Neurodegeneration In Rat Brain Research Articles

Exogenous monosodium glutamate exacerbates lipopolysaccharide-induced neurobehavioral deficits, oxidative damage, neuroinflammation, and cholinergic dysfunction in rat brain

Extensive experimental evidence points to neuroinflammation and oxidative stress as major pathogenic events that initiate and drive the neurodegenerative process. Monosodium glutamate (MSG) is a widely used food additive in processed foods known for its umami taste-enhancing properties. However, concerns about its potential adverse effects on the brain have been raised. Thus, the present study investigated the impact of MSG on lipopolysaccharide (LPS)-induced neurotoxicity in rat brains. Wistar rats weighing between 180 g and 200 g were randomly allocated into four groups: control (received distilled water), MSG (received 1.5 g/kg/day), LPS (received 250 µg/kg/day), and LPS + MSG (received LPS, 250 µg/kg, and MSG, 1.5 g/kg). LPS was administered intraperitoneally for 7 days while MSG was administered orally for 14 days. Our results showed that MSG exacerbated LPS-induced impairment in locomotor and exploratory activities in rats. Similarly, MSG exacerbated LPS-induced oxidative stress as evidenced by increased levels of malondialdehyde (MDA) with a concomitant decrease in levels of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and glutathione-s-transferase (GST) in the brain tissue. In addition, MSG potentiated LPS-induced neuroinflammation, as indicated by increased levels of pro-inflammatory cytokines such as interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) as well as myeloperoxidase (MPO) and nitric oxide (NO) in the brain. Moreover, MSG aggravated LPS-induced cholinergic dysfunction, as demonstrated by increased activity of acetylcholinesterase (AChE) in the brain. Further, we found a large number of degenerative neurons widespread in hippocampal CA1, CA3 regions, cerebellum, and cortex according to H&E staining. Taken together, our findings suggest that MSG aggravates LPS-induced neurobehavioral deficits, oxidative stress, neuroinflammation, cholinergic dysfunction, and neurodegeneration in rat brains.

Protective effect of gui zhi (Ramulus Cinnamomi) on abnormal levels of four amino acid neurotransmitters by chronically ma huang (Herb Ephedra) intoxicated prefrontal cortex in rats treated with a ma huang-gui zhi herb pair.

The Herb Ephedra (Ma Huang in Chinese)-Ramulus Cinnamomi (Gui Zhi in Chinese) herb pair is a classic traditional Chinese herb pair used to treat asthma, nose and lung congestion, and fever with anhidrosis. In previous study, we found that chronic administration of ma huang induced obvious neurodegeneration in rat brains, with the prefrontal cortex showing the greatest effect. Gui zhi decreased hyperactivity produced by repeated ma huang administration, and attenuated oxidative stress in rat prefrontal cortex induced by ma huang. The study was aimed to investigate the protective effect of gui zhi on ma huang-induced abnormal levels of four amino acid neurotransmitters in rat prefrontal cortex. All ma huang and ma huang-gui zhi herb pair extracts were prepared using methods of traditional Chinese medicine and were normalized based on the ephedrine content. Two-month-old male Sprague-Dawley rats (6 rats/group) were administered ma huang or ma huang-gui zhi herb pair extracts for 1, 3, 5 or 7 days (ephedrine=48mg/kg). The contents of ephedrine, glutamate (Glu), aspartic acid (Asp), glycine (Gly), and gamma-aminobutyric acid (GABA) in the prefrontal cortex were determined using ultra-high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) at 0.5, 1.0, 5.0h after administration. Ma huang significantly enhanced the levels of GABA, Gly, Glu and Asp in the prefrontal cortex, while gui zhi partially abolished the effects. Ma huang-induced neurotoxicity may be associated with its effects on amino acid neurotransmitters. Gui zhi is a promising neuroprotective agent against for ma huang-induced neurotoxicity. The information presented in this study will help supplement the available data for future ma huang-gui zhi herb pair compatibility studies.

