Here are the Society for Neuroscience abstracts that come up with "ampakine" as a search term:
Partial rescue of social deficits in the BTBR T+tf/J mouse model of autism by AMPA receptor modulator CX546
Location: Halls B-H
Presentation Time: Monday, Nov 15, 2010, 1:00 PM - 2:00 PM
Authors: *J. L. SILVERMAN, S. M. TURNER, J. N. CRAWLEY;
Lab. of Behavioral Neurosci., NIH, Natl. Inst. of Mental Hlth., BETHESDA, MD
Abstract: Animal models provide translational research tools for discovering treatments for autism spectrum disorders. BTBR T+tf/J (BTBR) is an inbred strain of mice that displays behavioral phenotypes with face validity to all three of the diagnostic symptoms of autism, including well-replicated social deficits, unusual patterns of vocalization, and high levels of repetitive self-grooming (McFarlane et al., 2007; Yang et al., 2007; Scattoni et al., 2008; Wöhr et al., 2010). We previously reported reductions in repetitive self-grooming in BTBR treated with the prototypic mGluR5 antagonist MPEP (Silverman et al., 2010). The present study tested an ampakine, CX546, that was previously reported to restore respiratory function in the Mecp2 mutant mouse model of Rett syndrome (Ogier et al., 2007), and to improve prepulse inhibition in mGluR5 knockout mice (Lipina et al., 2007). Ampakines modulate glutamatergic AMPA receptors and have been reported to elevate BDNF, rescue long-term potentiation deficits, and improve cognitive functions in rodent models of neuropsychiatric disorders (Lauterborn et al., 2003, 2007; Ren et al., 2006; Jourdi et al., 2009; Ng et al., 2009; Simmons et al. 2009; Damgaard et al., 2010). Adult male mice of the low sociability strain BTBR and the high sociability control strain C57BL/6J (B6) received an intraperitoneal injection of CX546 (25, 50, 75, or 100 mg/kg) or 25% ß-cyclodextrin vehicle, at an injection volume of 10 ml/kg, thirty minutes prior to sociability testing in our automated three-chambered social approach apparatus. In this task, sociability is defined as the subject mouse spending more time with a novel mouse than with a novel non-social object. On subsequent days, the same treatments were administered to BTBR and B6 for scoring of self-grooming and open field locomotion. Preliminary data indicate that acute administration of CX546 improved sociability in BTBR at the highest dose tested, while having no effect on sociability in B6. High doses of CX546 also increased time spent sniffing the novel mouse versus novel object, although vehicle alone elevated novel mouse sniff time in BTBR, presenting a confound potentially related to the vehicle. CX546 and vehicle had no effect on general exploratory locomotion during either the sociability phase or the habituation phase of the social approach task. CX546 and vehicle had no effect on novel open field exploratory locomotion in BTBR or B6, indicating the absence of sedation or hyperactivity. High repetitive self-grooming in BTBR was not reduced by CX546 or vehicle. Our findings suggest that modulation of AMPA receptors may improve components of sociability in a mouse model of autism.
Title: Amplitude-specific AMPA receptor modulator protects against excitotoxicity in hippocampus and is well tolerated with respect to stable GluR subunit levels after prolonged treatment
Location: Halls B-H
Presentation Time: Tuesday, Nov 16, 2010, 9:00 AM -10:00 AM
Authors: J. M. COOPER1, M. G. VARGA2, Q. BROWN2, J. HWANG1,2, C. N. QUACH3, G. A. ROGERS3, *B. A. BAHR1,2;
1Biotech. Res. and Training Ctr., Univ. of North Carolina, Pembroke, Pembroke, NC; 2Dept. of Pharmaceut. Sci. and the Neurosciences Program, Univ. of Connecticut, Storrs, CT; 3Cortex Pharmaceuticals Inc., Irvine, CA
Abstract: Ampakines are positive modulators of glutamatergic signaling that can enhance repair responses through the AMPA receptor-MAPK axis. The potent Ampakine 5-(1-piperidinylcarbonyl)-2,1,3-benzoxadiazole (CX691) enhances EPSP amplitude in hippocampal CA1 with an EC50 of 3 µM, as compared to its half-width EC50 of >500 µM. Single application of CX691 at 0.5 µM caused prolonged activation of the ERK MAPK pathway in hippocampal slice cultures, as indicated by increased pERK2 for more than 5 hours. As an evaluation of AMPA receptor maintenance, daily infusions of 1 µM CX691 into slice cultures were found to have no effect on GluR subunit levels, as well as no evidence of spectrin breakdown or GFAP induction over a 20-day period. Neuroprotection was tested in the hippocampal slice model consisting of a 17-min excitotoxin exposure to produce cytoskeletal and synaptic deterioration. When 0.5 µM CX691 was added to the slices immediately after excitotoxin washout, calpain-medicated cytoskeletal damage was reduced both early (1 h) after the excitotoxic insult as well as 20 h later. CX691’s neuroprotective action also promoted the maintenance of pre- and postsynaptic proteins and protected against cell death. The level of protection found in the present study appears to be as much as 200 times more potent than previous reports that used the Ampakine CX516 (Bahr et al. 2002, Exp Neurol 174:37-47; Kanju et al. 2008, Exp Neurol 214:55-61). These results show that long-term AMPA receptor modulation can be beneficial to reduce excitotoxic vulnerability without producing common tolerance issues of receptor down-regulation. Potent Ampakines may be effective for treating neurodegenerative disorders by enhancing MAPK and related trophic factor pathways.
