Ionotropic glutamate receptor subtypes activate c-fos transcription by distinct calcium-requiring intracellular signaling pathways

January 1993 Neuron

Leslie S. Lereab, a and James O. McNamara

Abstract

N-Methyl-Image -aspartate (NMDA) or non-NMDA receptor activation is sufficient to induce transcription of the immediate early gene c-fos in a calcium-requiring manner. We sought to determine whether the calcium-dependent mechanisms inducing c-fos transcription are identical following activation of these two receptor subtypes. We used in situ hybridization and fura-2 imaging to detect c-fos mRNA and intracellular calcium in individual dentate gyrus neurons maintained in vitro. Structurally distinct inhibitors of phospholipase A2 and cyclooxygenase abolished NMDA-but not kainic acid-induced increases of c-fos mRNA. Conversely, the calmodulin antagonist calmidazolium markedly inhibited kainic acid- but not NMDA-mediated increases of c-fos mRNA. We propose that the dissociation in the mechanisms transducing the calcium influx signals to the nucleus following NMDA and non-NMDA receptor activation is due to spatially distinct sites of calcium entry, resulting in activation of different enzymes located at distinct sites in the cell.

Vol. 293, Issue 2, 417-425, May 2000
Cyclooxygenase-2 Contributes to N-Methyl-D-aspartate-Mediated Neuronal Cell Death in Primary Cortical Cell Culture1

Sandra J. Hewett, Tracy F. Uliasz, Aniruddha S. Vidwans and James A. Hewett

Cyclooxygenase isozymes (COX-1 and COX-2) are found to be constitutively expressed in brain, with neuronal expression of COX-2 being rapidly induced after numerous insults, including cerebral ischemia.

Because overactivation of N-methyl-D-aspartate (NMDA) receptors has been implicated in the cell loss associated with ischemia, we characterized the expression of the COX isozymes in murine mixed cortical cell cultures and used isozyme-selective inhibitors to determine their relative contribution to NMDA receptor-stimulated prostaglandin (PG) production and excitotoxic neuronal cell death.

Immunocytochemical analysis of mixed cortical cell cultures revealed that COX-2 expression was restricted to neurons, whereas COX-1 was expressed in both neurons and astrocytes.

Brief exposure to NMDA (5 min; 100 µM) elicited a time-dependent accumulation of PGs in the culture medium that preceded neuronal cell death and correlated with the induction of COX-2 mRNA.

COX-1 expression remained unchanged.

Flurbiprofen, a nonselective COX-1/COX-2 inhibitor, blocked NMDA-stimulated PG production and attenuated neuronal death in a concentration-dependent manner.

Similar results were obtained with the specific COX-2 inhibitor NS-398 (10-30 µM) but not with the selective COX-1 inhibitor valeryl salicylate (10-300 µM). Inhibition of total constitutive COX activity with aspirin (100 µM, 1.5 h) before NMDA exposure did not prevent subsequent NMDA-mediated neuronal cell death. However, neuronal injury in aspirin-pretreated cultures was attenuated by flurbiprofen administration after NMDA exposure.

Finally, the protection afforded by COX-2 inhibition was specific for NMDA because neither flurbiprofen nor NS-398 protected neurons against kainate-mediated neurotoxicity.

Together, these results support the conclusion that newly synthesized COX-2 protein contributes to NMDA-induced neuronal injury.

http://jpet.aspetjournals.org/cgi/co...ract/293/2/417

Substance P is higher in spinal fluid with people with fibromyalgia, so it's interested me. I wonder if it's related to PD symptoms, too. It's related to NMDA and nitrous oxide and Cox-2....

NMDA and group I metabotropic glutamate receptors activation modulates substance P release from the arcuate nucleus and median eminence

Abstract

Glutamate participates in the regulation of secretion of several neuropeptides, including substance P (SP). Glutamate acts through ionotropic (iGluR) and metabotropic (mGluR) receptors. We have investigated whether glutamate receptor agonists and antagonists could affect SP release from the arcuate nucleus and the median eminence (ARC/ME). An increase in SP-like immunoreactivity (SP-LI) release from ARC/ME was induced by glutamate and N-methyl-d-aspartate (NMDA). This increase was prevented by d-(−)-2-amino-5-phosphono pentanoic acid (DAP5) (0.1 mM), a specific NMDA antagonist and by (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA) (0.1 mM), a selective antagonist of group I mGluR. The selective non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3(1H-4H)-dione (DNQX) (0.1 mM) and (RS)-greek small letter alpha-methyl-4-tetrazolylphenylglycine (MTPG) (0.1 mM), a group II and III mGluRs antagonist, did not affect the stimulatory effect of glutamate. A group I selective agonist, (S)-3,5-dihydroxyphenylglycine (DHPG) induced a significant increase in SP-LI release.

