+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Mild mitochondrial inhibition in vivo enhances glutamate-induced neuronal damage through calpain but not caspase activation: role of ionotropic glutamate receptors

Mild mitochondrial inhibition in vivo enhances glutamate-induced neuronal damage through calpain but not caspase activation: role of ionotropic glutamate receptors

Experimental Neurology 212(1): 179-188

Glutamate neurotoxicity is exacerbated when energy metabolism is impaired. In vitro studies show that neuronal death in these conditions is related to mitochondrial dysfunction, ATP depletion, and the loss of calcium homeostasis. We have recently observed that, in vivo, enhancement of glutamate toxicity elicited by previous mitochondrial inhibition does not involve severe ATP depletion, suggesting the involvement of other processes. Factors such as the activation of different proteases may determine the extent and type of cell death. Protease activation might be triggered by internal or external factors, such as mitochondrial damage or the activation of a particular glutamate receptor subtype. In the present study we aimed to investigate whether moderate inhibition of mitochondrial metabolism facilitates glutamate toxicity through caspase-3 or calpain activation, as well as the contribution of NMDA and non-NMDA glutamate ionotropic receptors to this activation. Rats were pre-treated with a subtoxic dose of 3-NP and 4 h later intrastriatally injected with glutamate. Results show that neither of these treatments alone (3-NP or Glu) or in combination (3-NP+Glu) activated caspase-3. Conversely, calpain activity is induced after glutamate injection both in intact and 3-NP pre-treated rats. Inhibition of calpain activity by MDL-28170 significantly prevented striatal damage. NMDA and non-NMDA receptors contributed equally to calpain activation and to the induction of neuronal death. Results suggest that enhancement of glutamate toxicity due to inhibition of mitochondrial metabolism in vivo, does not recruit caspase-dependent apoptosis but favors calpain activation through the stimulation of both subtypes of glutamate ionotropic receptors.

Please choose payment method:

(PDF emailed within 0-6 h: $19.90)

Accession: 032350058

Download citation: RISBibTeXText

PMID: 18495118

DOI: 10.1016/j.expneurol.2008.03.023

Related references

Role of caspase-3 and calpain activation in glutamate-induced neuronal death during mitochondrial inhibition. 2007

Activation of NOX2 by the stimulation of ionotropic and metabotropic glutamate receptors contributes to glutamate neurotoxicity in vivo through the production of reactive oxygen species and calpain activation. Journal of Neuropathology and Experimental Neurology 70(11): 1020-1035, 2011

Contribution of NMDA and non-NMDA receptors to in vivo glutamate-induced calpain activation in the rat striatum. Relation to neuronal damage. Neurochemical Research 33(8): 1475-1483, 2008

Capsaicin-induced glutamate release is implicated in nociceptive processing through activation of ionotropic glutamate receptors and group I metabotropic glutamate receptor in primary afferent fibers. Journal of Pharmacological Sciences 109(2): 233-241, 2009

In vivo activation of metabotropic glutamate receptors by tACPD potentiates agonist effects at ionotropic glutamate receptors. Society for Neuroscience Abstracts 18(1-2): 647, 1992

Blockade of ionotropic glutamate receptors produces neuronal apoptosis through the Bax-cytochrome C-caspase pathway: The causative role of Ca2+ deficiency. Journal of Neurochemistry 85(2): 525-533, 2003

Calpain-mediated truncation of glutamate ionotropic receptors. Methods for studying the effects of calpain activation in brain tissue. Methods in Molecular Biology 144: 203-217, 2000

Guanosine-5'-monophosphate induces cell death in rat hippocampal slices via ionotropic glutamate receptors activation and glutamate uptake inhibition. Neurochemistry International 55(7): 703-709, 2009

Ionotropic glutamate receptors and glutamate transporters are involved in necrotic neuronal cell death induced by oxygen-glucose deprivation of hippocampal slice cultures. Neuroscience 136(3): 779-794, 2005

Tyrosine phosphorylation of ionotropic glutamate receptors by Fyn or Src differentially modulates their susceptibility to calpain and enhances their binding to spectrin and PSD-95. Journal of Neurochemistry 79(2): 382-390, 2001

Ammonia-induced extracellular accumulation of taurine in the rat striatum in vivo: Role of ionotropic glutamate receptors. Neurochemical Research 27(1-2): 37-42, 2002

The effects of activation of group III metabotropic glutamate receptors in the nucleus tractus solitarius require ionotropic glutamate receptors. Society for Neuroscience Abstracts 24(1-2): 868, 1998

Ionotropic Glutamate Receptors Play a Modulatory Role in Hypoxia-Induced Excitation of Cat Pre-Botzinger Complex In Vivo. FASEB Journal 18(4-5): Abst 690 18, 2004

Chronic activation of glutamate receptors provides neuro-protection against glutamate-induced neuronal death in the rat retina. Revista Brasileira de Biologia 56(SUPPL 1 PART 1): 195-196, 1996

The lurcher mutation and ionotropic glutamate receptors: contributions to programmed neuronal death in vivo. Brain Pathology 8(4): 795-807, 1998