SNRP Investigators and Collaborators

Pedro A. Ferchmin, Ph.D, PI

Contribution to Science
Discovered of a novel nicotinic neuroprotective mechanism mediated by a tobacco diterpenoid.   Dr. Ferchmin tested one of the two most abundant tobacco diterpenoids, (1S,2E,4R,6R,-7E,11E)-2,7,11-cembratriene-4,6-diol called here 4R.  Dr. Ferchmin described that 4R is a noncompetitive nicotinic antagonist with a preferential affinity for α7.   As expected, 4R was neuroprotective by the same cell signaling mechanism as α7 antagonists.  Dr. Ferchmin demonstrated that inhibition of α7 nicotinic receptors activates a polysynaptic cascade which causes the activation of antiapoptotic subsynaptic NMDA receptors on pyramidal neurons.

Vesna A. Eterovic, Ph.D., PI

Contribution to Science
A novel mechanism for noncompetitive inhibition of the nicotinic acetylcholine receptor was described by Dr. Eterovic.  In addition, in vivo experiments with rats proved that 4R is found in brain tissue just seconds after i.v. injection, at a concentration sufficient to produce nicotinic effects. These results are consistent with the idea that tobacco cembranoids, which are inhaled together with nicotine, may modify nicotine actions in the smoker’s brain.

Carlos A. Jimenez, Ph.D., PI

Contribution to Science
A new physiological mechanism that may be related to cocaine addiction was discovered in Project 3: cocaine inhibition of prefrontal cortex involves noradrenergic transmission through alpha2 receptors. In addition, rats sensitized to cocaine show significant neurochemical differences from animals exposed to the same treatment that did not develop sensitization. The differences involve NMDA and AMPA glutamate receptors and a glutamate transporter.

Abimael D. Rodriguez, Ph.D., PI

Contribution to Science
Synthesized about a dozen derivatives from the natural cembranoid methylpseudoplexaurate using organic synthesis. They have also characterized many new cembranoids from marine corals. Systematic testing of these compounds on the nAChR produced the first structure-activity relationship study for the cembranoid binding site on this receptor.

Sylvette Ayala, Ph.D., PI
Carlos Torres, Ph.D., Co-Investigator

M. Flint Beal, M.D., Collaborator
Department of Neurology and Neuroscience
Weill Medical College of Cornell University

Contribution to Science
The results obtained so far indicate that in the R6/2 model of Huntington’s disease mtDNA damage accumulation correlates with the progression of the disease.  Treatment of these animals with the antioxidant AEOL decreases the amount of mtDNA.  In a different research project, we have demonstrated that aged mice are deficient in the repair of mtDNA damage induced by the neurotoxin 3-nitropropionic acid (3-NPA).  Our data suggest that aged mice exhibit a weaker DNA repair response than the young mice after 3-NPA treatment as suggested by the expression of Apex1, a mitochondrial Base Excision Repair (BER) enzyme and by the increased number of lesions in the mtDNA of aged mice.  Finally, we have demonstrated that yeast strains that are deficient in BER exhibit higher levels of mtDNA that the wild-type controls and that mtDNA damage correlates with the loss of mitochondrial dysfunction.

Serguei Skatchkov, Ph.D., PI
Misty Eaton, Ph.D., Co-Investigator
Hector Maldonado, Ph.D., Co-Investigator

Contribution to Science
Using astrocytes and HeLa cells expressing connexin-43 (HeLa-Cx43-eGFP) hemichannels,  Dr. Skatchkov demonstrated that spermine (SPM) permeates the membrane of astrocytes and HeLa-Cx43-eGFP cells via Connexin43 (Cx43) hemichannels.  Dr. Skatchkov concluded that SPM activates and then permeates Cx-43 hemichannels, therefore, both (i) a reduction of external cations and (ii) a decrease in external K+ (by glial K-buffering) provide the best conditions for SPM fluxes to regulate brain activity.

Colin G. Nichols, Ph.D., Collaborator
Department of Cell Biology & Physiology
Washington University, St. Louis

Contribution to Science
The experiments have revealed a complex and variable rectification of Kir4.1 channels that can help explain the variability reported for candidate Kir4.1 currents in native cells.  Most importantly, rectification seems to be incomplete, even at high polyamine concentrations. In excised membrane patches, with high levels of expression, and high concentrations of spermine, there is ~15% residual conductance that is insensitive to spermine. Dr. Nichols is proposing that spermine ‘punchthrough’ may be significant in Kir4 channels, and that this may be a major contributor to the weak rectification observed under physiological conditions.