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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.

Minocycline

This antibiotic has anti-inflammatory effects, and may also prevent the cascade of events leading to programmed cell death (apoptosis). These properties of minocycline suggest that it may also have neuroprotective effects. It has been used extensively for decades as an antibiotic and has also been used chronically to treat rheumatoid arthritis. The most common side effects are anorexia, nausea and vomiting, dizziness, rash, hypersensitivity reactions and headache. In rare cases, liver failure, azotemia, blood dyscrasias, intracranial hypertension, and black thyroid syndrome have been reported.

 

Scientific Rationale

Three proposed mechanisms:

1. Anti-inflammatory, inhibiting microglial activation caused by excitotoxicity. In this in vitro study, doses of 0.02 - 2 mcM, corresponding to concentrations of 1-0.01 mcg/mL, were effective.
2. Inhibits Nitric oxide mediated neuronal toxicity implicated in PD models.
3. Inhibits phosphorylation of p38 MAP kinase, thereby preventing activation of inflammatory mediators and caspase enzymes. May prevent caspase enzyme mediated apoptosis.

T ikka J Neurosci 2001; 21: 2580-2588
Du,PNAS 2001;98:14669-14674
Junn E, J Neurochem 2001;78:374-383.

Animal Model Data

RODENT:

Mouse: 45 mg/kg IP of minocycline, started 1 day before intrastriatal 6OH DA injection and continued for 14 days. Minocycline protected the decrease in DA neurons in the Substantia nigra on day 14 by 21%. There was a 47% decrease in microglial activation.

Mouse: 60, 90 or 120 mg/kg/day po minocycline was administered before, during and after MPTP (4 doses in 1 day). 7 days after MPTP, only the 90 and 120 mg/kg dose protected DA in a dose-dependent manner. When 120 mg/kg was given (4 h and 24h) AFTER MPTP, it protected DA neurons by the same amount.

He, Brain Res 2001; 909:187-193
Du, PNAS 2001;98:14669-14674

Pharmacokinetics (including blood brain barrier (BBB) penetration)

• After a single oral dose of 200mg in humans, peak concentration is 2.24 mcg/mL avg. (0.74-4.45). The half life is 11-22 h. Minocycline is the most lipophilic of the tetracyclines. 26% of plasma levels are achieved in the CSF.
• Concentrations in the CSF do not exceed 0.5 mg/L even though minocycline is the tetracycline that diffuses best through the BBB(With this info, combined with EC data from Scientific Rationale section, the concentrations in the brain should be in the range of those effective for neuroprotection in cell culture.)

M D Consult, 2002
Mandell: Principles and Practice of Infectious Disease, 5th ed, 2000
Saivin: Clinical Pharmacokinetics 1988; 15:355-366

Safety/Tolerability in Humans

Used extensively for decades as an antimicrobial agent in humans. Used in rheumatoid arthritis chronically. Most common adverse effects are: anorexia, nausea and vomiting, dizziness, rash, hypersensitivity reactions and headache. Rarely, liver failure, azotemia, blood dyscrasias, intracranial hypertension, and black thyroid syndrome have been reported. May cause enamel hypoplasia in fetuses or young children, so is contraindicated in pregnant women and children under age 11 yrs.

M D Consult, 2002
Thompson, Mod Pathol 1999;12:1181-1185.

Drug Interaction Potential

May decrease prothrombin activity, therefore may increase tendency to bleed in patients on anticoagulants, antiplatelets. In patients taking warfarin, INR usually monitored weekly after initiating minocycline until stable.

Absorption may be impaired by antacids or iron containing products. Metabolism induced by anticonvulsants (other than gabapentin) / rifampin. May reduce effectiveness of oral contraceptives. May raise levels of lithium, digoxin and theophylline.

M D Consult, 2002
Saivin: Clinical Pharmacokinetics 1988; 15:355-366

Clinical Trial/Epidemiological Evidence in Human PD

NONE

Last updated September 10, 2008