Intrastriatal Quinolinic Acid Administration Impairs Redox Homeostasis and Induces Inflammatory Changes: Prevention by Kynurenic Acid.

Kynurenic acid (KYNA) and quinolinic acid (QUIN) are metabolites formed in the degradation of tryptophan (Trp). QUIN is a selective NMDA receptor antagonist and may exert neurotoxic effects, whereas KYNA is an agonist of glutamatergic and cholinergic receptors and presents antioxidant properties. KYNA/QUIN ratio is decreased in several central nervous system disorders, but the mechanisms involved are not well elucidated. In the present study, we try to determine the neuroprotective capacity of KYNA on the QUIN effects in redox homeostasis changes (H2DCF oxidation, superoxide dismutase/catalase (SOD/CAT) ratio, glutathione peroxidase (GPx) activity, sulfhydryl content, and nitrite levels), as well as on inflammatory parameters (levels of TNF-α, IL-1ß, and IL-6). KYNA and QUIN effects on the activities of Na+,K+-ATPase and acetylcholinesterase (AChE) were also evaluated. Thirty-day-old male Wistar rats underwent stereotactic surgery and received intrastriatal injections as follows: group 1-control (PBS-injected), group 2-KYNA (100 µM), group 3-QUIN (150 nM), and group 4-KYNA + QUIN (KYNA-injected followed QUIN-injected). Results demonstrated that the KYNA administration was able to prevent the increase in reactive oxygen species, SOD/CAT ratio, and pro-inflammatory cytokines (IL-1ß and IL-6) and the decrease in GPx activity, sulfhydryl content, and nitrite levels caused by QUIN. KYNA was also able to partially prevent the decrease in Na+,K+-ATPase activity and the increase in AChE activity caused by QUIN. This study may help in the elucidation of neuroprotective effects of KYNA against oxidative and inflammatory insults caused by QUIN in the striatum of young male Wistar rats.

Generating Excitotoxic Lesion Models of Huntington's Disease.

In Huntington's disease (HD), the medium spiny projection neurons of the neostriatum degenerate early in the course of the disease. While genetic mutant models of HD provide an excellent resource for studying the molecular and cellular effects of the inherited polyQ huntingtin mutation, they do not typically present with overt atrophy of the basal ganglia, despite this being a major pathophysiological hallmark of the disease. By contrast, excitotoxic lesion models, which use quinolinic acid to specifically target the striatal projection neurons, are employed to study the functional consequences of striatal atrophy and to investigate potential therapeutic interventions that target the neuronal degeneration. This chapter provides a detailed guide to the generation of excitotoxic lesion models of HD in rats.

Toxic Synergism Between Quinolinic Acid and Glutaric Acid in Neuronal Cells Is Mediated by Oxidative Stress: Insights to a New Toxic Model.

It has been shown that synergistic toxic effects of quinolinic acid (QUIN) and glutaric acid (GA), both in isolated nerve endings and in vivo conditions, suggest the contribution of these metabolites to neurodegeneration. However, this synergism still requires a detailed characterization of the mechanisms involved in cell damage during its occurrence. In this study, the effects of subtoxic concentrations of QUIN and/or GA were tested in neuronal cultures, co-cultures (neuronal cells + astrocytes), and mixed cultures (neuronal cells + astrocytes + microglia) from rat cortex and striatum. The exposure of different cortical and striatal cell cultures to QUIN + GA resulted in cell death and stimulated different markers of oxidative stress, including reactive oxygen species (ROS) formation; changes in the activity of antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase; and depletion of endogenous antioxidants such as -SH groups and glutathione. The co-incubation of neuronal cultures with QUIN + GA plus the N-methyl-D-aspartate antagonist MK-801 prevented cell death but not ROS formation, whereas the antioxidant melatonin reduced both parameters. Our results demonstrated that QUIN and GA can create synergistic scenarios, inducing toxic effects on some parameters of cell viability via the stimulation of oxidative damage. Therefore, it is likely that oxidative stress may play a major causative role in the synergistic actions exerted by QUIN + GA in a variety of cell culture conditions involving the interaction of different neural types.

n-Butylidenephthalide exhibits protection against neurotoxicity through regulation of tryptophan 2, 3 dioxygenase in spinocerebellar ataxia type 3.

