Ginkgo Biloba & Down Syndrome Abstracts
J Comp Neurol 504 (4): 329-45 (2007 Oct)
Synaptic and cognitive abnormalities in mouse models of Down syndrome: Exploring genotype-phenotype relationships
Belichenko PV, Kleschevnikov AM, Salehi A, Epstein CJ, Mobley WC
Department of Neurology & Neurological Sciences and the Center for Research and Treatment of Down Syndrome, Stanford University Medical Center, Stanford, California 94305-5489, USA
Down syndrome (DS) is caused by trisomy of human chromosome 21. Because Ts65Dn and Ts1Cje mice are segmentally trisomic for a region of mouse chromosome 16, they genetically model DS and are used to study pathogenic mechanisms. Previously, we provided evidence for changes in both the structure and function of pre- and postsynaptic elements in the Ts65Dn mouse. Striking changes were evident in the size of the dendritic spines and in the ability to induce long-term potentiation (LTP) in the fascia dentata (FD). To explore the genetic basis for these changes, we examined Ts1Cje mice, which are trisomic for a completely overlapping but smaller segment of mouse chromosome 16. As in the Ts65Dn mouse, there was a regionally selective decrease in the density of dendritic spines (approximately 12%), an increase in the size of spine heads (approximately 26%), a decrease in the length of spine necks (approximately 26%), and reorganization of inhibitory inputs with a relative decrease in inputs to dendrite shafts and spine heads and a significant increase to the necks of spines (6.4%). Thus, all of the Ts65Dn phenotypes were present, but they were significantly less severe. In contrast, and just as was the case for the Ts65Dn mouse, LTP could not be induced unless the selective gamma-aminobutyric acid (GABA)(A) receptor antagonist picrotoxin was applied. Therefore, there was conservation of important synaptic phenotypes in the Ts1Cje mice. The analysis of data from this and earlier studies points to genotype-phenotype linkages in DS whose complexity ranges from relatively simple to quite complex.
Nat Neurosci 10 (4): 411-413 (2007 Apr)
Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome
Fabián Fernández, Wade Morishita, Elizabeth Zuñiga, James Nguyen, Martina Blank, Robert C Malenka, Craig C Garner
Department of Psychiatry and Behavioral Sciences, Nancy Pritzker Laboratory, Stanford University, Palo Alto, California 94304-5485, USA
Ts65Dn mice, a model for Down syndrome, have excessive inhibition in the dentate gyrus, a condition that could compromise synaptic plasticity and mnemonic processing. We show that chronic systemic treatment of these mice with GABA(A) antagonists at non-epileptic doses causes a persistent post-drug recovery of cognition and long-term potentiation. These results suggest that over-inhibition contributes to intellectual disabilities associated with Down syndrome and that GABA(A) antagonists may be useful therapeutic agents for this disorder.
Neurosci Lett 382 (3): 317-22 (2005 Jul)
Deficits in hippocampal CA1 LTP induced by TBS but not HFS in the Ts65Dn mouse: a model of Down syndrome
Costa AC, Grybko MJ
Eleanor Roosevelt Institute, University of Denver, 1899 Gaylord Street, Denver, CO 80206, USA
Down syndrome (DS) is the most common genetically defined cause of intellectual disabilities. Both hippocampal function and volume seem to be disproportionally reduced in individuals with DS and in at least one aneuploid murine model of DS, the Ts65Dn mouse. Two previous studies by one research group have reported deficits in long-term potentiation (LTP) induced by in vitro high-frequency stimulation (HFS) of hippocampal CA1 synapses of adult Ts65Dn mice. Here, we report on the results of our own investigation on LTP in Ts65Dn mice. This study was designed to confirm the previous findings and possibly shed some light onto potential mechanisms underlying the reported deficit in this important form of long-term synaptic plasticity in a mouse model of DS. LTP was induced in area CA1 with either theta burst stimulation (TBS) or HFS. Contrary to the previous reports, our results showed no significant difference in HFS-induced LTP between Ts65Dn and euploid littermate mice. We have found, however, a significant reduction of the amount of TBS-induced LTP in Ts65Dn mice compared to euploid controls. Because this specific LTP deficit can be rescued by bath application of picrotoxin (10 microM), we hypothesize that an increase in GABA(A)-mediated inhibition or in plasticity of the inhibitory circuitry in Ts65Dn mice may underlie the observed deficits. However, future experiments to examine the state of hippocampus CA1 GABAergic inhibition in Ts65Dn mice will be necessary to further explore these hypotheses.
