STATUS EPILEPTICUS REORGANIZES CANNABINOID RECEPTORS

Summary

Principal Investigator: ROBERT JOHN DELORENZO
Abstract: The central nervous system cannabinoid receptor (CB1) is one of the most abundant G-Protein coupled receptors in brain and mediates many of the effects of cannabinoid substances on neuronal function. Our laboratory has demonstrated that one hour of prolonged seizures (status epilepticus, SE) in the pilocarpine model of SE produces a long-term reorganization in the expression of the CB1 receptor ahd that these changes in CB1 expression persist for essentially the life of the animal. SE is a major neurological emergency that has a high mortality and morbidity, including acquired epilepsy (AE) and memory deficits. Our preliminary results suggest that the SE induced persistent changes in expression and function of the CB1 receptor are reorganized to be decreased on inhibitory and increased on excitatory nerve terminals, indicating that this long-term plasticity change may represent a significant modulator of neuronal function. This research effort will test the Central Hypothesis that SE (acute event) causes long lasting reorganization in the expression of the CB1 that results in persistent changes in the overall function of the endocannabinoid system, causing a greater inhibition of glutamate release and a smaller inhibition of GABA release in epileptic compared to control brain and ultimately in changes in the behavior of the animal, as manifested by memory deficits. To test this hypothesis we will conduct the following specific aims: Aim 1. Evaluate whether SE alone or with the development of AE causes persistent rearrangements in the immunoreactivity and expression of the CB1 receptor in brain and evaluate the time course of these changes;Aim 2. Determine if the SE induced changes in CB1 receptor expression are associated with corresponding changes in CB1 function as determined by G-protein activation, receptor binding and regulation of neurotransmiter release; Aim 3. Determine the association of SE induced CB1 receptor reorganization on excitatory and inhibitory nerve terminals;Aim 4. Determine the effects of long-term plasticity changes in CB1 expression and function on the long-term memory effects observed after SE. The goal of this research is to determine if changes in the expression of the CB1 system following SE contribute to altered neuronal excitability and memory deficits produced by SE. These studies may lead to the development of novel therapeutic interventions to reverse the effects of SE on AE and memory loss by pharmacologically regulating the endogenous CB1system.
Funding Period: ----------------2007 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Development of pharmacoresistance to benzodiazepines but not cannabinoids in the hippocampal neuronal culture model of status epilepticus
    Laxmikant S Deshpande
    Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA
    Exp Neurol 204:705-13. 2007
  2. pmc Alterations in neuronal calcium levels are associated with cognitive deficits after traumatic brain injury
    Laxmikant S Deshpande
    Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA
    Neurosci Lett 441:115-9. 2008
  3. pmc Epileptogenesis causes an N-methyl-d-aspartate receptor/Ca2+-dependent decrease in Ca2+/calmodulin-dependent protein kinase II activity in a hippocampal neuronal culture model of spontaneous recurrent epileptiform discharges
    Robert E Blair
    Department of Neurology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia 23298 0599, United States
    Eur J Pharmacol 588:64-71. 2008
  4. pmc Carisbamate prevents the development and expression of spontaneous recurrent epileptiform discharges and is neuroprotective in cultured hippocampal neurons
    Laxmikant S Deshpande
    Department of Neurology, Virginia Commonwealth University, Richmond, Virginia 23298, USA
    Epilepsia 49:1795-802. 2008
  5. pmc Levetiracetam inhibits both ryanodine and IP3 receptor activated calcium induced calcium release in hippocampal neurons in culture
    Nisha Nagarkatti
    Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, United States
    Neurosci Lett 436:289-93. 2008
  6. pmc Long-term decrease in calbindin-D28K expression in the hippocampus of epileptic rats following pilocarpine-induced status epilepticus
    Dawn S Carter
    Department of Neurology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, United States
    Epilepsy Res 79:213-23. 2008
  7. pmc Traumatic brain injury causes a long-lasting calcium (Ca2+)-plateau of elevated intracellular Ca levels and altered Ca2+ homeostatic mechanisms in hippocampal neurons surviving brain injury
    David A Sun
    Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA
    Eur J Neurosci 27:1659-72. 2008
  8. pmc Time course and mechanism of hippocampal neuronal death in an in vitro model of status epilepticus: role of NMDA receptor activation and NMDA dependent calcium entry
    Laxmikant S Deshpande
    Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA
    Eur J Pharmacol 583:73-83. 2008
  9. pmc In vitro status epilepticus but not spontaneous recurrent seizures cause cell death in cultured hippocampal neurons
    Laxmikant S Deshpande
    Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA
    Epilepsy Res 75:171-9. 2007
  10. pmc Activation of a novel injury-induced calcium-permeable channel that plays a key role in causing extended neuronal depolarization and initiating neuronal death in excitotoxic neuronal injury
    Laxmikant S Deshpande
    Department of Neurology, Virginia Common wealth University, School of Medicine, Richmond, VA 23298, USA
    J Pharmacol Exp Ther 322:443-52. 2007