A possible relationship between telomere length and markers of neurodegeneration in rat brain after welding fume inhalation exposure

Inhalation of welding fume (WF) can result in the deposition of toxic metals, such as manganese (Mn), in the brain and may cause neurological changes in exposed workers. Alterations in telomere length are indicative of cellular aging and, possibly, neurodegeneration. Here, we investigated the effect of WF inhalation on telomere length and markers of neurodegeneration in whole brain tissue in rats. Male Fischer-344 (F-344) rats were exposed by inhalation to stainless steel WF (20 mg/m3 x 3 h/d x 4 d/wk x 5 wk) or filtered air (control). Telomere length, DNA-methylation, gene expression of Trf1, Trf2, ATM, and APP, protein expression of p-Tau, α-synuclein, and presenilin 1 and 2 were assessed in whole brain tissue at 12 wk after WF exposure ended. Results suggest that WF inhalation increased telomere length without affecting telomerase in whole brain. Moreover, we observed that components of the shelterin complex, Trf1 and Trf2, play an important role in telomere end protection, and their regulation may be responsible for the increase in telomere length. In addition, expression of different neurodegeneration markers, such as p-Tau, presenilin 1-2 and α-synuclein proteins, were increased in brain tissue from the WF-exposed rats as compared to control. These findings suggest a possible correlation between epigenetic modifications, telomere length alteration, and neurodegeneration because of the presence of factors in serum after WF exposure that may cause extra-pulmonary effects as well as the translocation of potentially neurotoxic metals associated with WF to the central nervous system (CNS). Further studies are needed to investigate the brain region specificity and temporal response of these effects.

Rapamycin Confers Neuroprotection Against Aging-Induced Oxidative Stress, Mitochondrial Dysfunction, and Neurodegeneration in Old Rats Through Activation of Autophagy.

Brain aging is an intricate and natural phenomenon exclusively characterized by oxidative stress, accumulation of oxidatively damaged macromolecules, and alterations in structure and function of neurons that further increase the risk factor for most of the neurodegenerative diseases. In addition, age-dependent defective autophagy has also been implicated to favor the pathogenesis and prevalence of the neurological diseases. Therefore, the development of strategies that delay aging and the concomitant neurological disorders remain elusive. Thus, the present study was undertaken to investigate the effect of rapamycin-induced activation of autophagy on aging-related oxidative stress, cell death, neuroinflammation, and neurodegeneration in rat brain. Our data demonstrated the significant age-related oxidative stress, apoptotic cell death, elevated inflammatory response, and reduced level of markers associated with rejuvenation and neural integrity, including the activities of ion channel transporters (Na+/K+-ATPase and Ca2+-ATPase) and acetylcholinesterase in the brain of old aged rats. Furthermore, rapamycin (0.5 mg/kg b.w. for 28 days) induced activation of autophagy provided significant protection to aging rat brain by reducing the aging-induced oxidative stress, apoptotic cell death, and markers of neurodegeneration. Thus, our data confirmed that autophagy plays a pivotal role in delaying brain aging plausibly by maintaining the cellular homeostasis, and structural and functional integrity of cells in the brain.

N-acetyl-l-cysteine attenuates oxidative damage and neurodegeneration in rat brain during aging.

N-acetyl-l-cysteine (NAC) is a precursor of cysteine, which is known to increase the level of glutathione (GSH) in the brain. Several neurodegenerative changes linked to oxidative stress take place in the aging brain. This study aimed to assess the neuroprotective effect of NAC supplementation on age-dependent neurodegeneration in the rat brain. Young (4 months) and old (24 months) Wistar rats (n = 6 rats/group) were supplemented with NAC (100 mg/kg b.w. orally) for 14 days. Enzymatic and nonenzymatic antioxidants such as superoxide dismutase and catalase, and GSH and total thiol respectively, prooxidants such as protein carbonyl, advanced oxidation protein products, reactive oxygen species, and malondialdehyde were assessed in the brain homogenates. Furthermore, nitric oxide level, acetylcholinesterase activity, and Na+/K+-ATPase activity were measured and gene expression studies were also performed. The results indicated that NAC augmented the level of enzymatic and nonenzymatic antioxidants with a significant reduction in prooxidant levels in old rats. NAC supplementation also downregulated the expression of inflammatory markers (TNF-α, IL-1β, IL-6) and upregulated the expression of marker genes associated with aging (sirtuin-1) and neurodegeneration (neuron-specific enolase, neuroglobin, synapsin-I, myelin basic protein 2) in old rats. The present findings support a neuroprotective role of NAC which has therapeutic implication in controlling age-related neurological disorders.

