Protective effect of l -kynurenine and probenecid on 6-hydroxydopamine-induced striatal toxicity in rats: Implications of modulating kynurenate as a protective strategy

Abstract The neuroactive metabolite at the kynunerine pathway, kynurenic acid (KYNA), is a well-known competitive antagonist at the co-agonist glycine site of the n -methyl- d -aspartate receptor (NMDAr), and also decreases the extracellular levels of glutamate by blocking α7-nicotinic acetylcholine...

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Published in:Neurotoxicology and teratology 2011-03, Vol.33 (2), p.303-312
Main Authors: Silva-Adaya, Daniela, Pérez-De La Cruz, Verónica, Villeda-Hernández, Juana, Carrillo-Mora, Paul, González-Herrera, Irma Gabriela, García, Esperanza, Colín-Barenque, Laura, Pedraza-Chaverrí, José, Santamaría, Abel
Format: Article
Language:English
Subjects:
6-Hydroxydopamine
Acetylcholine receptors
Animals
Behavior, Animal - drug effects
Biological and medical sciences
Brain
Corpus Striatum - drug effects
Corpus Striatum - metabolism
Disease Models, Animal
Dopamine
Dose-Response Relationship, Drug
Drug Therapy, Combination
Emergency
Extracellular levels
Glial fibrillary acidic protein
Gliosis
Glutamatergic transmission
Glutamic acid receptors
Glycine
Immunohistochemistry
Kynurenic acid
Kynurenic Acid - metabolism
Kynurenine
Kynurenine - administration & dosage
Kynurenine - therapeutic use
Kynurenine pathway
Male
Medical Education
Medical sciences
Metabolites
Movement disorders
N-Methyl-D-aspartic acid receptors
Neostriatum
Neurodegeneration
Neurodegenerative diseases
Neuroprotection
Neuroprotective Agents - administration & dosage
Neuroprotective Agents - therapeutic use
Neurotoxicity
Neurotoxicity Syndromes - metabolism
Neurotoxicity Syndromes - prevention & control
Organic acids
Oxidopamine - toxicity
Parkinson's disease
Parkinson's disease model
Probenecid
Probenecid - administration & dosage
Probenecid - therapeutic use
Proteins
Rats
Rats, Wistar
rodents
Toxicity
Toxicology
Toxins
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Summary:Abstract The neuroactive metabolite at the kynunerine pathway, kynurenic acid (KYNA), is a well-known competitive antagonist at the co-agonist glycine site of the n -methyl- d -aspartate receptor (NMDAr), and also decreases the extracellular levels of glutamate by blocking α7-nicotinic acetylcholine receptor (α7-nAchr) located on glutamatergic terminals. KYNA has been often reported to be neuroprotective in different neurotoxic models. The systemic administration of l -kynurenine ( l -KYN) – the precursor of KYNA – together with probenecid (PROB) – an inhibitor of organic acids transport – to rodents increases KYNA levels in the brain in a dose-dependent manner. The striatal infusion of the toxin 6-hydroxydopamine (6-OHDA) to rodents is one of the common models used to simulate Parkinson's disease (PD). Different studies have linked PD alterations with excessive glutamatergic transmission in the striatum since NMDAr antagonists exert beneficial effects in PD models. In this work we investigated the effect that a systemic administration of l -KYN + PROB exerted on the toxic model induced by 6-OHDA in rats. PROB (50 mg/kg, i.p.) + l -KYN (75 mg/kg, i.p.) were given to rats for seven consecutive days. On day two of treatment, the animals were infused with a single injection of 6-OHDA (20 μg/2 μl) into the right striatum. Fourteen days post-lesion, rotation behavior was assessed as a marker of motor impairment. The total levels of dopamine (DA) were also estimated in striatal tissue samples of 6-OHDA-treated animals as a neurochemical marker of damage. In addition, twenty eight days post-lesion, the striatal damage was assessed by hematoxylin/eosin staining and immunohistochemistry against glial fibrillary acidic protein (GFAP) in the same animals. Neurodegeneration was also assessed by Fluoro Jade staining. 6-OHDA infusion increased rotation behavior, striatal reactive gliosis and neurodegeneration, while DA levels were decreased. For all markers evaluated, we observed protective effects of l -KYN + PROB on the dopaminergic damage induced by 6-OHDA. Our results suggest that this strategy was useful to mitigate dopaminergic toxicity in the hemiparkinsonian model. The combined use of l -KYN and PROB is a valuable tool to modulate glutamatergic and cholinergic activities, presumably by means of increased levels of endogenous KYNA.
ISSN:0892-0362
1872-9738
DOI:10.1016/j.ntt.2010.10.002