizer) is a small molecule currently approved for treatment of patients infected with R5-tropic HIV-1. It is metabolized by CYP3A4. The dose may have to be adjusted when given with CYP3A4 inducers or inhibitors, primarily drugs that are also used for HIV therapy, but also for several anticonvulsants. None of the subjects in the proposed trial will be entered if on these medications. The drug has a good pharmacokinetic profile with relatively low protein binding and high bioavailability when given at standard doses twice a day. It is moderately lipophilic, so it can penetrate the blood-brain barrier. At a single dose of 300 mg, time to maximum concentration occurred by two hours post-treatment in humans. The terminal half-life is 14-18 hours, so a single dose used during the time of training in the proposed protocol should be adequate, rather than the BID treatment for AIDS. Despite low CSF concentrations, the drug suppresses CSF viral load. It potently inhibits downstream CCR5 signaling and does not induce CCR5 internalization, suggesting that the drug is a functional CCR5 antagonist.