istradefylline and Inflammation

Parkinson's disease (PD) is a degenerative neurological disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the brain. The loss of the dopaminergic projection from the SNpc deprives the striatum of dopamine and results in a myriad of motor signs, including tremor, rigidity and ataxia. Although the stimulus for the initiation of the degenerative process is not understood, 80% of the dopaminergic neurons in the SNpc must be lost before the clinical symptoms of the disease are observed. This suggests that the degenerative process is initiated many years before clinical presentation of the disease. The neurodegeneration observed in PD is accompanied by inflammatory processes, and it has been suggested that anti-inflammatory drugs may be useful in slowing disease progression once the clinical signs of PD have been observed. This review summarizes and evaluates the progress that has been made in this area of research since 2006.

Topics: Animals; Anti-Inflammatory Agents; Benzoates; Bridged-Ring Compounds; Diterpenes; Drug Evaluation, Preclinical; Glucosides; Humans; Inflammation; Monoterpenes; Parkinson Disease; Phenanthrenes; Purines

The adenosine A(2A) receptor has recently emerged as a leading non-dopaminergic therapeutic target for Parkinson's disease, largely due to the restricted distribution of the receptor in the striatum and the profound interaction between adenosine and dopamine receptors in brain. Two lines of research in particular have demonstrated the promise of the A(2A) receptor antagonists as novel anti-parkinsonian drugs. First, building on extensive preclinical animal studies, the A(2A) receptor antagonist KW6002 has demonstrated its potential to increase motor activity in PD patients of the advanced stage in a recent clinical phase IIB trial. Second, recently two prospective epidemiological studies of large cohorts have firmly established the inverse relationship between the consumption of caffeine (a non-specific adenosine antagonist) and the risk of developing PD. The potential neuroprotective effect of caffeine and A(2A) receptor antagonists in PD is further substantiated by the demonstration that pharmacological blockade (by caffeine or specific A(2A) antagonists) or genetic depletion of the A(2A) receptor attenuated dopaminergic neurotoxicity and neurodegeneration in animal models of PD. Moreover, A(2A) receptor antagonism-mediated neuroprotection goes beyond PD models and can be extended to a variety of other brain injuries induced by stroke, excitotoxicity and mitochondrial toxins. Intensive investigations are under way to dissect out common cellular mechanisms (such as A(2A) receptor modulation of neuroinflammation) which may underlie the broad spectrum of neuroprotection by A(2A) receptor inactivation in brain.

Topics: Adenosine A2 Receptor Antagonists; Animals; Caffeine; Central Nervous System; Clinical Trials, Phase II as Topic; Disease Models, Animal; Glutamic Acid; Humans; Inflammation; Neuroprotective Agents; Parkinson Disease; Purines

Extracellular adenosine produced from ATP plays a role in energy processes, neurotransmission, and inflammatory responses. Istradefylline is a selective adenosine A2a receptor (A2aR) antagonist used for the treatment of Parkinson's disease. We previously showed using mouse models that adenosine primes hypersecretion of interleukin (IL)-17A

Topics: Adenosine; Adenosine A2 Receptor Antagonists; Animals; CD4-Positive T-Lymphocytes; Humans; Inflammation; Interleukin-17; Interleukin-8; Leukocytes, Mononuclear; Mice; Purinergic P1 Receptor Antagonists; Receptor, Adenosine A2A; T-Lymphocytes

The study shows effects of the nonselective adenosine A1/A2A receptor antagonist caffeine and the selective A2A receptor antagonist KW6002 on LPS-induced changes in the extracellular levels of dopamine (DA), glutamate, adenosine, hydroxyl radical, and A2A receptor density in the rat striatum. Intrastriatal LPS (10 μg) injection decreased extracellular level of DA and increased the level of adenosine, glutamate, and hydroxyl radical on the ipsilateral side 24 h after LPS administration. Caffeine (10 and 20 mg/kg i.p.) and KW6002 (1.5 and 3 mg/kg i.p.) given once daily for 6 days and on the 7th day 2 h before and 4 h after LPS injection reversed the LPS-induced changes in extracellular levels of DA, adenosine, glutamate, and hydroxyl radical production. Moreover, LPS-induced decrease in the striatal A2A receptor density was increased by caffeine and KW6002. In order to show the late LPS effect on oxidative damage of DA neurons, the contents of DA, DOPAC, HVA, and hydroxyl radical were determined 72 h after LPS (10 μg) administration into both striata. LPS decreased striatal and substantia nigra content of DA, DOPAC, and HVA while increased striatal but not nigral content of hydroxyl radical. Caffeine (20 mg/kg) and KW60002 (3 mg/kg) given once daily for 6 days and on the 7th day 2 h before and 4 h after intrastriatal injection of LPS normalized the content of DA and its metabolites in both brain regions as well as decreased LPS-induced increase in the striatal level of hydroxyl radical. In conclusion, our data demonstrated antioxidant effects of caffeine and KW6002 in the inflammatory model of PD.

Topics: Adenosine; Adenosine A2 Receptor Antagonists; Animals; Caffeine; Corpus Striatum; Dopamine; Dopaminergic Neurons; Glutamic Acid; Hydroxyl Radical; Inflammation; Lipopolysaccharides; Male; Microinjections; Parkinson Disease; Purines; Rats; Receptor, Adenosine A2A