Neuroprotective effects of peroxisome proliferator-activated receptor alpha and gamma agonists in model of parkinsonism induced by intranigral 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine

• Published in: Behavioural brain research Vol. 274; pp. 390 - 399
• Main Authors: BARBIERO, Janaína K, SANTIAGO, Ronise M, PERSIKE, Daniele Suzete, DA SILVA FERNANDES, Maria José, TONIN, Fernanda S, DA CUNHA, Claudio, BOSCHEN, Suelen Lucio, LIMA, Marcelo M. S, VITAL, Maria A. B. F
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier 01.11.2014
• Subjects: Adult and adolescent clinical studies; Animals; Avoidance Learning - drug effects; Biological and medical sciences; Caspase 3 - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Dopamine - analogs & derivatives; Dopamine - metabolism; Drug Administration Schedule; Drug Interactions; Exploratory Behavior - drug effects; Fenofibrate - therapeutic use; Male; Medical sciences; MPTP Poisoning - chemically induced; MPTP Poisoning - prevention & control; Neurology; Neuroprotective Agents - therapeutic use; Organic mental disorders. Neuropsychology; PPAR alpha - metabolism; PPAR gamma - metabolism; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Rats; Rats, Wistar; Substantia Nigra - drug effects; Swimming - psychology; Thiazolidinediones - therapeutic use; Time Factors; Tyrosine 3-Monooxygenase - metabolism; Neuroprotection; Nervous system diseases; Agonist; Parkinson's disease; Pioglitazone; Parkinson disease; Cerebral disorder; Fenofibrate; Central nervous system disease; Degenerative disease; Models; Peroxisome proliferator activated receptor; Extrapyramidal syndrome
• ISSN: 0166-4328; 1872-7549
• DOI: 10.1016/j.bbr.2014.08.014

A large body of evidence suggests that peroxisome proliferator-activated receptor (PPAR) agonists may improve some of the pathological features of Parkinson's disease (PD). In the present study, we evaluated the effects of the PPAR-α agonist fenofibrate (100mg/kg) and PPAR-γ agonist pioglitazone (30mg/kg) in a rat model of parkinsonism induced by intranigral 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine (MPTP). Male Wistar rats were pretreated with both drugs for 5 days and received an infusion of MPTP. The experiments were divided into two parts. First, 1, 7, 14, and 21 days after surgery, the animals were submitted to the open field test. On days 21 and 22, the rats were subjected to the forced swim test and two-way active avoidance task. In the second part of the study, 24h after neurotoxin administration, immunohistochemistry was performed to assess tyrosine hydroxylase activity. The levels of dopamine and its metabolites in the striatum were determined using high-performance liquid chromatography, and fluorescence detection was used to assess caspase-3 activation in the substantia nigra pars compacta (SNpc). Both fenofibrate as pioglitazone protected against hypolocomotion, depressive-like behavior, impairment of learning and memory, and dopaminergic neurodegeneration caused by MPTP, with dopaminergic neuron loss of approximately 33%. Fenofibrate and pioglitazone also protected against the increased activation of caspase-3, an effector enzyme of the apoptosis cascade that is considered one of the pathological features of PD. Thus, PPAR agonists may contribute to therapeutic strategies in PD.