Α7 nACh Receptors Research Articles

The α7 nicotinic ACh receptor agonist compound B and positive allosteric modulator PNU‐120596 both alleviate inflammatory hyperalgesia and cytokine release in the rat

Agonists selective for the α7 nicotinic acetylcholine (nACh) receptor produce anti-hyperalgesic effects in rodent models of inflammatory pain, via direct actions on spinal pain circuits and possibly via attenuated release of peripheral pro-inflammatory mediators. Increasingly, allosteric modulation of ligand-gated receptors is recognized as a potential strategy to obtain desired efficacy in the absence of the putative adverse effects associated with agonist activation. We compared the anti-hyperalgesic and anti-inflammatory effects of the α7 nACh receptor agonist compound B with the positive allosteric modulator (PAM) PNU-120596 and the standard non-steroidal anti-inflammatory drug (NSAID), diclofenac, in rats with hind paw inflammation induced by either formalin, carrageenan or complete Freund's adjuvant (CFA). When administered before carrageenan, both diclofenac (30 mg·kg(-1) ) and PNU-120596 (30 mg·kg(-1) ) significantly reduced mechanical hyperalgesia and weight-bearing deficits for up to 4 h. Compound B (30 mg·kg(-1) ) also attenuated both measures of pain-like behaviour, albeit less robustly. Whereas compound B and PNU-120596 attenuated the carrageenan-induced increase in levels of TNF-α and IL-6 within the hind paw oedema, diclofenac only attenuated IL-6 levels. Established mechanical hyperalgesia induced by carrageenan or CFA was also partially reversed by compound B and PNU-120596. However, diclofenac was considerably more efficacious. Formalin-induced nocifensive behaviours were only reversed by compound B, albeit at doses which disrupted motor performance. α7 nACh receptor PAMs could prove to be useful in the treatment of inflammatory pain conditions, which respond poorly to NSAIDs or in situations where NSAIDs are contra-indicated.

Serotonergic involvement in the amelioration of behavioral abnormalities in dopamine transporter knockout mice by nicotine

Dopamine transporter knockout (DAT KO) mice exhibit elevated extracellular dopamine levels in brain regions that include the striatum and the nucleus accumbens, but not the prefrontal cortex. DAT KO mice model some aspects of psychiatric disorders, including schizophrenia. Smoking is more common in patients with schizophrenia, suggesting that nicotine might ameliorate aspects of the behavioral abnormalities and/or treatment side effects seen in these individuals. We report nicotine-induced normalization of effects on locomotion and prepulse inhibition of acoustic startle (PPI) in DAT KO mice that require intact serotonin 5-HT1A systems. First, we observed that the marked hyperactivity displayed by DAT KO mice was reduced by administration of nicotine. This nicotine effect was blocked by pretreatment with the non-specific nicotinic acetylcholine (nACh) receptor antagonist mecamylamine, or the 5-HT1A antagonist WAY100635. Secondly, we examined the effects of nicotine on PPI in DAT KO mice. Treatment with nicotine significantly ameliorated the PPI deficits observed in DAT KO mice. The ameliorating action of nicotine on PPI deficits in DAT KO mice was blocked by mecamylamine, the α7 nACh receptor antagonist methyllycaconitine or WAY100635, while the α4β2 nACh receptor antagonist dihydro-β-erythroidinehydrobromide (DHβE) produced only a non-significant trend toward attenuation of nicotine effects. Finally, we observed that administration of the 5-HT1A receptor agonist 8-OH-DPAT also ameliorated the deficit in PPI observed in DAT KO mice. This amelioration was antagonized by pretreatment with WAY100635. These data support the idea that nicotine might ameliorate some of the cognitive dysfunctions found in schizophrenia in a 5-HT1A-dependent fashion.This article is part of a Special Issue entitled ‘Cognitive Enhancers’.

PNU-120596, a positive allosteric modulator of α7 nicotinic acetylcholine receptors, reverses a sub-chronic phencyclidine-induced cognitive deficit in the attentional set-shifting task in female rats

The α7 nicotinic acetylcholine receptors (nAChRs) have been highlighted as a target for cognitive enhancement in schizophrenia. Adult female hooded Lister rats received sub-chronic phencyclidine (PCP) (2 mg/kg) or vehicle i.p. twice daily for 7 days, followed by 7 days' washout. PCP-treated rats then received PNU-120596 (10 mg/kg; s.c.) or saline and were tested in the attentional set-shifting task. Sub-chronic PCP produced a significant cognitive deficit in the extra-dimensional shift (EDS) phase of the task (p < 0.001, compared with vehicle). PNU-120596 significantly improved performance of PCP-treated rats in the EDS phase of the attentional set-shifting task (p < 0.001). In conclusion, these data demonstrate that PNU-120596 improves cognitive dysfunction in our animal model of cognitive dysfunction in schizophrenia, most likely via modulation of α7 nACh receptors.

