PMID- 20933078
OWN - NLM
STAT- MEDLINE
DCOM- 20110722
LR  - 20131121
IS  - 1872-9738 (Electronic)
IS  - 0892-0362 (Linking)
VI  - 33
IP  - 2
DP  - 2011 Mar-Apr
TI  - Protective effect of L-kynurenine and probenecid on 6-hydroxydopamine-induced 
      striatal toxicity in rats: implications of modulating kynurenate as a protective 
      strategy.
PG  - 303-12
LID - 10.1016/j.ntt.2010.10.002 [doi]
AB  - 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 alpha7-nicotinic acetylcholine receptor (alpha7-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 mug/2 mul) 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.
CI  - Copyright (c) 2010 Elsevier Inc. All rights reserved.
FAU - Silva-Adaya, Daniela
AU  - Silva-Adaya D
AD  - Laboratorio de Aminoacidos Excitadores, Instituto Nacional de Neurologia y 
      Neurocirugia, Mexico City 14269, Mexico.
FAU - Perez-De La Cruz, Veronica
AU  - Perez-De La Cruz V
FAU - Villeda-Hernandez, Juana
AU  - Villeda-Hernandez J
FAU - Carrillo-Mora, Paul
AU  - Carrillo-Mora P
FAU - Gonzalez-Herrera, Irma Gabriela
AU  - Gonzalez-Herrera IG
FAU - Garcia, Esperanza
AU  - Garcia E
FAU - Colin-Barenque, Laura
AU  - Colin-Barenque L
FAU - Pedraza-Chaverri, Jose
AU  - Pedraza-Chaverri J
FAU - Santamaria, Abel
AU  - Santamaria A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20101007
PL  - United States
TA  - Neurotoxicol Teratol
JT  - Neurotoxicology and teratology
JID - 8709538
RN  - 0 (Neuroprotective Agents)
RN  - 343-65-7 (Kynurenine)
RN  - 8HW4YBZ748 (Oxidopamine)
RN  - H030S2S85J (Kynurenic Acid)
RN  - PO572Z7917 (Probenecid)
SB  - IM
MH  - Animals
MH  - Behavior, Animal/drug effects
MH  - Corpus Striatum/*drug effects/metabolism
MH  - Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - Drug Therapy, Combination
MH  - Kynurenic Acid/*metabolism
MH  - Kynurenine/administration & dosage/*therapeutic use
MH  - Male
MH  - Neuroprotective Agents/administration & dosage/*therapeutic use
MH  - Neurotoxicity Syndromes/metabolism/*prevention & control
MH  - Oxidopamine/*toxicity
MH  - Probenecid/administration & dosage/*therapeutic use
MH  - Rats
MH  - Rats, Wistar
EDAT- 2010/10/12 06:00
MHDA- 2011/07/23 06:00
CRDT- 2010/10/12 06:00
PHST- 2010/07/18 00:00 [received]
PHST- 2010/10/02 00:00 [revised]
PHST- 2010/10/03 00:00 [accepted]
PHST- 2010/10/12 06:00 [entrez]
PHST- 2010/10/12 06:00 [pubmed]
PHST- 2011/07/23 06:00 [medline]
AID - S0892-0362(10)00171-6 [pii]
AID - 10.1016/j.ntt.2010.10.002 [doi]
PST - ppublish
SO  - Neurotoxicol Teratol. 2011 Mar-Apr;33(2):303-12. doi: 10.1016/j.ntt.2010.10.002. 
      Epub 2010 Oct 7.