Spinocerebellar ataxia type 3 or Machado-Joseph disease (SCA3/MJD) is characterized by the repetition of a CAG codon in the ataxin-3 gene (ATXN3), which leads to the formation of an elongated mutant ATXN3 protein that can neither be denatured nor undergo proteolysis in the normal manner. This abnormal proteolysis leads to the accumulation of cleaved fragments, which have been identified as toxic and further they act as a seed for more aggregate formation, thereby increasing toxicity in neuronal cells. To date, there have been few studies or treatment strategies that have focused on controlling toxic fragment formation. The aim of this study is to develop a potential treatment strategy for addressing the complications of toxic fragment formation and to provide an alternative treatment strategy for SCA3. Our preliminary data on anti-aggregation and toxic fragment formation using an HEK (human embryonic kidney cells) 293T-84Q-eGFP (green fluorescent protein) cell model identified n-butylidenephthalide (n-BP) as a potential drug treatment for SCA3. n-BP decreased toxic fragment formation in both SCA3 cell and animal models. Moreover, results showed that n-BP can improve gait, motor coordination, and activity in SCA3 mice. To comprehend the molecular basis behind the control of toxic fragment formation, we used microarray analysis to identify tryptophan metabolism as a major player in controlling the fate of mutant ATXN3 aggregates. We also demonstrated that n-BP functions by regulating the early part of the kynurenine pathway through the downregulation of tryptophan 2, 3-dioxygenase (TDO2), which decreases the downstream neurotoxic product, quinolinic acid (QA). In addition, through the control of TDO2, n-BP also decreases active calpain levels, an important enzyme involved in the proteolysis of mutant ATXN3, thereby decreasing toxic fragment formation and associated neurotoxicity. Collectively, these findings indicate a correlation between n-BP, TDO2, QA, calpain, and toxic fragment formation. Thus, this study contributes to a better understanding of the molecular interactions involved in SCA3, and provides a novel potential treatment strategy for this neurodegenerative disease.

Non-Invasive, Focal Disconnection of Brain Circuitry Using Magnetic Resonance-Guided Low-Intensity Focused Ultrasound to Deliver a Neurotoxin.

Disturbances in the function of neuronal circuitry contribute to most neurologic disorders. As knowledge of the brain's connectome continues to improve, a more refined understanding of the role of specific circuits in pathologic states will also evolve. Tools capable of manipulating identified circuits in a targeted and restricted manner will be essential not only to expand our understanding of the functional roles of such circuits, but also to therapeutically disconnect critical pathways contributing to neurologic disease. This study took advantage of the ability of low-intensity focused ultrasound (FUS) to transiently disrupt the blood-brain barrier (BBB) to deliver a neurotoxin with poor BBB permeability (quinolinic acid [QA]) in a guided manner to a target region in the brain parenchyma. Ten male Sprague-Dawley rats were divided into two groups receiving the following treatments: (i) magnetic resonance-guided FUS + microbubbles + saline (n = 5), or (ii) magnetic resonance-guided FUS + microbubbles + QA (n = 5). Systemic administration of QA was well tolerated. However, when QA and microbubbles were systemically administered in conjunction with magnetic resonance-guided FUS, the BBB was disrupted and primary neurons were destroyed in the targeted subregion of the hippocampus in all QA-treated animals. Administration of vehicle (saline) together with microbubbles and FUS also disrupted the BBB but did not produce neuronal injury. These findings indicate the feasibility of non-invasively destroying a targeted region of the brain parenchyma using low-intensity FUS together with systemic administration of microbubbles and a neurotoxin. This approach could be of therapeutic value in various disorders in which disturbances of neural circuitry contribute to neurologic disease.

