Nicotinic receptors and fatty acid-mediated apoptosis of spinal cord neurons

Grants and Contracts Details

Description

Primary trauma to the spinal cord initiates a sequence of degenerative events which eventually lead to neurological deficits of the injured spinal cord. One of the first destructive processes which occur as a result of spinal cord trauma is damage of cellular membranes and release of free fatty acids. We have evidence that free fatty acids, and in particular arachidonic acid, when present in elevated concentrations, can cause spinal cord neurons to die through a unique process called apoptosis. In contrast to other forms of cell death, apoptosis is tightly regulated at the genetic level and is associated with activation of specific enzymes called caspases. We obtained exciting new evidence that stimulation of nicotinic receptors can block apoptosis of spinal cord neurons. This is a very significant finding, because adult spinal cord neurons cannot proliferate to generate new generations of cells, and thus, apoptosis can lead to a permanent spinal cord injury. Due to this phenomenon, pharmacological treatment which can inhibit apoptosis may have a most beneficial effect in spinal cord trauma. Regulatory mechanisms of antiapoptotic effects of nicotinic receptors are not known and are focus of the present research application. We propose that nicotinic receptor-mediated protection against fatty acid-induced apoptosis can be mediated by two processes, namely, inhibition of caspases and stimulation of production of specific neurotrophic factors, which can increase neuronal survival. Spinal cord neuron cultures, animal models of spinal cord trauma and a variety of cellular and molecular techniques will be employed to study the proposed hypotheses. This research proposal may have most significant implications in the understanding of pathophysiological events of spinal cord injury and clinical treatments of this disease. The potential therapeutic use of stimulators of nicotinic receptors in spinal cord injury is one of the most important elements which determines the novelty and importance of the current research application. The long term goal of our research is to provide substantial information about the therapeutic capability of analogs of nicotinic receptors in the treatment of pathophysiological events associated with spinal cord injury.
StatusFinished
Effective start/end date1/15/011/14/04

Funding

  • KY Spinal Cord and Head Injury Research Trust: $299,542.00

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