PMID- 20219555 OWN - NLM STAT- MEDLINE DCOM- 20100810 LR - 20131121 IS - 1872-7549 (Electronic) IS - 0166-4328 (Linking) VI - 210 IP - 2 DP - 2010 Jul 11 TI - Protective effect of systemic L-kynurenine and probenecid administration on behavioural and morphological alterations induced by toxic soluble amyloid beta (25-35) in rat hippocampus. PG - 240-50 LID - 10.1016/j.bbr.2010.02.041 [doi] AB - Amyloid beta (Abeta) peptide exerts different toxic effects at a cellular level, including over-activation of N-methyl-D-aspartate receptor (NMDAr) and excitotoxicity, synaptic dysfunction and neuronal death. Kynurenic acid (KYNA) is an endogenous antagonist of NMDAr and alpha7 nicotinic receptors. Systemic administrations of both the immediate metabolic precursor of KYNA, L-kynurenine (L-KYN), and a proved inhibitor of KYNA's brain transport, probenecid (PROB), have shown to produce neuroprotective effects in a considerable number of experimental toxic conditions; however, this strategy has not been tested in the toxic model Abeta peptide so far. In this study we evaluated the effects of systemic administration of PROB (50 mg/kg/day for 7 days), L-KYN (75 mg/kg/day for 7 days) and their combination, on behavioural (locomotor activity and spatial memory) and morphological alterations induced by an intrahippocampal infusion of Abeta 25-35 to rats. An additional group was administered with the potent NMDAr antagonist dizocilpine (MK-801, 0.8 mg/kg/day for 7 days) for comparative purposes. A significant improvement of spatial memory was evident in Abeta-lesioned rats since post-lesion day 21 with all treatments tested and this effect was correlated with a reduction of cell damage and a decrease in reactive gliosis in hippocampal CA1 area. Neither L-KYN, nor PROB, or their combination, produced major alterations in motor function when given alone to rats. These results suggest that modulation of NMDAr activity by mean of therapeutic strategies designed to enhance KYNA in the brain may help to counteract neurodegenerative events coursing with Abeta toxicity and excitotoxic patterns. CI - Copyright 2010 Elsevier B.V. All rights reserved. FAU - Carrillo-Mora, Paul AU - Carrillo-Mora P AD - Laboratorio de Aminoacidos Excitadores, Instituto Nacional de Neurologia y Neurocirugia, Mexico DF, Mexico. FAU - Mendez-Cuesta, Luis A AU - Mendez-Cuesta LA FAU - Perez-De La Cruz, Veronica AU - Perez-De La Cruz V FAU - Fortoul-van Der Goes, Teresa I AU - Fortoul-van Der Goes TI FAU - Santamaria, Abel AU - Santamaria A LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20100226 PL - Netherlands TA - Behav Brain Res JT - Behavioural brain research JID - 8004872 RN - 0 (Amyloid beta-Peptides) RN - 0 (Glial Fibrillary Acidic Protein) RN - 0 (Neuroprotective Agents) RN - 0 (Peptide Fragments) RN - 0 (amyloid beta-protein (25-35)) RN - 343-65-7 (Kynurenine) RN - 6LR8C1B66Q (Dizocilpine Maleate) RN - PO572Z7917 (Probenecid) SB - IM MH - Amyloid beta-Peptides/*toxicity MH - Animals MH - Behavior, Animal/drug effects MH - Dizocilpine Maleate/administration & dosage MH - Dose-Response Relationship, Drug MH - Drug Interactions MH - Glial Fibrillary Acidic Protein/metabolism MH - Hippocampus/*drug effects MH - Kynurenine/*administration & dosage/pharmacology MH - Male MH - Maze Learning/drug effects MH - Motor Activity/drug effects MH - Neuroprotective Agents/*administration & dosage/pharmacology MH - Peptide Fragments/*toxicity MH - Probenecid/*administration & dosage/pharmacology MH - Rats MH - Rats, Wistar MH - Statistics, Nonparametric MH - Time Factors EDAT- 2010/03/12 06:00 MHDA- 2010/08/11 06:00 CRDT- 2010/03/12 06:00 PHST- 2009/12/23 00:00 [received] PHST- 2010/02/18 00:00 [revised] PHST- 2010/02/19 00:00 [accepted] PHST- 2010/03/12 06:00 [entrez] PHST- 2010/03/12 06:00 [pubmed] PHST- 2010/08/11 06:00 [medline] AID - S0166-4328(10)00156-7 [pii] AID - 10.1016/j.bbr.2010.02.041 [doi] PST - ppublish SO - Behav Brain Res. 2010 Jul 11;210(2):240-50. doi: 10.1016/j.bbr.2010.02.041. Epub 2010 Feb 26.