Oxidative Stress, Disrupted Energy Metabolism, and Altered Signaling Pathways in Glutaryl-CoA Dehydrogenase Knockout Mice: Potential Implications of Quinolinic Acid Toxicity in the Neuropathology of Glutaric Acidemia Type I.

We investigated the effects of an acute intrastriatal QUIN administration on cellular redox and bioenergetics homeostasis, as well as on important signaling pathways in the striatum of wild-type (Gcdh +/+ , WT) and knockout mice for glutaryl-CoA dehydrogenase (Gcdh -/- ) fed a high lysine (Lys, 4.7 %) chow. QUIN increased lactate release in both Gcdh +/+ and Gcdh -/- mice and reduced the activities of complex IV and creatine kinase only in the striatum of Gcdh -/- mice. QUIN also induced lipid and protein oxidative damage and increased the generation of reactive nitrogen species, as well as the activities of the antioxidant enzymes glutathione peroxidase, superoxide dismutase 2, and glutathione-S-transferase in WT and Gcdh -/- animals. Furthermore, QUIN induced DCFH oxidation (reactive oxygen species production) and reduced GSH concentrations (antioxidant defenses) in Gcdh -/- . An early increase of Akt and phospho-Erk 1/2 in the cytosol and Nrf2 in the nucleus was also observed, as well as a decrease of cytosolic Keap1caused by QUIN, indicating activation of the Nrf2 pathway mediated by Akt and phospho-Erk 1/2, possibly as a compensatory protective mechanism against the ongoing QUIN-induced toxicity. Finally, QUIN increased NF-κB and diminished IκBα expression, evidencing a pro-inflammatory response. Our data show a disruption of energy and redox homeostasis associated to inflammation induced by QUIN in the striatum of Gcdh -/- mice submitted to a high Lys diet. Therefore, it is presumed that QUIN may possibly contribute to the pathophysiology of striatal degeneration in children with glutaric aciduria type I during inflammatory processes triggered by infections or vaccinations.

N-methyl-D-aspartate preconditioning prevents quinolinic acid-induced deregulation of glutamate and calcium homeostasis in mice hippocampus.

The search for new therapeutic strategies through modulation of glutamatergic transmission using effective neuroprotective agents is essential. Glutamatergic excitotoxicity is a major factor common to neurodegenerative diseases and in acute events such as cerebral ischemia, traumatic brain injury and epilepsy. We have previously demonstrated that N-methyl-D-aspartate (NMDA) preconditioning in mice showed 50 % of protection against seizures and full protection against damage to neuronal tissue induced by quinolinic acid (QA). In this study, cellular and molecular mechanisms involved on NMDA preconditioning and neuroprotection were investigated in mice treated with NMDA 24 h before QA insult. Calcium uptake and D-aspartate release from hippocampal slices obtained from mice treated with NMDA plus QA and not displaying seizures (protected mice) were similar to control (saline) or NMDA preconditioned mice. Increased calcium uptake and glutamate release is evidenced in unprotected (convulsed) mice as well as QA control, demonstrating that calcium and glutamate are involved in NMDA-induced preconditioning. Increased glutamate release evoked by QA was blocked by MK-801, whereas increased calcium uptake was abolished by voltage-dependent calcium channels inhibitors, but not MK-801. NMDA preconditioning is effective in normalizing the deregulation of glutamate transport and calcium homeostasis evoked by QA due to aberrant NMDA receptors activation that culminates in seizures and hippocampal cells damage.

Biochemical, histopathological and behavioral alterations caused by intrastriatal administration of quinolic acid to young rats.