The Journal of Neuroscience 24 (37): 8153-8160 (2004 Sep 15)
Alexander M. Kleschevnikov,¹ Pavel V. Belichenko,¹ Angela J. Villar,³ Charles J. Epstein,³ Robert C. Malenka,² and William C. Mobley¹
¹Department of Neurology and Neurological Sciences, and the Institute for Neuroscience, and ²Nancy Pritzker Laboratory, Department of Psychiatry, Stanford University Medical School, Stanford University, Stanford, California 94305, and ³Department of Pediatrics, University of California, San Francisco, San Francisco, California 94143
Although many genetic disorders are characterized by cognitive failure during development, there is little insight into the neurobiological basis for the abnormalities. Down syndrome (DS), a disorder caused by the presence of three copies of chromosome 21 (trisomy 21), is characterized by impairments in learning and memory attributable to dysfunction of the hippocampus. We explored the cellular basis for these abnormalities in Ts65Dn mice, a genetic model for DS. Although basal synaptic transmission in the dentate gyrus was normal, there was severe impairment of long-term potentiation (LTP) as a result of reduced activation of NMDA receptors. After suppressing inhibition with picrotoxin, a GABAA receptor antagonist, NMDA receptor-mediated currents were normalized and induction of LTP was restored. Several lines of evidence suggest that inhibition in the Ts65Dn dentate gyrus was enhanced, at least in part, because of presynaptic abnormalities. These findings raise the possibility that similar changes contribute to abnormalities in learning and memory in people with DS and, perhaps, in other developmental disorders with cognitive failure.
European Journal of Pharmacology 494 (2-3): 131-8 (2004 Jun)
Shelley H. Huanga, Rujee K. Dukea,b Mary Chebibb, Keiko Sasakic, Keiji Wadac, Graham A.R. Johnstona,d
aAdrien Albert Laboratory of Medicinal Chemistry, Department of Pharmacology, Faculty of Medicine, University of Sydney, Sydney, NSW 2006, Australia. bPharmaceutical Chemistry, Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia. cDepartment of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Japan. dHerbal Medicines Research and Education Centre, Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia
Ginkgolides A, B, and C are diterpene trilactones and active constituents of the 50:1 Ginkgo biloba leaf extract widely used in the symptomatic treatment of mild to moderate dementia. Using the two-electrode voltage clamp methodology, these ginkgolides were found to
be moderately potent antagonists at recombinant human α1β2γ2L GABAA receptors expressed in Xenopus oocytes. Ginkgolides A, B, and C inhibited the direct action of γaminobutyric acid (GABA) with Κi values of 14.5 ± 1.0, 12.7 ± 1.7, and 16.3 ± 2.4 µM respectively. Antagonism by these ginkgolides at α1β2γ2L GABAA receptors appears to be noncompetitive as indicated by the nonparallel right shift and reduced maximal GABA response in their GABA concentration–effect curves.
European Journal of Pharmacology 464 (1): 1-8 (2003 Mar)
Shelley H. Huanga, Rujee K. Dukea,b Mary Chebibb, Keiko Sasakic, Keiji Wadac, Graham A.R. Johnstona,d
aAdrien Albert Laboratory of Medicinal Chemistry, Department of Pharmacology, Faculty of Medicine, University of Sydney, Sydney, NSW 2006, Australia. bPharmaceutical Chemistry, Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia. cDepartment of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Japan. dHerbal Medicines Research and Education Centre, Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia
The sesquiterpene trilactone bilobalide is one of the active constituents of the 50:1 Ginkgo biloba leaf extract widely used to enhance memory and learning. Bilobalide was found to antagonise the direct action of γ-aminobutyric acid (GABA) on recombinant α1β2γ2L GABAA receptors. The effect of bilobalide on the direct action of GABA at α1β2γ2L GABAA receptors expressed in Xenopus laevis oocytes using two-electrode voltage-clamp method was evaluated and compared with the effects of the classical GABAA receptor competitive antagonist bicuculline and noncompetitive antagonist picrotoxinin. Bilobalide (IC50 = 4.6 ± 0.5 µM) was almost as potent as bicuculline and pictrotoxinin (IC50 = 2.0 ± 0.1 and 2.4 ± 0.5 µM, respectively) at α1β2γ2L GABAA receptors against 40 µM GABA (GABA EC50). While bilobalide and picrotoxinin were clearly noncompetitive antagonists, the potency of bilobalide decreased at high GABA concentrations suggesting a component of competitive antagonism.
Res Commun Mol Pathol Pharmacol 96 (1): 45-56 (1997 Apr)
Bilobalide, a constituent of Ginkgo biloba L., potentiates drug-metabolizing enzyme activities in mice: possible mechanism for anticonvulsant activity against 4-O-methylpyridoxine-induced convulsions
Sasaki K, Wada K, Hatta S, Ohshika H, Haga M.
Department of Toxicology and Environmental Health Faculty of Pharmaceutical Science, Health Sciences University of Hokkaido, Japan
Anticonvulsant effects of bilobalide, one of the constituents of Ginkgo biloba L., on the convulsions induced by 4-O-methylpyridoxine (MPN) were investigated in mice. Bilobalide reduced the duration and incidence of MPN-induced convulsions depending on its dose and the period of treatment. In addition, the anticonvulsant effect was manifested more than 24 hours after treatment and the effect lasted for 7 days after its withdrawal. In mice treated with bilobalide (30 mg/kg, p.o., once a day for 4 days), hepatic 7-methoxycoumarin O-demethylase activity was potentiated, and the disappearance of MPN in blood after MPN injection was faster than in controls. From these results, it is assumed that the anticonvulsant effect of bilobalide against convulsions induced by MPN partly involves modulation of hepatic drug-metabolizing enzyme activity, which leads to accelerated elimination of MPN.