Thursday, March 22, 2007
In a multidisciplinary investigation led by Inderjit Singh, Ph.D, a breakthrough has been made in relation to the treatment of spinal cord injuries (SCI). Set for publication in the April issue of the Journal of Neurochemistry (101, 182-200), the study investigates the efficacy of atorvastatin (AT), commonly known as Lipitor, as a treatment for spinal cord injuries following trauma. The report demonstrates, for the first time, that by using AT in treating spinal cord injuries after they have occurred, animal models with hind-limb paralysis showed significant functional recovery and less secondary tissue damage. Importantly, scientists discovered that AT also protects the cells responsible for producing myelin in the spinal cord, a substance which maintains normal function by insulating nerve fibers that carry signals through the spinal cord. Therefore, this discovery of post-injury AT treatment may be extremely valuable in preserving neurological function and walking following spinal cord injuries.
Singh is a Pediatrics distinguished university professor, Division of Developmental Neurogenetics director and Darby Children's Research Institute scientific director.
Spinal cord injury is a major cause of disability, and the current therapy with high dose steroids offers little benefit. Statins, including AT, belong to a class of drugs that are known to affect numerous cellular processes. Experimental investigations and clinical trials in patients have established the neuroprotective efficacy of statin treatment in multiple sclerosis, Alzheimer's disease, stroke and spinal cord injuries.
"These exciting findings suggest that AT shelters myelin producing cells and neurons during the inflammatory storm produced by trauma, and that when the storm has passed that such cells resume myelin production," said DCRI executive director, neurologist and neuroscientist Bernard Maria, M.D. "It opens up a new paradigm for treatment of spinal cord injury by preserving the integrity of progenitor cells that would otherwise have died off."
It is now accepted that the site, nature, and duration of secondary inflammations occurring immediately after a spinal cord injury determine the extent of functional loss or paralysis, and early reduction of these events is shown to minimize functional loss and enhance recovery. As a result, anti-inflammatory and neuroprotective agents, including statins, are the favored first line of defense as therapeutic agents in spinal cord injuries.
Singh said, "I am blessed to be leading a team of talented investigators who do pioneering work to delineate the mysteries of nature to develop novel treatments for neurological disorders. I'm especially proud of the pioneering work performed in the Darby Children's Research Institute to protect the brain stem cells for regeneration in various disease processes, such as multiple sclerosis and spinal cord injury. Presently, these drugs are being evaluated for therapy in inflammatory neurological disorders."
Neurodegeneration post-injury is evident in the form of white matter destruction that includes loss of tissue viability, degeneration of severed axons and myelin destruction. AT treatment post-SCI reduced these processes. Furthermore, AT treatment prevented apoptotic neuronal loss. This is of critical value in spinal cord injuries, as neuroprotective treatments after injury have the potential to lead to improved functional recovery and only a few residual axons (5-10%) are needed to achieve significant functional recovery.
While considering regenerative approaches, depending on the nature and extent of injury, it is likely that AT by itself or maybe in combination with other therapeutic approaches, such as stem cell transplantation, could prove beneficial and augment functional recovery. As immune suppression has been found beneficial for survival of transplanted cells, it is likely that anti-inflammatory actions of post-injury AT treatment could compliment cell grafting by creating a growth supportive environment to augment survival and differentiation of these cells to enhance the reparative process.
Emphasizing the therapeutic potential of post-injury AT treatment in spinal cord injuries, the investigation also strengthens the idea of long-term benefits that include reduction of secondary pathology through suppression of inflammation, Wallerian degeneration, gliosis, and most importantly - neuronal apoptosis.
This study is only the beginning of an endeavor to uncover the extensive potential of AT in treating spinal cord injuries as the various facets of this drug need to be carefully examined to more precisely determine the clinical effects of statins, the differential potency of statins, and to evaluate whether combination therapy might be more effective than monotherapy. However, due to the long-established human safety of statins, this report is likely to have positive clinical implications for spinal cord treatment.
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