Quinolinic acid (QUIN) is a neuroactive metabolite of the kinurenine pathway, and is considered to be involved in aging and some neurodegenerative disorders, including Huntington's disease. QUIN was injected intrastriatally into adolescent rats, and biochemical and histopathological analyses in the striatum, cortex, and hippocampus, as well as behavioral tests, were carried out in the rats over a period of 21 days after drug injection. Decreased [(3)H]glutamate uptake and increased (45)Ca(2+) uptake were detected shortly after injection in the striatum and cerebral cortex. In the hippocampus, increased (45)Ca(2+) uptake preceded the decreased [(3)H]glutamate uptake, without histopathological alterations. Also, corticostriatal astrogliosis was observed 7 days later, progressing to neuronal death at day 14. QUIN-treated rats also showed cognitive deficits 24 h after injection, concurrently with striatal astrogliosis. Motor deficits appeared later, after corticostriatal neurodegeneration. We assume that glutamate excitotoxicity could represent, at least in part, a molecular mechanism associated with the cognitive and motor impairments, corticostriatal astrogliosis and neuronal death observed in the QUIN-treated rats. We propose that our findings could be relevant for understanding the pathophysiology of human neurodegenerative diseases affecting young people, such as the juvenile form of Huntington's disease, and for the design of potential therapeutic strategies to slow down the progression of the disease.

The absence of indoleamine 2,3-dioxygenase expression protects against NMDA receptor-mediated excitotoxicity in mouse brain.

We previously showed that the expression and activity of indoleamine 2,3-dioxygenase (Ido1) are chronically elevated in the striatum of YAC128 mouse model of HD. This was followed by increased production of neurotoxic metabolite hydroxykynurenine (3-HK) in the striatum of symptomatic mice. We therefore hypothesized that the chronic Ido1 induction in the striatum of YAC128 mice leads to increased neurotoxicity in this mouse model; based on this hypothesis, we predicted that the absence of Ido1 expression would result in decreased sensitivity to neurotoxicity in mice. The work described in this brief communication will include the characterization of Ido(-/-) striatum in terms of enzymatic expression and activity in the first step of the pathway. Additionally, we assessed the sensitivity of the striatum to excitotoxic insult in the absence of Ido1 expression in the striatum of constitutive Ido1 null mice (Ido(-/-)) and demonstrated that Ido(-/-) mice are less sensitive to QA-induced striatal neurotoxicity. Finally, through measurement of kynurenine pathway (KP) metabolites in Ido(-/-) mice, we showed decreased levels of 3-HK in the striatum of these mice. This study suggests that the inhibition of the first step in the KP may be neuroprotective and should be considered as a potential therapeutic target in HD and other neurodegenerative diseases.

NMDA preconditioning attenuates cortical and hippocampal seizures induced by intracerebroventricular quinolinic acid infusion.

Searching for new therapeutic strategies through modulation of glutamatergic transmission using effective neuroprotective agents is essential. Glutamatergic excitotoxicity is a common factor to neurodegenerative diseases and acute events such as cerebral ischemia, traumatic brain injury, and epilepsy. This study aimed to evaluate behavioral and electroencephalographic (EEG) responses of mice cerebral cortex and hippocampus to subconvulsant and convulsant application of NMDA and quinolinic acid (QA), respectively. Moreover, it aimed to evaluate if EEG responses may be related to the neuroprotective effects of NMDA. Mice were preconditioned with NMDA (75 mg/kg, i.p.) and EEG recordings were performed for 30 min. One day later, QA was injected (36.8 nmol/site) and EEG recordings were performed during 10 min. EEG analysis demonstrated NMDA preconditioning promotes spike-wave discharges (SWDs), but it does not display behavioral manifestation of seizures. Animals that were protected by NMDA preconditioning against QA-induced behavioral seizures, presented higher number of SWD after NMDA administration, in comparison to animals preconditioned with NMDA that did display behavioral seizures after QA infusion. No differences were observed in latency for the first seizure or duration of seizures. EEG recordings after QA infusion demonstrated there were no differences in the number of SWD, latency for the first seizure or duration of seizures in animals pretreated with saline or in animals preconditioned by NMDA that received QA. A negative correlation was identified between the number of NMDA-induced SWD and QA-induced seizures severity. These results suggest a higher activation during NMDA preconditioning diminishes mice probability to display behavioral seizures after QA infusion.