Title: Ampakines as proneurogenic modulators in murine subventricular zone cell cultures
Location: Halls B-H
Presentation Time: Wednesday, Nov 17, 2010, 9:00 AM -10:00 AM
Authors: *C. S. SCHITINE1, F. AGASSE2, S. XAPELLI2, A. P. SILVA3, R. A. M. REIS1, F. G. DE MELLO1, J. O. MALVA2;
1Carlos Chagas Filho Biophysics Inst., Federal Univ. of Rio De Janeiro, Rio de Janeiro, Brazil; 2Neuroprotection and Neurogenesis in Brain Repair, Ctr. for Neurocience of Coimbra, Univ. of Coimbra, Coimbra, Portugal; 3Fac. of Med., Inst. of Biomed. Res. on Light and Image (IBILI), Univ. of Coimbra, Coimbra, Portugal
Abstract: Neurogenesis is a constitutive process that persists in two restricted niches in the adult mammalian brain, the subventricular zone (SVZ) and the hippocampal dendate gyrus subgranular zone. Neural stem cells from SVZ generate neuroblasts that migrate throughout the SVZ and along the rostral migratory stream to the olfatory bulb where they differentiate into interneurons.
AMPAkines are positive modulators of the ionotropic AMPA subtype of glutamate receptors, potentiating excitatory signals and enhancing cognitive properties including hippocampal-dependent memory. AMPAkines effects are presumably mediated as a result of an increase in the synaptic efficiency of excited neuronal circuits. As neurogenesis has been described to sustain hippocampal-dependent memory and learning, it is reasonable to speculate that AMPA and AMPAkines may positively regulate neurogenesis. Here, we examine the putative pro-neurogenic effects of an excitatory stimulation, through AMPA and AMPAkines treatment in SVZ cell cultures derived from postnatal mice.
AMPA and CX546 treatment triggered an increase in proliferation, evaluated in cultures through the BrdU incorporation protocol after 48h. However, while AMPA enhanced cell death levels, CX546 did not cause toxicity on the SVZ cultures revealed by the TUNEL assay. AMPA and AMPAkines stimulated neuronal differentiation evaluated by the numbers of NeuN mature neurons 7 days after treatment. Moreover AMPA and AMPAkine treatment increased the numbers of functional neurons, evaluated by single cell calcium imaging.
JNK is one of the signaling pathways activated mediating axonogenesis. Immunodetection of the phosphorylated form of the JNK signaling pathway after 6 hour treatment with 1 µM AMPA or 5 µM AMPAkine CX546 promoted an increase in the number and in the total length of the ramifications per neurosphere, indicating that CX546 can induce neuronal maturation.
Altogether, this work demonstrates that AMPA and AMPAkines CX546 are positive modulators of neurogenesis in SVZ cell cultures. Considering that modulating stem cell dynamic and neurogenesis is envisaged as a way to replace dead cells in the diseased brain, AMPAkines may prove to be an importante tool in future stem cell-based therapies.
Title: BDNF and BDNF upregulation restores synaptic plasticity in middle-aged ovariectomized rats
Location: Halls B-H
Presentation Time: Wednesday, Nov 17, 2010, 2:00 PM - 3:00 PM
Authors: *E. A. KRAMAR, L. Y. CHEN, J. C. LAUTERBORN, D. A. SIMMONS, C. M. GALL, G. LYNCH;
Univ. California, IRVINE, CA
Abstract: Ovariectomy leads to major impairments in long-term potentiation (LTP), an observation that helps explain the memory problems that sometimes accompany low levels of circulating estrogen in humans. Stabilization of hippocampal LTP depends on remodeling of the dendritic spine actin cytoskeleton and we have shown that acute estrogen infusion restores activity-induced F-actin assembly and LTP in hippocampal slices from middle-aged ovariectomized (OVX) rats. The present studies further characterized estrogen effects on actin-regulatory systems and then tested if BDNF, which is known to facilitate both actin remodeling and LTP, can restore LTP in OVX rats. We previously reported that estrogen activates the GTPase RhoA which is known to signal to filamentous (F-) actin. Here we show that estrogen infusion leads to increases in spine levels of the phosphorylated cofilin; increases in phosphorylation of this RhoA effector is consistent with the conclusion that estrogen elicits signaling through a RhoA-to-cofilin signaling cascade. We then tested if another known Rho-GTPase activator, brain-derived neurotrophic factor (BDNF), could, like estrogen, correct impairments of activity-induced F-actin assembly and LTP in OVX rats. A 60 min infusion of BDNF (2nM) normalized LTP in slices prepared from 8-month old OVX rats without causing detectable changes to baseline transmission. A comparable result was obtained with 4 days of daily injections with the short-half life AMPA receptor modulator (ampakine) CX929 in tests conducted 18 hrs after the last injection. Consistent with our previous report, ovariectomy eliminated the actin polymerization that normally occurs within spines after LTP induction. BDNF infusion, and in vivo ampakine treatments which were verified to increase endogenous BDNF expression, rescued both activity-induced actin polymerization and LTP. These results provide the first evidence that minimally invasive drug treatments that increase BDNF protein content can restore spine cytoskeletal reorganization in the presence of depressed estrogen levels and, in association with this, restore LTP.
Long story short:
1.ampakines provide some symptom improvement in an animal model of autism.
2. Ampakines protect against excitotoxicity in vitro.
3. Ampakines have been identified as potentially improving outcomes in stem cell therapy.
4. Ampakines match the effect of BDNF in restoring LTP in estrogen-poor rats, further evidence that ampakines provide the therapeutic benefits associated with BDNF.
I can't think of another class of compounds with nearly the promise of ampakines. This company may go under, but I very much hope that one way or other, these drugs reach patients.
