Priorities & Actions
Parkinson's Plan 2006
Parkinson's Matrix
Research Agenda
Research Resources
Animal Models
Antibody Resources
Clinical Research
Gene Therapy
Genetic Resources
Brain Banks Across the
United States
Funding Research
Funding Announcements
Clinical Trials
Related Literature
Research Centers
NIH Intramural Research
Udall Centers of
Excellence
Patient/Caregiver Information
Parkinson's Disease
PD Clinical Trials
NINDS is part of the
National Institutes of
Health
Join our electronic mailing list
A number of compounds were identified as candidates for further study by the Committee to Identify Neuroprotective Agents in Parkinson's (CINAPS). Of these compounds, Minocycline, Creatine , CoQ10 and GPI 1485 have been selected for testing in the Neuroprotection Clinical Trial.
COX INHIBITORS
COX-2 enzymes are more familiar in arthritis, but the enzymes produce inflammation in all damaged tissues, including the brain. Many researchers are beginning to see inflammation as a critical process in neurodegenerative diseases Research in mice suggests that commonly used, anti-inflammatory painkillers (COX-2 inhibitors) hold promise for treating Parkinson's disease. These drugs have a potential for accentuating bleeding when used with other agents that inhibit platelet or coagulation function or that are GI toxic.
Scientific Rationale
There is evidence of an inflammatory response in PD, marked by glial activation, increased cytokines and elevated levels of COX II.1 Both salicylates2 and aspirin (COX I and II inhibitors)3 and the selective COX II inhibitor meloxicam4 have been shown to confer neuroprotection in a mouse model of MPTP- induced PD. While COX inhibition may be the protective mechanism, other agents such as acetominophen, diclofenac and ibuprofen (COX I) were ineffective.2 Preliminary investigations in animals suggest that the effects of ASA and salicylates are likely due to the hydroxyl radical scavenging activity of the two agents.2, 3
1. Vila, M Current Opinion in Neurol 2001, 14:483-489.
2. Mohanakumar, Brain Res 2000; 864:281-290
3. Aubin, J Neurochem 1998; 71:1635-1642
4. Teismann, P, Synapse 2001 39:167-174
Animal Model Data
RODENT: Mice given 30 mg/kg intraperitoneally (ip) x 2, 16 hours apart were also given either 10, 25, 50 or 100 mg/kg of salicylate (SA) 30 min before each MPTP dose and compared to control. MPTP alone caused a 60% decrease in DA in the nucleus caudate putamen (NCP) at day 7. Both the 50 and 100 mg/kg doses of SA completely abolished the DA depletion and the inhibition of DOPAC. When given 30 minutes after MPTP, SA 50 and 100 mg/kg significantly preserved DA concentration (by HPLC), compared to MPTP alone. There were no significant effects on HVA or MAO activity. In a separate group of animals, SA 25 and 50 mg/kg were shown to preserve glutathione compared to animals given MPTP alone. In another substudy, SA was shown to dose-dependently scavenge the OH formed in vivo immediately after MPTP administration (30 minutes).
Mice were given 15 mg/kg subcutaneously (SC) of MPTP as a single dose and striatal DA levels were measured 2 days later and
compared to controls. MPTP animals had a 50% depletion of DA which was prevented in a dose dependant manner by pretreatment
(1 h before) with salicylate, aspirin and a lysine salt of aspirin, with the highest doses: 100, 100 and 200 mg/kg, respectively
totally preventing DA depletion. In a separate set of animals, the protective effect was related to the dose of MPTP given,
with the highest doses only partially protecting striatal dopamine when 50 mg/kg MPTP was used.
In addition, optimal protection was achieved when aspirin was given at the same time as, or up to one h after, MPTP. No protection
was seen when ASA was delayed >4 h. Paracetomol (100 mg/kg ip) ibuprofen 20 mg/kg ip, indomethacin 100 mg/kg ip, diclofenac
100 mg/kg ip or dexamethasone 3, 10 and 30 mg/kg were all tried and none decreased the neurotoxicity of MPTP.
Mice were given meloxicam (2, 7.5, 50 mg/kg ip) immediately prior to administration of MPTP (one dose, 30 mg/kg, SC) and sacrificed after 7 days. MPTP treated had a >53% reduction of TH+ neurons compared to 88 and 91% for meloxicam (7.5, 50). Dose dependent protection was also seen in dopamine levels and metabolite levels, as well as in locomotion 1 day after MPTP administration.
Mohanakumar, Brain Res 2000;864:281-290
Aubin, J Neurochem 1998;71:1635-1642
Teismann, P, Synapse 2001 39:167-174
Pharmacokinetics (including BBB penetration)
Salicylate and aspirin have been used for over 100 years in humans but it is unclear whether the dosages that will be needed in humans (50 mg/kg = 3500 mg in a 70 kg person) will be above those easily tolerated. As dosages of aspirin exceed 325 mg/day, increasing GI toxicity occurs in elderly patients. Less GI toxicity is associated with selective COX II inhibitors.
Safety/Tolerability in Humans
Unknown
Drug Interaction Potential
Potential for accentuating bleeding when used with other agents that inhibit platelet or coagulation function or that are GI toxic. Potential for protein binding displacement interactions at high serum concentrations.
Clinical Trial/Epidemiological Evidence in Human PD
NONE
Last updated February 09, 2005