Essential role of excessive tryptophan and its neurometabolites in fatigue.

PURPOSE: Serotonin, a neurotransmitter synthesized from tryptophan, has been proposed to play a key role in central fatigue. In this study, we examined whether tryptophan itself and/or its two metabolites, kyneurenic acid (KYNA) and quinolinic acid (QUIN), are involved in central fatigue. MATERIALS AND METHODS: Experiments were conducted using Sprague-Dawley rats (SDR) and Nagase analbuminemic rats (NAR). Central fatigue was assessed by treadmill running and a Morris water maze test. Microdialysis was used to collect samples for measurement of extracellular concentration of tryptophan, serotonin and 5-hydroxyindoleacetic acid (5-HIAA) and to infuse test agents. To examine the kinetics of release, synaptosomes in the striatum were prepared in vitro to measure intra- and extrasynaptosomal concentration of tryptophan, serotonin and 5-HIAA. RESULTS: The concentration of tryptophan secreted into the extracellular space of the striatum was higher during fatigue only, and quickly returned to basal levels with recovery from fatigue. Running time to exhaustion was reduced by activation of tryptophan receptors. Time to exhaustion was shorter in NAR, which maintain a higher extracellular level of striatum tryptophan than SDR. Impaired memory performance in a water maze task after tryptophan treatment was attributable to high levels of KYNA and QUIN in the hippocampus acting synergistically on N-methyl-D-aspartic acid receptors. When branched-chain amino acids were administered, tryptophan transport to the extracellular space of the striatum was drastically inhibited. CONCLUSION: Our findings demonstrate that the increase in fatigue which occurs because of excessively elevated brain tryptophan can be further amplified by the use of synthetic KYNA and QUIN.

Nucleus accumbens and delay discounting in rats: evidence from a new quantitative protocol for analysing inter-temporal choice.

RATIONALE: There is evidence that the core of the nucleus accumbens (AcbC) is involved in inter-temporal choice behaviour. OBJECTIVE: A new behavioural protocol was used to examine the effect of destruction of the AcbC on delay discounting in inter-temporal choice schedules in rats. METHOD: Rats with excitotoxic lesions of the AcbC or sham lesions made repeated choices on an adjusting-delay schedule between a smaller reinforcer (A) that was delivered immediately and a larger reinforcer (B) that was delivered after a delay which increased or decreased depending on the subject's choices. In two phases of the experiment, reinforcer sizes were selected which enabled theoretical parameters expressing delay discounting and sensitivity to reinforcer size to be estimated from the ratio of the indifference delays (i.e. the quasi-stable values of the adjusting delay seen after extended training) obtained in the two phases. RESULTS: In both groups, indifference delays were shorter when the sizes of A and B were 14 and 25 µl than when they were 25 and 100 µl of a 0.6 M sucrose solution. Indifference delays were shorter in AcbC-lesioned than in sham-lesioned rats. Estimates of delay discounting rate based on the ratio of the indifference delays were lower in the AcbC-lesioned than in the sham-lesioned rats. The size sensitivity parameter did not differ between the groups. Adjusting delays in successive blocks of trials were analysed using Fourier transform. The period corresponding to the dominant frequency of the power spectrum and power within the dominant frequency band did not differ between the groups. CONCLUSIONS: Destruction of the AcbC increased the rate of delay discounting.

Striatal-enriched protein tyrosine phosphatase expression and activity in Huntington's disease: a STEP in the resistance to excitotoxicity.