Fisetin as a caloric restriction mimetic protects rat brain against aging induced oxidative stress, apoptosis and neurodegeneration

AimIn the present study, attempts have been made to evaluate the potential role of fisetin, a caloric restriction mimetic (CRM), for neuroprotection in D-galactose (D-gal) induced accelerated and natural aging models of rat. Main methodsFisetin was supplemented (15mg/kg b.w., orally) to young, D-gal induced aged (D-gal 500mg/kg b.w subcutaneously) and naturally aged rats for 6weeks. Standard protocols were employed to measure pro-oxidants, antioxidants and mitochondrial membrane potential in brain tissues. Gene expression analysis with reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to assess the expression of autophagy, neuronal, aging as well as inflammatory marker genes. We have also evaluated apoptotic cell death and synaptosomal membrane-bound ion transporter activities in brain tissues. Key findingsOur data demonstrated that fisetin significantly decreased the level of pro-oxidants and increased the level of antioxidants. Furthermore, fisetin also ameliorated mitochondrial membrane depolarization, apoptotic cell death and impairments in the activities of synaptosomal membrane-bound ion transporters in aging rat brain. RT-PCR data revealed that fisetin up-regulated the expression of autophagy genes (Atg-3 and Beclin-1), sirtuin-1 and neuronal markers (NSE and Ngb), and down-regulated the expression of inflammatory (IL-1β and TNF-α) and Sirt-2 genes respectively in aging brain. SignificanceThe present study suggests that fisetin supplementation may provide neuroprotection against aging-induced oxidative stress, apoptotic cell death, neuro-inflammation, and neurodegeneration in rat brain.

Effect of caffeine, caffeic acid and their various combinations on enzymes of cholinergic, monoaminergic and purinergic systems critical to neurodegeneration in rat brain—In vitro

Caffeine and caffeic acid are two bioactive compounds that are present in plant foods and are major constituent of coffee, cocoa, tea, cola drinks and chocolate. Although not structurally related, caffeine and caffeic acid has been reported to elicit neuroprotective properties. However, their different proportional distribution in food sources and possible effect of such interactions are not often taken into consideration. Therefore, in this study, we investigated the effect of caffeine, caffeic acid and their various combinations on activities of some enzymes [acetylcholinesterase (AChE), monoamine oxidase (MAO) ecto-nucleoside triphosphate diphosphohydrolase (E-NTPase), ecto-51-nucleotidase (E-NTDase) and Na+/K+ ATPase relevant to neurodegeneration in vitro in rat brain. The stock concentration of caffeine and caffiec acid and their various proportional combinations were prepared and their interactions with the activities of these enzymes were assessed (in vitro) in different brain structures. The Fe2+ and Cu2+ chelating abilities of the samples were also investigated. The results revealed that caffeine, caffeic acid and their various combinations exhibited inhibitory effect on activities of AChE, MAO, E-NTPase and E-NTDase, but stimulatory effect on Na+/K+ ATPase activity. The combinations also exhibited Fe2+ and Cu2+ chelating abilities. Considering the various combinations, a higher caffeine to caffeic acid ratio produced significantly highest enzyme modulatory effects; these were significantly lower to the effect of caffeine alone but significantly higher than the effect of caffeic acid alone. These findings may provide new insight into the effect of proportional combination of these bioactive compounds as obtained in many foods especially with respect to their neuroprotective effects.

The investigation of the prenatal and postnatal alcohol exposure-induced neurodegeneration in rat brain: protection by betaine and/or omega-3.