Deconstruction of the α4β2 Nicotinic Acetylcholine Receptor Positive Allosteric Modulator Desformylflustrabromine

Desformylflustrabromine (dFBr; 1), perhaps the first selective positive allosteric modulator of α4β2 neuronal nicotinic acetylcholine (nACh) receptors, was deconstructed to determine which structural features contribute to its actions on receptors expressed in Xenopus ooycytes using two-electrode voltage clamp techniques. Although the intact structure of 1 was found to be optimal, several deconstructed analogs retained activity. Neither the 6-bromo substituent nor the entire 2-position chain is required for activity. In particular, reduction of the olefinic side chain of 1, as seen with 6, not only resulted in retention of activity/potency but in enhanced selectivity for α4β2 versus α7 nACh receptors. Pharmacophoric features for the allosteric modulation of α4β2 nACh receptors by 1 were identified.

On the antioxidant properties of kynurenic acid: Free radical scavenging activity and inhibition of oxidative stress

Kynurenic acid (KYNA) is an endogenous metabolite of the kynurenine pathway for tryptophan degradation and an antagonist of both N-methyl- d-aspartate (NMDA) and alpha-7 nicotinic acetylcholine (α7nACh) receptors. KYNA has also been shown to scavenge hydroxyl radicals ( OH) under controlled conditions of free radical production. In this work we evaluated the ability of KYNA to scavenge superoxide anion (O 2 −) and peroxynitrite (ONOO −). The scavenging ability of KYNA (expressed as IC 50 values) was as follows: OH = O 2 − > ONOO −. In parallel, the antiperoxidative and scavenging capacities of KYNA (0–150 μM) were tested in cerebellum and forebrain homogenates exposed to 5 μM FeSO 4 and 2.5 mM 3-nitropropionic acid (3-NPA). Both FeSO 4 and 3-NPA increased lipid peroxidation (LP) and ROS formation in a significant manner in these preparations, whereas KYNA significantly reduced these markers. Reactive oxygen species (ROS) formation were determined in the presence of FeSO 4 and/or KYNA (0–100 μM), both at intra and extracellular levels. An increase in ROS formation was induced by FeSO 4 in forebrain and cerebellum in a time-dependent manner, and KYNA reduced this effect in a concentration-dependent manner. To further know whether the effect of KYNA on oxidative stress is independent of NMDA and nicotinic receptors, we also tested KYNA (0–100 μM) in a biological preparation free of these receptors – defolliculated Xenopus laevis oocytes – incubated with FeSO 4 for 1 h. A 3-fold increase in LP and a 2-fold increase in ROS formation were seen after exposure to FeSO 4, whereas KYNA attenuated these effects in a concentration-dependent manner. In addition, the in vivo formation of OH evoked by an acute infusion of FeSO 4 (100 μM) in the rat striatum was estimated by microdialysis and challenged by a topic infusion of KYNA (1 μM). FeSO 4 increased the striatal OH production, while KYNA mitigated this effect. Altogether, these data strongly suggest that KYNA, in addition to be a well-known antagonist acting on nicotinic and NMDA receptors, can be considered as a potential endogenous antioxidant.

Regulation of Glutamate Release by α7 Nicotinic Receptors: Differential Role in Methamphetamine-Induced Damage to Dopaminergic and Serotonergic Terminals