Striatal-enriched protein tyrosine phosphatase (STEP) is highly expressed in striatal projection neurons, the neuronal population most affected in Huntington's disease. Here, we examined STEP expression and phosphorylation, which regulates its activity, in N-terminal exon-1 and full-length mutant huntingtin mouse models. R6/1 mice displayed reduced STEP protein levels in the striatum and cortex, whereas its phosphorylation was increased in the striatum, cortex, and hippocampus. The early increase in striatal STEP phosphorylation levels correlated with a deregulation of the protein kinase A pathway, and decreased calcineurin activity at later stages further contributes to an enhancement of STEP phosphorylation and inactivation. Accordingly, we detected an accumulation of phosphorylated ERK2 and p38, two targets of STEP, in R6/1 mice striatum at advanced stages of the disease. Activation of STEP participates in excitotoxic-induced cell death. Because Huntington's disease mouse models develop resistance to excitotoxicity, we analyzed whether decreased STEP activity was involved in this process. After intrastriatal quinolinic acid (QUIN) injection, we detected higher phosphorylated STEP levels in R6/1 than in wild-type mice, suggesting that STEP inactivation could mediate neuroprotection in R6/1 striatum. In agreement, intrastriatal injection of TAT-STEP increased QUIN-induced cell death. R6/2, Tet/HD94, and Hdh(Q7/Q111) mice striatum also displayed decreased STEP protein and increased phosphorylation levels. In Tet/HD94 mice striatum, mutant huntingtin transgene shutdown reestablished STEP expression. In conclusion, the STEP pathway is severely downregulated in the presence of mutant huntingtin and may participate in compensatory mechanisms activated by striatal neurons that lead to resistance to excitotoxicity.

γ-Aminobutyric acid type B receptor changes in the rat striatum and substantia nigra following intrastriatal quinolinic acid lesions.

Changes in the regional distribution of the metabotropic GABA type B receptors (GABA(B)) were investigated in a rat model of Huntington's disease. Animals received a unilateral intrastriatal injection of quinolinic acid (QA), and GABA(B) immunoreactivity was monitored 3, 11, and 21 days postinjection in the striatum and substantia nigra (SN). Two antibodies, recognizing either the GABA(B1) or the GABA(B2) receptor subtypes, were used. QA injection rapidly induced a protracted increase in GABA(B1) or GABA(B2) immunoreactivity in the lesioned striatum, despite the neuronal loss. In the SN, a continuous increase in GABA(B1) and GABA(B2) immunoreactivity was observed at all time points in the ipsilateral pars reticulata (SNr), whereas the pars compacta (SNc) was unaffected by this phenomenon. This increase was supported by a densitometric analysis. At day 21 postlesion induction, intensely labeled stellate cells and processes were found in the ipsilateral SNr, in addition to immunoreactive neurons. Double labeling of GABA(B1) and glial fibrillary acidic protein (GFAP) showed that the stellate cells were reactive astrocytes. Hence, part of the sustained increase in GABA(B) immunoreactivity that takes place in the SNr and possibly the striatum may be ascribed to reactive astrocytes. It is suggested that GABA(B) receptors are up-regulated in these reactive astrocytes and that agonists might influence the extent of this astroglial reaction.

BDNF regulation under GFAP promoter provides engineered astrocytes as a new approach for long-term protection in Huntington's disease.

Brain-derived neurotrophic factor (BDNF) is the main candidate for neuroprotective therapeutic strategies for Huntington's disease. However, the administration system and the control over the dosage are still important problems to be solved. Here we generated transgenic mice overexpressing BDNF under the promoter of the glial fibrillary acidic protein (GFAP) (pGFAP-BDNF mice). These mice are viable and have a normal phenotype. However, intrastriatal administration of quinolinate increased the number of reactive astrocytes and enhanced the release of BDNF in pGFAP-BDNF mice compared with wild-type mice. Coincidentally, pGFAP-BDNF mice are more resistant to quinolinate than wild-type mice, suggesting a protective effect of astrocyte-derived BDNF. To verify this, we next cultured astrocytes from pGFAP-BDNF and wild-type mice for grafting. Wild-type and pGFAP-BDNF-derived astrocytes behave similarly in nonlesioned mice. However, pGFAP-BDNF-derived astrocytes showed higher levels of BDNF and larger neuroprotective effects than the wild-type ones when quinolinate was injected 30 days after grafting. Interestingly, mice grafted with pGFAP-BDNF astrocytes showed important and sustained behavioral improvements over time after quinolinate administration as compared with mice grafted with wild-type astrocytes. These findings show that astrocytes engineered to release BDNF can constitute a therapeutic approach for Huntington's disease.