Supporting the participation of nitric oxide (NO) in the effect of glutamate on SP-LI release, NAME (0.5 mM), a NO synthase inhibitor, reduced the glutamate-induced increase in SP-LI release from ARC/ME.

Similarly, glutamate did not induce an increase in SP-LI release in the presence of meloxicam (0.1 mM) (a cyclooxygenase-2 (COX-2) specific inhibitor) indicating that prostaglandins production may also be involved in the glutamate effect. These data indicate that glutamate increases SP-LI release from the ARC/ME by acting through NMDA and group I mGluRs in the male rat. This stimulatory effect could be mediated by nitric oxide and prostaglandin production.


http://www.sciencedirect.com/science...c17217bbef3d1b

Ahah!

Loss of brainstem serotonin- and substance P-containing neurons in Parkinson's disease.

Halliday GM, Blumbergs PC, Cotton RG, Blessing WW, Geffen LB.

Centre for Neuroscience, Flinders Medical Centre, Bedford Park, Australia.

Using postmortem immunohistochemical analysis, we have identified degeneration of several different neuronal cell groups in the brainstem of patients dying with idiopathic Parkinson's disease. We report the first chemically identified loss of presumed serotonin neurons in the median raphe nucleus of the pons and of substance P-containing preganglionic neurons in the dorsal motor vagal nucleus. This evidence is concordant with other evidence that the primary neuropathological process is not confined either to a single pathway or to neurons containing a particular transmitter. Rather it appears that Parkinson's disease affects several classes of neurons in localized areas of the brainstem.

http://www.ncbi.nlm.nih.gov/pubmed/1691042

SUBSTANCE P-CONTAINING NEURONS IN THE MESOPONTINE TEGMENTUM ARE SEVERELY AFFECTED IN PARKINSON'S DISEASE

http://brain.oxfordjournals.org/cgi/...act/114/5/2253

SUMMARY

Substance P immunoreactive (SP+) neurons were analysed quantitatively in serial sections of the mesopontine tegmentum in 6 patients with idiopathic Parkinson's disease and 5 age-matched normal controls. In the tegmentum of the Parkinson's disease brains many SP+ neurons contained swollen, twisted neuronal processes as well as Lewy bodies. There were significant reductions in the total number of SP+neurons in the pedunculopontine tegmental nucleus (loss 43%), in the laterodorsal tegmental nucleus (loss 28%), in the oral pontine reticular nucleus(loss 41%) and in the median raphe nucleus (loss 76%). It was the large SP+ (>20µm) neurons that were particularly affected. In our control group we did not document a significant relationship between age at death and number of SP+neurons in these tegmental nuclei or between age at death and number of pigmented neurons in the locus coeruleus. In contrast, in patients with Parkinson's disease, there was a strong inverse relationship between age at death and numbers of SP+ and pigmented neurons. Our findings suggest an interaction between the pathophysiological mechanisms initiated by Parkinson's disease and other processes related to ageing.

Since tegmental SP+neurons are affected by the primary pathological processes underlying Parkinson's disease as severely as catecholamine-synthesizing neurons are affected, theories of pathogenesis and therapeutic strategies in Parkinson's disease will need to take into account the involvement of these SP+neurons.

Old theory, but interesting:

1: J Theor Biol. 1986 Jun 7;120(3):353-62.Links
Substance P and Parkinson's disease: a causal relationship?
Barker R.

Parkinson's disease (PD) is a common condition that is thought to result from a marked degeneration of dopaminergic neurones of midbrain origin. Here I present evidence to show that PD may result from a primary loss of active tachykinin, probably substance P (SP) in the substantia nigra (SN), and that this loss leads to a secondary degeneration of the dopaminergic neurones. This raises the possibility of treating and curing patients with PD by giving them SP agonsts.

I am pretty sure that in the U.K there was a panic over Cox Inhibitors with G.Ps(Primary Care) phoning patients to stop them immediatly.I think it was something to do with heart disease.

It's the COX-2 inhibitors which increase the risk of cardiovascular problems. Vioxx was the worst. The other cox-2 inhibitos do increase the risk, but not so much to take them off the market.

Celebrex, Vioxx, Meloxicam, are specifically Cox-2 inhibitors.

Other NASIDs also inhibit Cox 1, but preferentially inhibit COX-2, like the one I take, etodolac. It works as well as Vioxx for osteoarthritis of the knee. I take something to protect my stomach, because it does inhibit COX-1 which lowers the amount of prostaglandins which protect the stomach lining. I take misoprostol, a prostaglandin.

The misoprostol is important for another reason. Artane can cause constipation (Arimidex, too), and misoprostol can cause diarrhea. With the combo, I'm perfect! Never more regular in my life.