We aim to study the effect of neurodegeneration on the brain of rat pups caused by prenatal and postnatal ethanol exposure with modified liquid diet to elucidate protective effects of betaine and omega-3 supplementation. When ethanol is consumed during prenatal and postnatal periods, it may result in fetal alcohol syndrome (FAS) in the offspring. Rats were divided into control, ethanol, ethanol + betaine, ethanol + omega-3, ethanol + omega-3 + betaine groups. The effect of betaine and omega-3 in response to ethanol-induced changes on the brain, by biochemical analyses cytochrome c, caspase-3, calpain, cathepsin B and L, DNA fragmentation, histological and morfometric methods were evaluated. Caspase-3, calpain, cathepsin B, and cytochrome c levels in ethanol group were significantly higher than control. Caspase-3, calpain levels were decreased in ethanol + betaine, ethanol + omega-3, and ethanol + omega-3 + betaine groups compared to ethanol group. Cathepsin B in ethanol + omega-3 + betaine group was decreased compared to ethanol, ethanol + betaine groups. Cathepsin L and DNA fragmentation were found not statistically significant. We found similar results in histological and morfometric parameters. We found that pre- and postnatal ethanol exposure is capable of triggering necrotic cell death in rat brains, omega-3, and betaine reduce neurodegeneration. Omega-3 and betaine may prove beneficial for neurodegeneration, particularly in preventing FAS.

Arsenic induced oxidative stress and mitochondrial dysfunction in rat brain

The present study was undertaken to reveal the effects of chronic arsenic exposure (25ppm intragastrically for 12 weeks) on mitochondrial functions and oxidative stress in male Wister rats. Chronic arsenic exposure resulted in decrease in the activities of the mitochondrial complexes. There was increased generation of ROS followed by decrease in MnSOD activity. The generation of oxidative stress was associated with increased protein oxidation and lipid peroxidation in rat brain as evident by FTIR spectra. The RT-PCR analysis of NRF 1, NRF 2 and PGC 1α revealed decrease in gene expression suggesting decreased biogenesis following chronic exposure in rat brain. Thus, the findings of the present study reveal that arsenic induced decrease in mitochondrial biogenesis may be responsible for the decreased metabolic response that may be further involved in the generation of oxidative stress and neurodegeneration in rat brain.

The role of neuroinflammation in α-synuclein-linked dopaminergic neurodegeneration in rat brain

Event Abstract Back to Event The role of neuroinflammation in α-synuclein-linked dopaminergic neurodegeneration in rat brain Anke Van Der Perren1*, Francesca Macchi1, James Dooley2, Adrian Liston2, Chris Van Den Haute1 and Veerle Baekelandt1 1 KU Leuven, Neurosciences, Belgium 2 KU Leuven, Department of Microbiology and Immunology, Belgium Alpha-synuclein (α-SYN) is considered a key player in Parkinson’s disease (PD), but the exact relationship between α-SYN aggregation and dopaminergic (DA) neurodegeneration remains unresolved. There is increasing evidence that neuroinflammatory processes are closely linked to DA cell death, but whether the inflammatory process is causally involved in PD or rather reflects secondary consequences of nigrostriatal pathway injury is still under debate. We have recently shown that treatment of rats overexpressing α-SYN in the substantia nigra by means of adeno-associated viral vectors serotype 2/7 (rAAV2/7 A53T α-SYN) with the immunosuppressant FK506 for four weeks significantly increased the survival of dopaminergic neurons (DNs) in the substantia nigra (SN) in a dose-dependent way. In order to further understand this process, we investigated in detail the inflammatory component versus α-SYN aggregation and neurodegeneration by histopathological and FACS analysis, motor behavior and non-invasive PET imaging. No reduction in α-synuclein aggregation was apparent in this time window but FK506 significantly lowered the infiltration of CD4+ and CD8+ T-cells and the number of microglia/ macrophages, suggesting an early role for α-SYN and neuroinflammation in PD pathogenesis. Next, to determine whether T-cell infiltration is causally involved in or simply a consequence of the observed DN degeneration, we are currently comparing the effect of α-SYN overexpression in the SN of rats lacking mature T-cells (FoxN1nu/nu) and their wild type littermates (FoxN1nu/+). In conclusion, a better understanding of the exact role of neuroinflammation in α-SYN-linked DA neurodegeneration will contribute to the development of novel therapeutic strategies for PD. Acknowledgements Research was funded by the IWT-Vlaanderen (IWT SBO/80020), the FWO Vlaanderen (G.0768.10), the Academische Stichting Leuven, by the EC-FP6 program ‘DiMI’ (LSHB-CT-2005-512146), the FP7 RTD project MEFOPA (HEALTH-2009-241791), the FP7 program ‘INMiND’ (HEALTH-F2-2011-278850), the KU Leuven (IOF-KP/07/001, OT/08/052A, IMIR PF/10/017), and the MJFox Foundation (Target validation 2010). Keywords: Neuroinflammation, animal model, T-cells, Parkinson's disease, alpha-Synuclein Conference: 11th National Congress of the Belgian Society for Neuroscience, Mons, Belgium, 22 May - 22 May, 2015. Presentation Type: Oral or Poster presentation Topic: Neuroscience Citation: Van Der Perren A, Macchi F, Dooley J, Liston A, Van Den Haute C and Baekelandt V (2015). The role of neuroinflammation in α-synuclein-linked dopaminergic neurodegeneration in rat brain. Front. Neurosci. Conference Abstract: 11th National Congress of the Belgian Society for Neuroscience. doi: 10.3389/conf.fnins.2015.89.00042 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 30 Apr 2015; Published Online: 05 May 2015. * Correspondence: PhD. Anke Van Der Perren, KU Leuven, Neurosciences, Leuven, Belgium, anke.vanderperren@med.kuleuven.be Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Anke Van Der Perren Francesca Macchi James Dooley Adrian Liston Chris Van Den Haute Veerle Baekelandt Google Anke Van Der Perren Francesca Macchi James Dooley Adrian Liston Chris Van Den Haute Veerle Baekelandt Google Scholar Anke Van Der Perren Francesca Macchi James Dooley Adrian Liston Chris Van Den Haute Veerle Baekelandt PubMed Anke Van Der Perren Francesca Macchi James Dooley Adrian Liston Chris Van Den Haute Veerle Baekelandt Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Tributyltin induces oxidative damage, inflammation and apoptosis via disturbance in blood–brain barrier and metal homeostasis in cerebral cortex of rat brain: An in vivo and in vitro study