Regulation of glutamate release is an important underlying mechanism in mediating excitotoxic events such as damage to dopamine (DA) and serotonin (5-HT) neurons observed after exposure to methamphetamine (Meth). One way to regulate glutamate release may be through the modulation of α7 nicotinic acetylcholine (nACh) receptors. Meth administration is known to increase acetylcholine release; however, it is unknown whether Meth increases glutamate release and causes long-term damage to both DA and 5-HT terminals through the activation of α7 nACh receptors. To test this hypothesis, the α7 nACh receptor antagonist, methyllycaconitine (MLA), was administered before the administration of repeated doses of Meth while simultaneously monitoring extracellular striatal glutamate with in vivo microdialysis. In addition, the subsequent long-term decreases in markers of dopaminergic and serotonergic terminals, including DA reuptake transporter (DAT), serotonin reuptake transporter (SERT), vesicular monoamine transporter-2, vesicular DA, and vesicular 5-HT content in the rat striatum, were measured. The results show that MLA pretreatment prevented Meth-induced increases in striatal glutamate and protected against the subsequent long-term decreases in striatal DAT and vesicular DA content without affecting the hyperthermia produced by Meth. In contrast, the Meth-induced decreases in striatal SERT immunoreactivity and vesicular 5-HT content were not affected by MLA. This suggests that the α7 nACh receptor differentially mediates glutamate-dependent damage to DA but not 5-HT terminals in a manner that is independent of hyperthermia. Furthermore, antagonism of α7 nACh receptors may be a possible therapeutic strategy for decreasing extracellular glutamate and preventing the excitotoxic damage observed in other DA-related neurodegenerative disorders.

Neuronal stimulation with 5-hydroxytryptamine 4 receptor induces anti-inflammatory actions via α7nACh receptors on muscularis macrophages associated with postoperative ileus

BackgroundThe main symptom of postoperative ileus (POI) is an intestinal motility disorder in which monocytes/macrophages and neutrophils play crucial roles. Prokinetic 5-hydroxytryptamine 4 receptor (5-HT4R) agonists and dopamine receptor antagonists...

A new model for the study of high-K+-induced preconditioning in cultured neurones: Role of N-methyl-d-aspartate and α7-nicotinic acetylcholine receptors

Spreading depression (SD), whether elicited by local application of high K+ medium to the cortical surface or by other stimuli, can increase the brain’s tolerance to a subsequent, severe ischaemic insult in vivo, a phenomenon termed preconditioning. Herein, we have developed and validated a robust in vitro protocol for high-K+-preconditioning of cultured neurones. This new model is especially appropriate to unravel the molecular mechanisms underlying neuronal preconditioning and subsequent ischaemic tolerance. With this new, optimised preparation, preconditioning was found to be dependent upon culture day in vitro, cell density, K+ concentration and duration of treatment. Finally, preconditioning was shown to be dependent upon N-methyl-d-aspartate (NMDA), CAM-kinase II signalling and α7-nicotinic (α7 nACh) receptor function, which is analogous to in vivo preconditioning induced by various stimuli.

360 POSTER Ror2 in renal cell carcinoma: evaluating its role in RCC tumorigenesis

The α7 nicotinic acetylcholine (nACh) receptor expressed in microglia has a crucial role in neuroprotection. Simulation of α7 nACh receptor leads to increased expression of glutamate/aspartate transporter (GLAST), which in turn decreases synaptic glutamate levels. However, the upregulation of GLAST in cultured rat cortical microglia appears long after (over 18 h) stimulation of the α7 nACh receptor with nicotine. Thus, the current study elucidated the pathway responsible for the induction of GLAST expression in cultured cortical microglia. Nicotine-induced GLAST mRNA expression was significantly inhibited by cycloheximide pretreatment, indicating that a protein intermediary, such as a growth factor, is required for GLAST expression. The expression of fibroblast growth factor-2 (FGF-2) mRNA in cortical microglia was significantly increased 6 and 12 h after treatment with nicotine, and this increase was potently inhibited by pretreatment with methyllycaconitine, a selective α7 nACh receptor antagonist. The treatment with nicotine also significantly increased FGF-2 protein expression. Furthermore, treatment with recombinant FGF-2 increased GLAST mRNA, protein expression and 14C-glutamate uptake, a functional measurement of GLAST activity. Conversely, pretreatment with PD173074, an inhibitor of FGF receptor (FGFR) tyrosine kinase, significantly prevented the nicotine-induced expression of GLAST mRNA, its protein and 14C-glutamate uptake. Reverse transcription polymerase chain reaction confirmed FGFR1 mRNA expression was confined to cultured cortical microglia. Together, the current findings demonstrate that the neuroprotective effect of activation of microglial α7 nACh receptors could be due to the expression of FGF-2, which in turn increases GLAST expression, thereby clearing glutamate from synapse and decreasing glutamate neurotransmission.

