Search results for "Excitatory Amino Acid Agonists"
showing 9 items of 29 documents
Glycogen synthase kinase 3β links neuroprotection by 17β-estradiol to key Alzheimer processes
2004
Estrogen exerts many of its receptor-mediated neuroprotective functions through the activation of various intracellular signal transduction pathways including the mitogen activating protein kinase (MAPK), phospho inositol-3 kinase and protein kinase C pathways. Here we have used a hippocampal slice culture model of kainic acid-induced neurotoxic cell death to show that estrogen can protect against oxidative cell death. We have previously shown that MAPK and glycogen synthase kinase-3beta (GSK-3beta) are involved in the cell death/cell survival induced by kainic acid. In this model and other cellular and in vivo models we have shown that estrogen can also cause the phosphorylation and hence …
Pharmacological activity of C10-substituted analogs of the high-affinity kainate receptor agonist dysiherbaine
2009
Kainate receptor antagonists have potential as therapeutic agents in a number of neuropathologies. Synthetic modification of the convulsant marine toxin neodysiherbaine A (NDH) previously yielded molecules with a diverse set of pharmacological actions on kainate receptors. Here we characterize three new synthetic analogs of NDH that contain substituents at the C10 position in the pyran ring of the marine toxin. The analogs exhibited high-affinity binding to the GluK1 (GluR5) subunit and lower affinity binding to GluK2 (GluR6) and GluK3 (GluR7) subunits in radioligand displacement assays with recombinant kainate and AMPA receptors. As well, the natural toxin NDH exhibited approximately 100-f…
Reduced presynaptic efficiency of excitatory synaptic transmission impairs LTP in the visual cortex of BDNF-heterozygous mice
2006
The neurotrophin brain-derived neurotrophic factor (BDNF) plays an important role in neuronal survival, axonal and dendritic growth and synapse formation. BDNF has also been reported to mediate visual cortex plasticity. Here we studied the cellular mechanisms of BDNF-mediated changes in synaptic plasticity, excitatory synaptic transmission and long-term potentiation (LTP) in the visual cortex of heterozygous BDNF-knockout mice (BDNF(+/-)). Patch-clamp recordings in slices showed an approximately 50% reduction in the frequency of miniature excitatory postsynaptic currents (mEPSCs) compared to wild-type animals, in the absence of changes in mEPSC amplitudes. A presynaptic impairment of excita…
Beta-amyloid monomers are neuroprotective
2009
The 42-aa-long β-amyloid protein—Aβ1-42—is thought to play a central role in the pathogenesis of Alzheimer's disease (AD) (Walsh and Selkoe, 2007). Data from AD brain (Shankar et al., 2008), transgenic APP (amyloid precursor protein)-overexpressing mice (Lesné et al., 2006), and neuronal cultures treated with synthetic Aβ peptides (Lambert et al., 1998) indicate that self-association of Aβ1-42monomers into soluble oligomers is required for neurotoxicity. The function of monomeric Aβ1-42is unknown. The evidence that Aβ1-42is present in the brain and CSF of normal individuals suggests that the peptide is physiologically active (Shoji, 2002). Here we show that synthetic Aβ1-42monomers support …
Dendritic Ih selectively blocks temporal summation of unsynchronized distal inputs in CA1 pyramidal neurons.
2004
The active dendritic conductances shape the input-output properties of many principal neurons in different brain regions, and the various ways in which they regulate neuronal excitability need to be investigated to better understand their functional consequences. Using a realistic model of a hippocampal CA1 pyramidal neuron, we show a major role for the hyperpolarization-activated current, I-h, in regulating the spike probability of a neuron when independent synaptic inputs are activated with different degrees of synchronization and at different distances from the soma. The results allowed us to make the experimentally testable prediction that the I-h in these neurons is needed to reduce ne…
The effects of glutamate receptor antagonists on cerebellar granule cell survival and development.
2007
N-Methyl-d-aspartate (NMDA) receptor stimulation promotes neuronal survival and differentiation under both in vitro and in vivo conditions. We studied the effects of various NMDA receptor antagonists acting at different NMDA receptor binding sites and non-NMDA receptor antagonists on the development and survival of cerebellar granule cell (CGC) culture. Only three of the drugs tested induced neurotoxicity-MK-801 (non-competitive NMDA channel blocking antagonist), ifenprodil (an antagonist of the NR2B site and polyamine site of the NMDA receptor) and L-701.324 (full antagonist at glycine site), while CGP-37849 (a competitive NMDA antagonist), (+)-HA-966 (a partial agonist of the glycine site…
Endoplasmic Reticulum Stress Inhibition Protects against Excitotoxic Neuronal Injury in the Rat Brain
2007
Elevated brain glutamate with activation of neuronal glutamate receptors accompanies neurological disorders, such as epilepsy and brain trauma. However, the mechanisms by which excitotoxicity triggers neuronal injury are not fully understood. We have studied the glutamate receptor agonist kainic acid (KA) inducing seizures and excitotoxic cell death. KA caused the disintegration of the endoplasmic reticulum (ER) membrane in hippocampal neurons and ER stress with the activation of the ER proteins Bip, Chop, and caspase-12. Salubrinal, inhibiting eIF2α (eukaryotic translation initiation factor 2 subunit α) dephosphorylation, significantly reduced KA-induced ER stress and neuronal deathin vivo…
Cannabinoid CB1 receptor in dorsal telencephalic glutamatergic neurons: distinctive sufficiency for hippocampus-dependent and amygdala-dependent syna…
2013
A major goal in current neuroscience is to understand the causal links connecting protein functions, neural activity, and behavior. The cannabinoid CB1 receptor is expressed in different neuronal subpopulations, and is engaged in fine-tuning excitatory and inhibitory neurotransmission. Studies using conditional knock-out mice revealed necessary roles of CB1 receptor expressed in dorsal telencephalic glutamatergic neurons in synaptic plasticity and behavior, but whether this expression is also sufficient for brain functions is still to be determined. We applied a genetic strategy to reconstitute full wild-type CB1 receptor functions exclusively in dorsal telencephalic glutamatergic neurons a…
Transgenic overexpression of corticotropin releasing hormone provides partial protection against neurodegeneration in an in vivo model of acute excit…
2008
Abstract Corticotropin releasing hormone (CRH) is the central modulator of the mammalian hypothalamic–pituitary–adrenal (HPA) axis. In addition, CRH affects other processes in the brain including learning, memory, and synaptic plasticity. Moreover, CRH has been shown to play a role in nerve cell survival under apoptotic conditions and to serve as an endogenous neuroprotectant in vitro . Employing mice overexpressing murine CRH in the CNS, we observed a differential response of CRH-overexpressing mice (CRH-COE hom -Nes) to acute excitotoxic stress induced by kainate compared with controls (CRH-COE con -Nes). Interestingly, CRH-overexpression reduced the duration of epileptic seizures and pre…