Tributyltin (TBT), a member of the organotin family, is primarily used for its biocidal activity. Persistent environmental levels of TBT pose threat to the ecosystem. Since neurotoxic influence of TBT remains elusive, we therefore, studied its effect on cerebral cortex of male Wistar rats. A single oral dose of Tributyltin-Chloride (TBTC) (10, 20, 30mg/kg) was administered and the animals were sacrificed on day 3 and day 7. Blood–brain barrier permeability remained disrupted significantly till day 7 with all the doses of TBTC. Pro-oxidant metal levels (Fe, Cu) were increased with a concomitant decrease in Zn. ROS generation was substantially raised resulting in oxidative damage (increased protein carbonylation and lipid peroxidation) with marked decline in tissue antioxidant status (GSH/GSSG levels). Protein expression studies indicated astrocyte activation, upregulation of inflammatory molecules (IL-6, Cox-2 and NF-κB) and simultaneous elevation in the apoptotic index (Bax/Bcl2). Neurodegeneration was evident by reduced neurofilament expression and increased calpain cleaved Tau levels.The in-vitro study demonstrated involvement of calcium and signaling molecules (p38), with downstream activation of caspase-3 and -8, and apoptotic cell death was evident by nuclear fragmentation, DNA laddering and Annexin V binding experiments. Ca2+ inhibitors (BAPTA-AM, EGTA, and RR) and free radical scavengers (NAC and biliprotein [C-PC]) increased cell viability (MTT assay), signifying specific roles of Ca2+ and ROS. Significance of p38 signaling was evaluated on pro-apoptotic proteins by using SB203580, a selective p38 inhibitor. Our data collectively illustrates that TBTC can disrupt BBB, induce oxidative stress, cause cell death and initiate neurodegeneration in rat brain.

Activation of Trim17 by PPARγ is involved in Di(2-ethylhexyl) phthalate (DEHP)-induced apoptosis on Neuro-2a cells

Di-(2-ethylhexyl) phthalate (DEHP) is widely used as a plasticizer in plastics. Its reproductive toxicity and teratogenic effects are well known. DEHP can cause liver damage and peroxisome proliferation, as well as carcinogenesis. Animal study has shown that DEHP causes neurodegeneration in rat brain. Prenatal exposure to DEHP disrupts brain development and decreases brain weight in rats. But its mechanism of action in the brain is not clear. This study used a neuroblastoma cell line, Neuro-2a cells, to investigate the toxic effect of DEHP. The results revealed that DEHP inhibits cell proliferation, activate caspase-3, induce apoptosis in a dose and time dependent manner, and activate expression of the PPARγ and Trim17 protein. Administration of the PPARγ agonist (troglitazone) enhanced DEHP-induced Trim17 protein expression and this enhancement could be reversed by the PPARγ antagonist (GW9662). These results suggest that DEHP activates the Trim17 protein via PPARγ leading to cleavage pro-caspase-3 and apoptosis. This finding may account for the central nervous system toxicity of DEHP and implies DEHP can impair fetal brain development.

