Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration
 

I take etodolac, which reduces COX-2 (and also, some COX-1, so I take misoprostol with it.) It works great for osteoarthritis. Anyone else on a COX-2 inhibitor?

Neuroscience

PNAS | April 29, 2003 | vol. 100 | no. 9 | 5473-5478


Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration

Peter Teismann*, Kim Tieu*, Dong-Kug Choi*, Du-Chu Wu*, Ali Naini*, Stéphane Hunotdagger , Miquel Vila*, Vernice Jackson-Lewis*, and Serge Przedborski*,Dagger ,§,¶


Parkinson's disease (PD) is a neurodegenerative disorder of uncertain pathogenesis characterized by the loss of the nigrostriatal dopaminergic neurons, which can be modeled by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

Increased expression of cyclooxygenase type 2 (COX-2) and production of prostaglandin E2 have been implicated in neurodegeneration in several pathological settings.

Here we show that COX-2, the rate-limiting enzyme in prostaglandin E2 synthesis, is up-regulated in brain dopaminergic neurons of both PD and MPTP mice.

COX-2 induction occurs through a JNK/c-Jun-dependent mechanism after MPTP administration. We demonstrate that targeting COX-2 does not protect against MPTP-induced dopaminergic neurodegeneration by mitigating inflammation. Instead, we provide evidence that COX-2 inhibition prevents the formation of the oxidant species dopamine-quinone, which has been implicated in the pathogenesis of PD.

This study supports a critical role for COX-2 in both the pathogenesis and selectivity of the PD neurodegenerative process. Because of the safety record of the COX-2 inhibitors, and their ability to penetrate the blood-brain barrier, these drugs may be therapies for PD.

cox 2 inhibitors
 

My husband takes Mobic 7.5 mgm/day. one of the neurologists with whom we consulted ~3 yrs ago mentioned that she had quite a number of patients in her practice who reported positive effects from taking Mobic--purely anecdotal; am unsure whether the drug is still under patent, though it has been around for awhile, so my guess is there will not be any studies utilizing this drug for PD--

I don't think Mobic was approved in the US yet when I began etodolac. I'd read about Mobic, and it seems like a great drug. Excellent choice IMHO!

pass the fish oil....
 

Fish oil also blocks Cox-2.

Mobic is now available generically.

pharmacology:
http://www.uspharmacist.com/oldforma...article_id=617

It is a Cox-1 and Cox-2 inhibitor. It is not specific for only Cox-2.

anti-inflammatories and PD
 

FYI and an update: my husband stopped Mobic due to increases in one of his renal function blood tests. The results returned to normal after being off this anti inflammatory for 4 weeks.....

asprin and Glucosamine as anti-inflamatory
 

... the posted article is technichally beyond me but I take both asprin and Glucosamine as anti-inflamatory... hoping they would help PD (both are relatively safe). any ideas?

Mobic is related to Piroxicam (Feldene) which is the most toxic NSAID, after
Indocin.

I'm sorry your hubby had that happen...but you caught it in time.
It gives me the willies when doctors DON'T supervise this drug properly.
They think it is very "safe" and it is not.

NSAIDs etc
 

Something of interest which I ran across- Ibuprofen delays or prevents, but most NSAIDs don't. What is different about ibuprofen? In another unrelated abstract I ran across the report that ibuprofen does a similar thing to the NMDA receptors that dextromethorphan cough syrup does. That is an action unrelated to inflammation (or coughing). That doesn't mean that inflammation is not important - in fact, it is critical - but rather that the NMDA receptors are of great importance. They are also the ones that MSG playshell with.

Rick, I've wondered that about ibuprufen with regard to another ailment that I can't think of now.

Similarly Zocor helps to prevent PD but Lipitor does not; both are statins. I think it's because Zocor gets in the brain easier.