Chronic nicotine exposure induces a long-lasting and pathway-specific facilitation of LTP in the amygdala

Nicotine, in the form of tobacco, is the most commonly used drug of abuse. In addition to its rewarding properties, nicotine also affects many cognitive and emotional processes that involve several brain regions, including hippocampus and amygdala. Long-term changes in synaptic strength in these brain regions after drug exposure may be importantly correlated with behavioral changes induced by nicotine. Here, we study the effect of chronic oral administration of nicotine on the long-term synaptic potentiation in the amygdala, a key structure for emotional memory. We find that oral administration of nicotine for 7 d produces a significant enhancement of LTP in the amygdala. This facilitation is pathway specific: Nicotine selectively facilitates LTP in the cortical-lateral amygdala pathway, but not the thalamic-lateral and the lateral-basolateral synaptic pathway. The synaptic facilitation induced by a 7-d exposure to nicotine is long-lasting, it persists for 72 h after cessation of nicotine but decays 8 d after its cessation. In contrast, a shorter exposure of nicotine (24 h) induces only a short-lasting facilitation of synaptic plasticity that dissipates 24 and 72 h after cessation of nicotine. The facilitation of LTP in the amygdala after exposure to nicotine is mediated by removal of GABAergic inhibition, is dependent on the activation NMDA receptors, and can be prevented by blocking either alpha7 or beta2 nACh receptors. Our results indicate that chronic exposure to nicotine can promote the induction of long-lasting modifications of synapses in a specific pathway in the amygdala. These changes in synaptic plasticity may contribute to the complex neural adaptations and behaviors caused by nicotine.

Hippocampal interneurons co-express transcripts encoding the α7 nicotinic receptor subunit and the cannabinoid receptor 1

The notion of functional interactions between the α7 nicotinic acetylcholine (α7 nACh) and the cannabinoid systems is emerging from recent in vitro and in vivo studies. Both the α7 nACh receptor and the cannabinoid receptor 1 (CB1) are highly expressed in the hippocampus. To begin addressing possible anatomical interactions between the α7 nACh and the cannabinoid systems in the rat hippocampus, we investigated the distribution of neurons expressing α7 nACh mRNA in relation to those containing CB1 mRNA. By in situ hybridization we found that the α7 nACh mRNA is diffusely expressed in principal neurons and is highly expressed in a subset of interneurons. We observed that the pattern of distribution of hippocampal interneurons co-expressing transcripts encoding α7 nACh and glutamate decarboxylase (GAD; synthesizing enzyme of GABA) closely resembles the one displayed by interneurons expressing CB1 mRNA. By double in situ hybridization we established that the majority of hippocampal interneurons expressing α7 nACh mRNA have high levels of CB1 mRNA. As CB1 interneurons contain cholecystokinin (CCK), we investigated the degree of cellular co-expression of α7 nACh mRNA and CCK, and found that the cellular co-existence of α7 nACh and CCK varies within the different layers of the hippocampus. In summary, we established that most of the hippocampal α7 nACh expressing interneurons are endowed with CB1 mRNA. We found that these α7 nACh/CB1 interneurons are the major subpopulation of hippocampal interneurons expressing CB1 mRNA. The α7 nACh expressing interneurons represent half of the detected population of CCK containing neurons in the hippocampus. Since it is well established that the vast majority of hippocampal interneurons expressing CB1 mRNA have 5-HT type 3 (5-HT 3) receptors, we conclude that these hippocampal α7 nACh/5HT 3/CB1/CCK interneurons correspond to those previously postulated to relay inputs from diverse cortical and subcortical regions about emotional, motivational, and physiological states.

Differential Subcellular Localization of RIC-3 Isoforms and Their Role in Determining 5-HT3 Receptor Composition