Scientific Experts

  • Robert E Blair
  • Nisha Nagarkatti
  • Laxmikant S Deshpande
  • Robert J Delorenzo
  • Sompong Sombati
  • Dawn S Carter
  • Julie M Ziobro
  • Katherine W Falenski
  • David A Sun
  • Billy R Martin
  • Katherine W Sayers
  • Anne J Harrison
  • Robert J Hamm
  • Anya Baranova
  • Elisa Attkisson
  • Margaret S Wilson
  • Ali Mian
  • Jeffrey K Lou
  • K W Falenski
  • Mohsin Raza
  • Laura J Sim-Selley
  • Peter T Nguyen
  • Azhar Rafiq
  • R J DeLorenzo
  • B R Martin
  • L J Sim-Selley
  • David D Limbrick

Detail Information

Publications25

  1. pmc Development of pharmacoresistance to benzodiazepines but not cannabinoids in the hippocampal neuronal culture model of status epilepticus
    Laxmikant S Deshpande
    Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA
    Exp Neurol 204:705-13. 2007
    ..Thus, the use of cannabinoids in the treatment of SE may offer a unique approach to controlling SE without the development of pharmacoresistance observed with conventional treatments...
  2. pmc Alterations in neuronal calcium levels are associated with cognitive deficits after traumatic brain injury
    Laxmikant S Deshpande
    Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA
    Neurosci Lett 441:115-9. 2008
    ....
  3. pmc Epileptogenesis causes an N-methyl-d-aspartate receptor/Ca2+-dependent decrease in Ca2+/calmodulin-dependent protein kinase II activity in a hippocampal neuronal culture model of spontaneous recurrent epileptiform discharges
    Robert E Blair
    Department of Neurology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia 23298 0599, United States
    Eur J Pharmacol 588:64-71. 2008
    ....
  4. pmc Carisbamate prevents the development and expression of spontaneous recurrent epileptiform discharges and is neuroprotective in cultured hippocampal neurons
    Laxmikant S Deshpande
    Department of Neurology, Virginia Commonwealth University, Richmond, Virginia 23298, USA
    Epilepsia 49:1795-802. 2008
    ..Thus, development of drugs that would prevent or decrease the onset of epilepsy following brain injury represents an important area of research...
  5. pmc Levetiracetam inhibits both ryanodine and IP3 receptor activated calcium induced calcium release in hippocampal neurons in culture
    Nisha Nagarkatti
    Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, United States
    Neurosci Lett 436:289-93. 2008
    ..Thus, the ability of LEV to modulate the two major CICR systems demonstrates an important molecular effect of this agent on a major second messenger system in neurons...
  6. pmc Long-term decrease in calbindin-D28K expression in the hippocampus of epileptic rats following pilocarpine-induced status epilepticus
    Dawn S Carter
    Department of Neurology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, United States
    Epilepsy Res 79:213-23. 2008
    ..This decrease in hippocampal calbindin may be a major contributing factor underlying some of the plasticity changes that occur in epileptogenesis and contribute to the alterations in Ca(2+) homeostasis associated with AE...
  7. pmc Traumatic brain injury causes a long-lasting calcium (Ca2+)-plateau of elevated intracellular Ca levels and altered Ca2+ homeostatic mechanisms in hippocampal neurons surviving brain injury
    David A Sun
    Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA
    Eur J Neurosci 27:1659-72. 2008
    ....
  8. pmc Time course and mechanism of hippocampal neuronal death in an in vitro model of status epilepticus: role of NMDA receptor activation and NMDA dependent calcium entry
    Laxmikant S Deshpande
    Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA
    Eur J Pharmacol 583:73-83. 2008
    ....
  9. pmc In vitro status epilepticus but not spontaneous recurrent seizures cause cell death in cultured hippocampal neurons
    Laxmikant S Deshpande
    Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA
    Epilepsy Res 75:171-9. 2007
    ....
  10. pmc Activation of a novel injury-induced calcium-permeable channel that plays a key role in causing extended neuronal depolarization and initiating neuronal death in excitotoxic neuronal injury
    Laxmikant S Deshpande
    Department of Neurology, Virginia Common wealth University, School of Medicine, Richmond, VA 23298, USA
    J Pharmacol Exp Ther 322:443-52. 2007
    ....
  11. pmc Status epilepticus causes a long-lasting redistribution of hippocampal cannabinoid type 1 receptor expression and function in the rat pilocarpine model of acquired epilepsy
    K W Falenski
    Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA
    Neuroscience 146:1232-44. 2007
    ....
  12. pmc Aging is associated with elevated intracellular calcium levels and altered calcium homeostatic mechanisms in hippocampal neurons
    Mohsin Raza
    Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, United States
    Neurosci Lett 418:77-81. 2007
    ....
  13. pmc Cannabinoid CB1 receptor antagonists cause status epilepticus-like activity in the hippocampal neuronal culture model of acquired epilepsy
    Laxmikant S Deshpande