Protective effect of rofecoxib and nimesulide against intra-striatal quinolinic acid-induced behavioral, oxidative stress and mitochondrial dysfunctions in rats.

Role of cyclooxygenase (COX) enzyme has been well documented in both physiological and pathological conditions. COX-1 and COX-2 converts arachidonic acid into prostaglandins. Non-selective inhibition of COXs produces undesirable effects, whereas selective COX-2 inhibition produces protective effects in various inflammatory diseases. Recently, cyclooxygenase (COX) inhibitors have been implicated as a neuroprotectant in the treatment of various neurodegenerative diseases. Quinolinic acid is an endogenous excitotoxin that causes neurotoxicity in diverse areas of the brain and produces motor dysfunction. Present study is an attempt to investigate the possible role of COX inhibitors (selective COX-2 inhibitor and preferential COX-2 inhibitors) against quinolinic acid-induced behavioral, oxidative stress and mitochondrial enzyme complex alterations in rats. Intra-striatal administration of quinolinic acid (300 nmol) caused significant reduction in body weight (9%), motor in-coordination, oxidative damage [increased MDA (100%), nitrite concentration (195%), depleted SOD (71%), catalase levels (70%)] and alteration in mitochondrial enzyme complex activity (decreased complex I (50%), II (50%) and IV(62%)) as compared to sham operated animals. Chronic treatment with rofecoxib (10 and 20 mg/kg, p.o.) and nimesulide (10 and 20mg/kg, p.o.) significantly attenuated quinolinic acid-induced behavioral and biochemical alterations as compared to quinolinic acid 300 nmol treated group. Further, rofecoxib (10, 20 mg/kg) and nimesulide (20 mg/kg) significantly restored mitochondrial enzyme complex activities in striatum as compared to quinolinic acid 300 nmol treated group. Present study highlights the therapeutic potential of cyclooxygenase inhibitors against quinolinic acid induced neurotoxicity.

Slowed progression in models of Huntington disease by adipose stem cell transplantation.

OBJECTIVE: Adipose-derived stem cells (ASCs) are readily accessible and secrete multiple growth factors. Here, we show that ASC transplantation rescues the striatal pathology of Huntington disease (HD) models. METHODS: ASCs were isolated from human subcutaneous adipose tissue. In a quinolinic acid (QA)-induced rat model of striatal degeneration, human ASCs (1 million cells) were transplanted into the ipsilateral striatal border immediately after the QA injection. In 60-day-old R6/2 mice transgenic for HD, ASCs (0.5 million cells) were transplanted into each bilateral striata. In in vitro experiments, we treated mutant huntingtin gene-transfected cerebral neurons with ASC-conditioned media. RESULTS: In the QA model, human ASCs reduced apomorphine-induced rotation behavior, lesion volume, and striatal apoptosis. In R6/2 transgenic mice, transplantation of ASCs improved Rota-Rod performance and limb clasping, increased survival, attenuated the loss of striatal neurons, and reduced the huntingtin aggregates. ASC-transplanted R6/2 mice expressed elevated levels of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) and reactive oxygen defense enzymes and showed activation of the Akt/cAMP-response element-binding proteins. ASC-conditioned media decreased the level of N-terminal fragments of mutant huntingtin and associated apoptosis, and increased PGC-1alpha expression. INTERPRETATION: Collectively, ASC transplantation slowed striatal degeneration and behavioral deterioration of HD models, possibly via secreted factors.

Impact of co administration of selenium and quinolinic acid in the rat's brain.