RIC-3 has been identified as a chaperone molecule involved in promoting the functional expression of nicotinic acetylcholine and 5-HT(3) receptors in mammalian cells. In this study, we examined the effects of RIC-3a (isoform a) and a truncated isoform (isoform d) on RIC-3 localization, mobility, and aggregation and its effect on 5-HT3 receptor composition in mammalian cells. Human RIC-3a possesses an amino-terminal signal sequence that targets it to the endoplasmic reticulum where it is distributed within the reticular network, often forming large diffuse "slicks" and bright "halo" structures. RIC-3a is highly mobile within and between these compartments. Despite the propensity for RIC-3a to aggregate, its expression enhances the level of surface 5-HT3A (homomeric) receptors. In contrast, RIC-3a exerts an inhibitory action on the surface expression of heteromeric 5-HT3A/B receptors. RIC-3d exhibits an altered subcellular distribution, being localized to the endoplasmic reticulum, large diffuse slicks, tubulo-vesicular structures, and the Golgi. Bidirectional trafficking between the endoplasmic reticulum and Golgi suggests that RIC-3d constitutively cycles between these two compartments. In support of the large coiled-coil domain of RIC-3a being responsible for protein aggregation, RIC-3d, lacking this cytoplasmic domain, does not aggregate or induce the formation of bright aggregates. Regardless of these differences, isoform d is still capable of enhancing homomeric, and inhibiting heteromeric, 5-HT3 receptor expression. Thus, both isoforms of RIC-3 play a role in determining 5-HT3 receptor composition.

Synthesis of desformylflustrabromine and its evaluation as an α4β2 and α7 nACh receptor modulator

Desformylflustrabromine (dFBr; 1) and desformylflustrabromine-B (dFBr-B; 2) have been previously isolated from natural sources, and the former has been demonstrated to be a novel and selective positive allosteric modulator of α4β2 nicotinic acetylcholine (nACh) receptors. The present study describes the synthesis of water-soluble salts of 1 and 2, and confirms and further investigates the actions of 1 and 2 using two-electrode voltage clamp recordings.

Toxoplasma gondii and Schizophrenia: Linkage Through Astrocyte-Derived Kynurenic Acid?

Toxoplasma gondii and Schizophrenia: Linkage Through Astrocyte-Derived Kynurenic Acid?

Aporphine metho salts as neuronal nicotinic acetylcholine receptor blockers

( S)-Aporphine metho salts with the 1,2,9,10 oxygenation pattern displaced radioligands from recombinant human α7 and α4β2 neuronal nicotinic acetylcholine receptors (nAChR) at low micromolar concentrations. The affinity of the nonphenolic glaucine methiodide ( 4) (vs [ 3H]cytisine) was the lowest at α4β2 nAChR ( K i = 10 μM), and predicentrine methiodide ( 2) and xanthoplanine iodide ( 3), with free hydroxyl groups at C-2 or C-9, respectively, had the highest affinity at these receptors ( K i ≈ 1 μM), while the affinity of the diphenolic boldine methiodide ( 1) was intermediate between these values. At homomeric α7 nAChR, xanthoplanine had the highest affinity ( K i = 10 μM) vs [ 125I]α-bungarotoxin while the other three compounds displaced the radioligand with K i values between 15 and 21 μM. At 100 μM, all four compounds inhibited the responses of these receptors to EC 50 concentrations of ACh. The effects of xanthoplanine iodide ( 3) were studied in more detail. Xanthoplanine fully inhibited the EC 50 ACh responses of both α7 and α4β2 nACh receptors with estimated IC 50 values of 9 ± 3 μM (α7) and 5 ± 0.8 μM (α4β2).

Aryloxyethylamines: Binding at α7 nicotinic acetylcholine receptors

Structure–affinity relationships for the binding of 3-[2-( N, N, N-trimethylammonium)ethoxy]pyridine (AXPQ) at α7 nACh receptors were investigated due to its close structural similarity to a known α7 antagonist.

Halogenated cytisine derivatives as agonists at human neuronal nicotinic acetylcholine receptor subtypes

Cytisine (cy) is a potent and competitive partial agonist at α4 subunit-containing nicotinic acetylcholine (nACh) receptors while at homomeric α7-nACh receptors it behaves as a full agonist with a relatively lower potency. In the present study, we assessed the effects of bromination or iodination of the pyridone ring of cy and N-methylcytisine ( N-Me-cy) on the effects of these compounds on recombinant human (h) α7, hα4β2 and hα4β4 nACh receptors expressed in clonal cell lines and Xenopus oocytes. Halogenation at C(3) of cy or N-Me-cy usually brings about a marked increase in both affinity and efficacy at hα7, hα4β2 and hα4β4 nACh, the extent of which depends on whether the halogen is bromine or iodine, and upon receptor subtype. The effects of halogenation at C(5) are strongly influenced by the specific halogen substituent so that bromination causes a decrease in both affinity and efficacy while iodination decreases affinity but its effects on efficacy range from a decrease (hα7, hα4β4 nACh receptors) to a marked increase (hα4β2 nACh receptors). Based on these findings, which differ from those showing that neither the affinity nor efficacy of nicotine, 3-(2-azetidinylmethoxy)-pyridine or epibatidine are greatly affected by halogenation, dehalogenation or halogen exchange at equivalent positions, we suggest that cy, N-Me-cy and their halo-isosteres bind to neuronal nACh receptors in a different orientation allowing the halogen atom to interact with a hydrophobic halogen-accepting region within the predominantly hydrophobic agonist-binding pocket of the receptors.