    Department of Neurology, Virginia Commonwealth University, Richmond, Virginia 23298, USA
    Neurosci Lett 411:11-6. 2007
    ..The regulation of seizure activity and prevention of status epilepticus by the endocannabinoid system offers an important insight into understanding the basic mechanisms that control the development of continuous epileptiform discharges...
  14. pmc The novel antiepileptic drug carisbamate (RWJ 333369) is effective in inhibiting spontaneous recurrent seizure discharges and blocking sustained repetitive firing in cultured hippocampal neurons
    Laxmikant S Deshpande
    Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA
    Epilepsy Res 79:158-65. 2008
    ....
  15. pmc Statistical parametric mapping reveals regional alterations in cannabinoid CB1 receptor distribution and G-protein activation in the 3D reconstructed epileptic rat brain
    Katherine W Sayers
    Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA, U S A
    Epilepsia 53:897-907. 2012
    ..Therefore, statistical parametric mapping (SPM), a whole-brain unbiased approach, was used to study the long-term effect of pilocarpine-induced SE on CB(1) -receptor binding and G-protein activation in rats with AE...
  16. pmc Prolonged cannabinoid exposure alters GABA(A) receptor mediated synaptic function in cultured hippocampal neurons
    Laxmikant S Deshpande
    Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA
    Exp Neurol 229:264-73. 2011
    ....
  17. pmc Characterization of spontaneous recurrent epileptiform discharges in hippocampal-entorhinal cortical slices prepared from chronic epileptic animals
    Dawn S Carter
    Department of Neurology, Virginia Commonwealth University, Richmond, VA, United States
    Seizure 20:218-24. 2011
    ..Epileptiform discharges were found to propagate around hippocampal circuits. HEC slices from epileptic animals that manifest SREDs provide a novel model to study in vitro seizure activity in tissue prepared from epileptic animals...
  18. pmc An organotypic hippocampal slice culture model of excitotoxic injury induced spontaneous recurrent epileptiform discharges
    Julie M Ziobro
    Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA
    Brain Res 1371:110-20. 2011
    ....
  19. pmc Acetaminophen inhibits status epilepticus in cultured hippocampal neurons
    Laxmikant S Deshpande
    Department of Neurology, Virginia Commonwealth University, Richmond, Virginia, USA
    Neuroreport 22:15-8. 2011
    ..CB1 receptor antagonist SR 141716A (1 μM) blocked this inhibitory effect of acetaminophen on SE, indicating that acetaminophen was mediating its anticonvulsant effects through CB1 receptors...
  20. pmc Dantrolene inhibits the calcium plateau and prevents the development of spontaneous recurrent epileptiform discharges following in vitro status epilepticus
    Nisha Nagarkatti
    Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA
    Eur J Neurosci 32:80-8. 2010
    ..These findings offer potential for a novel treatment to prevent the development of epileptiform discharges following brain injuries...
  21. pmc Development of a prolonged calcium plateau in hippocampal neurons in rats surviving status epilepticus induced by the organophosphate diisopropylfluorophosphate
    Laxmikant S Deshpande
    Department of Neurology, Virginia Commonwealth University, Richmond, Virginia 23298, USA
    Toxicol Sci 116:623-31. 2010
    ..This model is ideally suited to test effective countermeasures for OP exposure and study molecular mechanisms underlying neurological disorders following OP intoxication...
  22. pmc Prolonged exposure to WIN55,212-2 causes downregulation of the CB1 receptor and the development of tolerance to its anticonvulsant effects in the hippocampal neuronal culture model of acquired epilepsy
    Robert E Blair
    Department of Neurology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
    Neuropharmacology 57:208-18. 2009
    ....
  23. pmc Development of the calcium plateau following status epilepticus: role of calcium in epileptogenesis
    Nisha Nagarkatti
    Department of, Virginia Commonwealth University, Richmond, VA 23298, USA
    Expert Rev Neurother 9:813-24. 2009
    ..Thus, characterization of the post-injury Ca(2+) plateau may be important in eventually understanding the pathophysiology of epileptogenesis and preventing the progression to chronic epilepsy after brain injury...
  24. pmc Age-dependent mortality in the pilocarpine model of status epilepticus
    Robert E Blair
    Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA
    Neurosci Lett 453:233-7. 2009
    ....
  25. pmc Temporal characterization of changes in hippocampal cannabinoid CB(1) receptor expression following pilocarpine-induced status epilepticus
    Katherine W Falenski
    Department of Neurology, Virginia Commonwealth University, PO Box 980599, Richmond, VA 23298, USA
    Brain Res 1262:64-72. 2009
    ..This suggests a role for dysregulation of the endocannabinoid system during epileptogenesis and indicates that the CB(1) receptor redistribution temporally correlates with the emergence of epileptic seizures...