Status epilepticus is associated with significant long-term morbidity, including intellectual impairment, focal neurologic dysfunction, and recurrent seizures. Part of this morbidity is related to the neuronal injury resulting from prolonged, excessive electrical activity. Although various lines of evidence suggest that excitatory amino acids and their receptors are important mediators of seizure-induced injury, very little is known about the cellular defense against this excitotoxic injury. The central theme of the proposed research plan is to explore the relationship between stress protein (SP) expression and protection from seizure-induced neuronal injury. The overall hypothesis is that heat-shock proteins and other stress proteins are expressed by CNS cells in response to prolonged seizures, and that this expression is part of the cell's protective mechanism against excitotoxic injury. There are two major goals of the proposed research. The first is to characterize the scope, temporal sequence, and cellular location of stress proteins induced by prolonged seizures within the hippocampus. Two well-characterized in vivo models of seizures will be used, and SP expression will be analyzed via one and two-dimensional polyacrylamide gel electrophoresis, immunoblotting, and immunocytochemistry. The second goal is to use cell culture systems to determine whether stress proteins protect CNS cells against toxic factors, such as excitatory amino acids, that may be involved in the pathogenesis of seizure-induced neuronal damage. SP expression (induced by traditional methods and by exposure to excitatory amino acids) will first be characterized in primary cultures of rat neurons and glia. Various approaches will then be used to modulate the activity of SPs, in order to determine whether there is a causal relationship between SP expression and protection of CNS cells. The research training is designed to build upon the applicant's expertise in the clinical aspects of status epilepticus, and his fellowship training in molecular biology. Upon completion of the program, he will have obtained the experience and background necessary to develop an independent research program investigating the pathophysiology of status epilepticus at the molecular level.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
Project #
Application #
Study Section
Neurological Disorders Program Project Review B Committee (NSPB)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Schools of Medicine
San Francisco
United States
Zip Code
Lowenstein, D H (1996) Recent advances related to basic mechanisms of epileptogenesis. Epilepsy Res Suppl 11:45-60
Lowenstein, D H; Gwinn, R P; Seren, M S et al. (1994) Increased expression of mRNA encoding calbindin-D28K, the glucose-regulated proteins, or the 72 kDa heat-shock protein in three models of acute CNS injury. Brain Res Mol Brain Res 22:299-308
Lowenstein, D H (1994) Basic concepts of molecular biology for the epileptologist. Epilepsia 35 Suppl 1:S7-19
Parent, J M; Lowenstein, D H (1994) Treatment of refractory generalized status epilepticus with continuous infusion of midazolam. Neurology 44:1837-40
Lowenstein, D H; Alldredge, B K (1993) Status epilepticus at an urban public hospital in the 1980s. Neurology 43:483-8
Hicks, R R; Smith, D H; Lowenstein, D H et al. (1993) Mild experimental brain injury in the rat induces cognitive deficits associated with regional neuronal loss in the hippocampus. J Neurotrauma 10:405-14
Lowenstein, D H; Seren, M S; Longo, F M (1993) Prolonged increases in neurotrophic activity associated with kainate-induced hippocampal synaptic reorganization. Neuroscience 56:597-604
Eide, F F; Lowenstein, D H; Reichardt, L F (1993) Neurotrophins and their receptors--current concepts and implications for neurologic disease. Exp Neurol 121:200-14
Yaffe, K; Lowenstein, D H (1993) Prognostic factors of pentobarbital therapy for refractory generalized status epilepticus. Neurology 43:895-900
Lowenstein, D H; Thomas, M J; Smith, D H et al. (1992) Selective vulnerability of dentate hilar neurons following traumatic brain injury: a potential mechanistic link between head trauma and disorders of the hippocampus. J Neurosci 12:4846-53

Showing the most recent 10 out of 20 publications