The effect of two different doses (1 microg and 50 microg Se/100 g body wt) of selenium on quinolinic acid toxicity was investigated in rat's brain. Male albino rats were maintained for 60 days as follows: (1) control group (normal diet), (2) Quinolinic acid group (55 microg/100 g body wt)/day, (3) high dose selenium (50 microg/100 g body wt)/day, (4) high dose selenium ((50 microg/100 g body wt) + Quinolinic acid (55 microg/100 g body wt)/day (5) low dose selenium (1 microg/100 g body wt)/day and (6) low dose selenium (1 microg/100 g body wt) + Quinolinic acid (55 microg/100 g body wt)/day. Results revealed that quinolinic acid intake lead to an increase in the oxidative stress as evidenced by decreased activity of antioxidant enzymes (SOD, catalase and GR), increased amount of lipid peroxidation products (MDA,HP and CD) and free fatty acids compared to control group. Co administration of selenium at a dose of 1 microg/100 g body wt along with quinolinic acid had reduced the oxidative stress induced by quinolinic acid and it also led to a change in the brain architecture as evidenced by the decreased activity of acetyl cholinesterase and decreased concentration of neurotransmitters. Histopathological studies revealed that selenium at a dose of 1 microg was more effective in reducing the oxidative stress and higher dose of selenium was toxic.

Pre-surgical training ameliorates orbitofrontal-mediated impairments in spatial reversal learning.

We recently reported that orbitofrontal cortical (OFC) lesions impaired reversal learning of an instrumental two-lever spatial discrimination task, a deficit manifested as increased perseveration on the pre-potent response. Here we examine whether exposure to reversal learning test pre-operatively may have a beneficial effect for future reversal learning of OFC-lesioned animals. Rats were trained on a novel instrumental two-lever spatial discrimination and reversal learning task, measuring both 'cognitive flexibility' and constituent processes including response inhibition. Both levers were presented, only one of which was reinforced. The rat was required to respond on the reinforced lever under a fixed ratio 3 schedule of reinforcement. Following attainment of criterion, two reversals were introduced. Rats were then matched according to their reversal performance and subjected to bilateral excitotoxic OFC lesions. Following recovery, a series of four reversals was presented. OFC lesions impaired neither retention nor reversal phases. These data, together with the previously reported reversal deficit following OFC lesions, suggest that OFC is not needed when task experience has been gained but it is necessary when task demands are relatively high.

Effect of quinolinic acid-induced lesions of the subthalamic nucleus on performance on a progressive-ratio schedule of reinforcement: a quantitative analysis.

UNLABELLED: The subthalamic nucleus (STN), a major relay in the indirect striatofugal pathway, plays an important role in extrapyramidal motor control. Recent evidence indicates that it may also be involved in regulating the incentive value of food reinforcers. OBJECTIVE: To examine the effect of lesions of the STN on performance on a progressive-ratio schedule using a quantitative model that dissociates effects of interventions on motor and motivational processes [Killeen PR. Mathematical principles of reinforcement. Behav Brain Sci 1994;17:105-72]. Rats with bilateral quinolinic acid-induced lesions of the STN (n=14) or sham lesions (n=14) were trained to press a lever for food-pellet reinforcers under a progressive-ratio schedule. In Phase 1 (90 sessions) the reinforcer was one pellet; in Phase 2 (30 sessions) it was two pellets; in Phase 3 (30 sessions) it was again one pellet. RESULTS: The performance of both groups conformed to the model of progressive-ratio schedule performance. The motor parameter, delta, was significantly higher in the STN-lesioned than the sham-lesioned group, reflecting lower overall response rates in the lesioned group. The motivational parameter, a, was significantly higher in the STN-lesioned group than in the sham-lesioned group, consistent with enhanced reinforcer value in the STN-lesioned group compared to the sham-lesioned group. In both groups, a was sensitive to changes in reinforcer size, being significantly greater under the two-pellet condition (Phase 2) than under the one-pellet condition (Phases 1 and 3). The results suggest that destruction of the STN impairs response capacity and enhances the incentive value of food reinforcers.