Structure-Activity Relationships in a Peptidic α7 Nicotinic Acetylcholine Receptor Antagonist

α-Conotoxins are small disulfide-constrained peptide toxins which act as antagonists at specific subtypes of nicotinic acetylcholine receptors (nACh receptors). In this study, we analyzed the structures and activities of three mutants of α-conotoxin ImI, a 12 amino acid peptide active at α7 nACh receptors, in order to gain insight into the primary and tertiary structural requirements of neuronal α-conotoxin specificity. NMR solution structures were determined for mutants R11E, R7L, and D5N, resulting in representative ensembles of 20 conformers with average pairwise RMSD values of 0.46, 0.52, and 0.62Å from their mean structures, respectively, for the backbone atoms N, Cα, and C′ of residues 2-11. The R11E mutant was found to have activity near that of wild-type ImI, while R7L and D5N demonstrated activities reduced by at least two orders of magnitude. Comparison of the structures reveals a common two-loop architecture, with variations observed in backbone and side-chain dihedral angles as well as surface electrostatic potentials upon mutation. Correlation of these structures and activities with those from previously published studies emphasizes that existing hypotheses regarding the molecular determinants of α-conotoxin specificity are not adequate for explaining peptide activity, and suggests that more subtle features, visualized here at the atomic level, are important for receptor binding. These data, in conjunction with reported characterizations of the acetylcholine binding site, support a model of toxin activity in which a single solvent-accessible toxin side-chain anchors the complex, with supporting weak interactions determining both the efficacy and the subtype specificity of the inhibitory activity.

3-Nitropropionic acid (3-NPA)-induced toxicity of endothelial cells in vitro is mediated by nitric oxide dependent and independent mechanisms

Kynurenic acid (KYNA) is an endogenous metabolite of the kynurenine pathway for tryptophan degradation and an antagonist of both N-methyl-d-aspartate (NMDA) and alpha-7 nicotinic acetylcholine (α7nACh) receptors. KYNA has also been shown to scavenge hydroxyl radicals (OH) under controlled conditions of free radical production. In this work we evaluated the ability of KYNA to scavenge superoxide anion (O2−) and peroxynitrite (ONOO−). The scavenging ability of KYNA (expressed as IC50 values) was as follows: OH = O2− > ONOO−. In parallel, the antiperoxidative and scavenging capacities of KYNA (0–150 μM) were tested in cerebellum and forebrain homogenates exposed to 5 μM FeSO4 and 2.5 mM 3-nitropropionic acid (3-NPA). Both FeSO4 and 3-NPA increased lipid peroxidation (LP) and ROS formation in a significant manner in these preparations, whereas KYNA significantly reduced these markers. Reactive oxygen species (ROS) formation were determined in the presence of FeSO4 and/or KYNA (0–100 μM), both at intra and extracellular levels. An increase in ROS formation was induced by FeSO4 in forebrain and cerebellum in a time-dependent manner, and KYNA reduced this effect in a concentration-dependent manner. To further know whether the effect of KYNA on oxidative stress is independent of NMDA and nicotinic receptors, we also tested KYNA (0–100 μM) in a biological preparation free of these receptors – defolliculated Xenopus laevis oocytes – incubated with FeSO4 for 1 h. A 3-fold increase in LP and a 2-fold increase in ROS formation were seen after exposure to FeSO4, whereas KYNA attenuated these effects in a concentration-dependent manner. In addition, the in vivo formation of OH evoked by an acute infusion of FeSO4 (100 μM) in the rat striatum was estimated by microdialysis and challenged by a topic infusion of KYNA (1 μM). FeSO4 increased the striatal OH production, while KYNA mitigated this effect. Altogether, these data strongly suggest that KYNA, in addition to be a well-known antagonist acting on nicotinic and NMDA receptors, can be considered as a potential endogenous antioxidant.