Phosphorylation of eIF-2[alpha] and Expression of Neuronal NOS in Human Temporal Lobe Epilepsy.
Abstract number :
2.046
Submission category :
Year :
2001
Submission ID :
273
Source :
www.aesnet.org
Presentation date :
12/1/2001 12:00:00 AM
Published date :
Dec 1, 2001, 06:00 AM
Authors :
C. Watson, MD, PhD, Neurology, Wayne State University School of Medicine, Detroit, MI; J.A. Rafols, PhD, Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI; T. Petrov, MD, PhD, Anatomy and Cell Biology, Wayne State University
RATIONALE: Hippocampal sclerosis (HS) is the most common neuropathologic finding in patients with medically refractory temporal lobe epilepsy (TLE). The mechanisms resulting in neuronal injury and cell loss in HS are incompletely understood, but inhibition of protein synthesis may play a pivotal role in these processes. This study examined the relationships between two molecules known to be involved in reduced protein synthesis in animals subjected to traumatic brain injury.
METHODS: Translational initiation of protein synthesis does not occur without the key participation of eukaryotic initiation factor 2[alpha] (eIF-2[alpha]), and phosphorylation of the [alpha] subunit (eIF-2[alpha](P)) inhibits protein synthesis. Recently, nitric oxide (NO) has been shown to reduce protein synthesis by phosphorylating eIF-2[alpha]. Therefore, we performed immunocytochemistry for eIF-2[alpha](P) and histochemistry (NADPH-D reaction) for nitric oxide synthase (NOS) to determine the distribution of these molecules in hippocampi removed from patients undergoing anterior temporal lobectomy for medically intractable TLE due to HS.
RESULTS: The greatest number of eIF-2[alpha](P) positive cells was in the CA1 sector of the hippocampus, followed by the hilus of the dentate gyrus. NADPH-D positive neurons were observed most often in the hilus. Labeling in both instances involved neuronal cell body cytoplasm and varicose processes. Combination of both staining procedures revealed close relationships between differentially labeled neurons within the hilus.
CONCLUSIONS: The results suggest that NO phosphorylates eIF-2[alpha] after delivery to neurons by synaptic boutons or by diffusion, since it is a soluble gas. In human TLE protein synthesis inhibition may occur at the translational level since the eIF-2[alpha](P) labeling is cytoplasmic, in contrast to rodents where nuclear labeling suggests transcriptional inhibition. Protein synthesis inhibition may contribute to neuronal cell injury and death in HS.
Support: NIH Grant [pound]: NS 39860