Cerebral Metabolism in Brains of Rats Infected with Neuropathogenic Murine Leukemia Viruses

Friend murine leukemia virus A8 and PVC211 cause spongiform neurodegeneration in rat brains. Glutamate is an important neurotransmitter synthesized from alpha-ketoglutaric acid, an intermediate product of the citric acid cycle, and glutamine is synthesized from glutamate. To examine the brain metabolism of rats infected with neuropathogenic viruses, the amount of glutamate and glutamine in the brains of rats infected with A8, PVC211, and non-neuropathogenic 57 was measured using high performance liquid chromatography, and the (13)C-label incorporation into the C4 position of glutamate and glutamine from [1-(13)C] glucose was measured with (13)C nuclear magnetic resonance. In the cerebral hemisphere and region containing the brain stem and basal ganglia of rats infected with A8 and PVC211 at 8-9 weeks post-infection (wpi), the amount of glutamine was decreased compared with the 57-infected rats. The amount of glutamate was decreased in the cerebral hemisphere of the A8-infected rats and the region containing the brain stem and basal ganglia of PVC211-infected rats at 8-9 wpi. The amount of [4-(13)C] glutamine and [4-(13)C] glutamate in the cerebral hemisphere and region containing the brain stem and basal ganglia of rats infected with A8 and PVC211 at 8-9 wpi was equivalent to that of the 57-infected rats. These results suggest that in the brains of rats infected with neuropathogenic viruses, de novo synthesis of glutamate and glutamine is not decreased, but the ability to maintain quantitative levels of glutamate and glutamine is decreased compared with the brains of rats infected with non-neuropathogenic virus.

Studies on the neuroprotective effect of the enantiomers of AR-A008055, a compound structurally related to clomethiazole, on MDMA ("ecstasy")-induced neurodegeneration in rat brain.

3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") administration produces neurotoxic degeneration of 5-HT nerve endings in several regions of rat brain. Administration of the GABAmimetic drug clomethiazole protects against this damage. We wished to see whether the enantiomers of AR-A008055 (1-4-methyl-5-thiazolyl-1-phenyl-methylamine), a compound structurally related to clomethiazole, were also neuroprotective against MDMA-induced degeneration. (R)-(+)-AR-A008055 or (S)-(-)-AR-A008055 (100 mg/kg IP) was injected 5 min prior to and 55 min after MDMA (15 mg/kg IP) administration to Dark Agouti rats. Rectal temperature was measured during this time and the concentration of 5-HT and 5-HIAA measured in hippocampus, cortex and striatum 7 days later. [3H]-Paroxetine binding was also measured in cortex. Both enantiomers abolished the acute MDMA-induced hyperthermia and attenuated the subsequent neurotoxic loss of 5-HT, 5-HIAA and [3H]-paroxetine binding. When rats given the enantiomer plus MDMA were warmed to keep their rectal temperature elevated to near that of animals given only MDMA, the neuroprotective effect of (S)-(-)-AR-A008055 was still seen, while the effect of (R)-(+)-AR-A008055 was abolished. Protection was also seen when (S)-(-)-AR-A008055 (50 mg/kg) was given, a dose which produced only a modest attenuation of MDMA-induced hyperthermia. The current data suggest that a major proportion of the neuroprotective action of (S)-(-)-AR-A008055 did not involve an attenuating effect on MDMA-induced hyperthermia. The protection afforded by (R)-(+)-AR-A008055, which is not a GABA agonist, appears to be solely due to its action on body temperature, strengthening the contention that abolishing the acute MDMA-induced hypothermia can produce neuroprotection. Since (S)-(-)-AR-A008055 has a similar pharmacology to clomethiazole, these data suggest that drugs which increase GABAA receptor channel opening are neuroprotective against MDMA-induced damage.