Vioxx behaves very differently in the cardiovascular system than celebrex; both are cox-2 inhibitors. It's the law of unintended consequences. Some are good; others are not. Some Cox-2's are good at fighting cancer; others are not.

The makers of the drugs don't seem to spend much time worrying about unintended consequences. Only when they turn out to be good do they pay any attention, with research dollars. It's seems son, anyway.

Here's a bad consequence re: ibuprufen:

I can email the full article if desired.

Deficits in spatial learning and synaptic plasticity induced by the rapid and competitive broad-spectrum cyclooxygenase inhibitor ibuprofen are reversed by increasing endogenous brain-derived neurotrophic factor

* Kendra N. Shaw,
* Sean Commins and
* Shane M. O'Mara

Cyclooxygenase (COX), which is present in two isoforms (COX1 and 2), synthesizes prostaglandins from arachidonic acid; it plays a crucial role in inflammation in both central and peripheral tissues.

Here, we describe its role in synaptic plasticity and spatial learning in vivo via an effect on brain-derived neurotrophic factor (BDNF) and prostaglandin E2 (PGE2; both measured by Elisa).

We found that broad-spectrum COX inhibition (BSCI) inhibits the induction of long-term potentiation (LTP; the major contemporary model of synaptic plasticity), and causes substantial and sustained deficits in spatial learning in the watermaze.

Increases in BDNF and PGE2 following spatial learning and LTP were also blocked. Importantly, 4 days of prior exercise in a running wheel increased endogenous BDNF levels sufficiently to reverse the BSCI of LTP and spatial learning, and restored a parallel increase in LTP and learning-related BDNF and PGE2. In control experiments, we found that BSCI had no effect on baseline synaptic transmission or on the nonhippocampal visible-platform task; there was no evidence of gastric ulceration from BSCI.

COX2 is inhibited by glucorticoids; there was no difference in blood corticosterone levels as measured by radioimmunoassay in any condition.

Thus, COX plays a previously undescribed, permissive role in synaptic plasticity and spatial learning via a BDNF-associated mechanism.

http://www.blackwell-synergy.com/doi...8.2003.02643.x

....The slow, time-dependent, reversible COX inhibitor indomethacin (Dannhardt & Kiefer, 2001) does not, however, block the induction of LTP (Williams & Bliss, 1989; Yamagata et al., 1993); it is possible that the particular pharmacological profile of indomethacin accounts for this lack of an inhibitory effect on LTP. To date, there has been no systematic evaluation of the effects of the many other COX-inhibiting drugs on synaptic plasticity.....

....Apart from these studies, there appear to be few data available on the effects of COX inhibition or activation on synaptic plasticity or learning; the NMDA-receptor-related regulation of COX activity is suggestive of a role for COX in synaptic plasticity (see also Miettinen et al., 1997; who have shown that spreading depression, another form of neuroplasticity, also induces COX-2 activation in cortical neurons)......


....We therefore have provided the first evidence that COX is involved in BDNF expression, LTP and spatial learning; we have provided the first evidence that exercise, which increases levels of endogenous BDNF, also reverses ibuprofen-induced deficit in LTP and spatial learning. We have shown for the first time that PGE2 plays an important regulatory role in synaptic plasticity and learning. We have also confirmed here our previous data (Gooney et al., 2002) showing that both spatial learning and LTP are associated with an increase in BDNF. ....

...Salvemini et al. (1993) found that COX2 is modulated by nitric oxide (NO), a gaseous molecule that plays a role in synaptic plasticity and cellular death. In view of the many regulatory signals involved in COX2 activity and its localization in spines, Kauffman et al. (1996) suggest that COX2 may generate a diffusible signal as a function of the activity at specific synapses. C-fos is rapidly induced by hippocampal NMDA activation and blocked by COX inhibition (Lerea & McNamara, 1993). Because c-fos activity must involve events in the nucleus, it suggests a COX-dependent signal linking receptor activation and gene expression.....

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.

In U.K
 

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.