Deltamethrin induces delayed apoptosis and altered expression of p53 and bax in rat brain

Our previous work indicates that deltamethrin induces degeneration and apoptosis in rat brain at 24 and 48 h after treatment. To determine whether molecular characteristics of apoptosis is involved in neurodegeneration in rat brain after deltamethrin treatment, we investigated the effects of deltamethrin on the mRNA expression of p53 and bax and their correlation with deltamethrin-induced apoptotic cell death in rat brain. Hematoxylin-eosin and cresyl violet staining revealed numerous degenerative cells in cortex and hippocampus at 5 and 24 h after deltamethrin treatment. Apoptotic cells were detected in cortex and hippocampus of treated rats at 24 h by in situ end labeling, whereas no apoptotic cells were observed in the same brain regions at 5 h after treatment. By using in situ hybridization, it was demonstrated that the increase of p53 and bax mRNA levels appeared at 5 and also at 24 h after treatment. The alterations in mRNA expression of p53 and bax preceded the occurrence of delayed apoptotic cell death in the same brain regions after deltamethrin treatment. These results indicate that (1) deltamethrin induces delayed apoptotic cell death, which may play an important role in deltamethrin-elicited neurodegeneration; (2) deltamethrin leads to the persistent increase of p53 and bax mRNA levels, which may contribute to delayed apoptosis in rat brain following deltamethrin treatment.

Melatonin suppresses iron-induced neurodegeneration in rat brain

The antioxidative action of melatonin on iron-induced neurodegeneration in the nigrostriatal dopaminergic system was evaluated in vivo. Intranigral infusion of iron chronically degenerated the dopaminergic transmission of the nigrostriatal system. An increase in lipid peroxidation in the infused substantia nigra and reductions in dopamine levels and dopaminergic terminals in the ipsilateral striatum were observed 7 d after iron infusion. Whereas local infusion of melatonin (60 μg/μl, 1 μl) alone did not alter dopaminergic transmission, coinfusion of melatonin with iron suppressed iron-induced oxidative damages. Systemic infusion of melatonin via osmotic pumps had no effect on iron-induced neurodegeneration. However, repetitive intraperitoneal injections of melatonin (10 mg/kg) prevented iron-induced oxidative injuries. The ratio of glutathione (GSH)/oxidized glutathione (GSSG) was moderately increased in the lesioned substantia nigra of the melatonin-treated rats compared to that of the lesioned group in control rats. The antioxidative effect of melatonin was verified in cortical homogenates. Melatonin dose-dependently suppressed autoxidation and iron-induced lipid peroxidation. Melatonin was as effective as GSH and was less effective than Trolox (a water-soluble analogue of vitamin E) in inhibiting iron-elevated lipid peroxidation of brain homogenates. Our data suggest that melatonin is capable of at least partially preventing the iron-induced neurodegeneration in the nigrostriatal dopaminergic system.

Application of magnetic resonance imaging to the measurement of neurodegeneration in rat brain: MRI data correlate strongly with histology and enzymatic analysis

Focal brain ischemia was induced by middle cerebral artery occlusion in the rat. The volume of cerebral damage was determined 2 days later by MRI in vivo and in the same animals histologically. The edema volume as measured by MRI and the histologically determined infarction was highly correlated. As a consequence, the neuroprotective effect of the N-methyl- d-aspartate (NMDA) receptor antagonists CGP 40116 and MK 801 were similar with both methods. Excitotoxic neurodegeneration in the rat striatum was induced by direct injection of quinolinic acid. The degree of damage was evaluated in vivo 1 day later by quantitative MRI, and 7 days later by measuring the activities of neuronal marker enzymes choline acetyltransferase and glutamic acid decarboxylase. Striatal damage assessed using the three approaches was highly correlated. Cerebroprotective efficacy of the NMDA receptor antagonist CGP 40116 was indistinguishable based on all methods. MRI was more reproducible than the enzymatic methods and was faster and simpler than histologic examination for routine analysis of excitotoxic damage and cerebroprotection in vivo in a pharmaceutical research environment.