OBJECTIVE: Sequelae of behavioral impairments associated with human traumatic brain injury (TBI) include neurobehavioral problems. We compared exploratory, cognitive, and depressive-like behaviors in pediatric and adult male mice exposed to controlled cortical impact (CCI).METHODS: Pediatric (21 to 25 days old) and adult (8 to 12 weeks old) male C57Bl/6 mice underwent CCI at a 2-mm depth of deflection. Hematoxylin and eosin staining was performed 3 to 7 days after recovery from CCI, and injury volume was analyzed using ImageJ. Neurobehavioral characterization after CCI was performed using the Barnes maze test (BMT), passive avoidance test, open-field test, light/dark test, tail suspension test, and rotarod test. Acutely and subacutely (3 and 7 days after CCI, respectively), CCI mice showed graded injury compared to sham mice for all analyzed deflection depths.RESULTS: Time-dependent differences in injury volume were noted between 3 and 7 days following 2-mm TBI in adult mice. In the BMT, 2-mm TBI adults showed spatial memory deficits compared to sham adults (P < 0.05). However, no difference in spatial learning and memory was found between sham and 2-mm CCI groups among pediatric mice. The open-field test, light/dark test, and tail suspension test did not reveal differences in anxiety-like behaviors in both age groups.CONCLUSION: Our findings revealed a graded injury response in both age groups. The BMT was an efficient cognitive test for assessing spatial/non-spatial learning following CCI in adult mice; however, spatial learning impairments in pediatric mice could not be assessed.
Adult ; Animals ; Brain Injuries ; Eosine Yellowish-(YS) ; Hematoxylin ; Hindlimb Suspension ; Humans ; Learning ; Male ; Memory ; Mice ; Rotarod Performance Test ; Spatial Learning ; Spatial Memory

Parkinson's disease is a neurodegenerative disease characterized by the progressive loss of dopaminergic neurons within the substantia nigra pars compacta. In the present study, we investigated whether β-Lapachone (β-LAP), a natural naphthoquinone compound isolated from the lapacho tree (Tabebuia avellanedae), elicits neuroprotective effects in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease mouse model. β-LAP reduced the tyrosine hydroxylase (TH)-immuno-reactive fiber loss induced by MPTP in the dorsolateral striatum, and alleviated motor dysfunction as determined by the rotarod test. In addition, β-LAP protected against MPTP-induced loss of TH positive neurons, and upregulated B-cell lymphoma 2 protein (Bcl-2) expression in the substantia nigra. Based on previous reports on the neuroprotective role of nuclear factor-E2-related factor-2 (Nrf2) in neurodegenerative diseases, we investigated whether β-LAP induces upregulation of the Nrf2-hemeoxygenae-1 (HO-1) signaling pathway molecules in MPTP-injected mouse brains. Western blot and immunohistochemical analyses indicated that β-LAP increased HO-1 expression in glial fibrillary acidic protein-positive astrocytes. Moreover, β-LAP increased the nuclear translocation and DNA binding activity of Nrf2, and the phosphorylation of upstream adenosine monophosphate-activated protein kinase (AMPK). β-LAP also increased the localization of p-AMPK and Nrf2 in astrocytes. Collectively, our data suggest that β-LAP exerts neuroprotective effect in MPTP-injected mice by upregulating the p-AMPK/Nrf2/HO-1 signaling pathways in astrocytes.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ; Adenosine ; Animals ; Astrocytes ; Blotting, Western ; Brain ; DNA ; Dopaminergic Neurons ; Lymphoma, B-Cell ; Mice ; Neurodegenerative Diseases ; Neurons ; Neuroprotection ; Neuroprotective Agents ; Parkinson Disease ; Pars Compacta ; Phosphorylation ; Protein Kinases ; Rotarod Performance Test ; Substantia Nigra ; Trees ; Tyrosine 3-Monooxygenase ; Up-Regulation

BACKGROUND: The use of aroma oils dates back to at least 3000 B.C., where it was applied to mummify corpses and treat the wounds of soldiers. Since the 1920s, the term “aromatherapy” has been used for fragrance therapy with essential oils. The purpose of this study was to determine whether the essential oil of Eucalyptus (EOE) affects pain pathways in various pain conditions and motor coordination. METHODS: Mice were subjected to inhalation or intraperitoneal injection of EOE, and its analgesic effects were assessed by conducting formalin, thermal plantar, and acetic acid tests; the effects of EOE on motor coordination were evaluated using a rotarod test. To determine the analgesic mechanism, 5′-guanidinonaltrindole (κ-opioid antagonist, 0.3 mg/kg), naltrindole (δ-opioid antagonist, 5 mg/kg), glibenclamide (δ-opioid antagonist, 2 mg/kg), and naloxone (μ-opioid antagonist, 4, 8, 12 mg/kg) were injected intraperitoneally. RESULTS: EOE showed an analgesic effect against visceral pain caused by acetic acid (EOE, 45 mg/kg); however, no analgesic effect was observed against thermal nociceptive pain. Moreover, it was demonstrated that EOE did not have an effect on motor coordination. In addition, an anti-inflammatory effect was observed during the formalin test. CONCLUSIONS: EOE, which is associated with the μ-opioid pain pathway, showed potential effects against somatic, inflammatory, and visceral pain and could be a potential therapeutic agent for pain.
Acetic Acid ; Analgesics ; Animals ; Aromatherapy ; Cadaver ; Eucalyptus ; Formaldehyde ; Glyburide ; Humans ; Inhalation ; Injections, Intraperitoneal ; Mice ; Military Personnel ; Naloxone ; Narcotic Antagonists ; Nociceptive Pain ; Oils ; Oils, Volatile ; Pain Measurement ; Rotarod Performance Test ; Visceral Pain ; Wounds and Injuries

Vacuolar protein sorting-associated protein 13B (VPS13B), also known as COH1, is one of the VPS13 family members which is involved in transmembrane transport, Golgi integrity, and neuritogenesis. Mutations in the VPS13B gene are associated with Cohen syndrome and other cognitive disorders such as intellectual disabilities and autism spectrum disorder (ASD). However, the patho-physiology of VPS13B-associated cognitive deficits is unclear, in part, due to the lack of animal models. Here, we generated a Vps13b exon 2 deletion mutant mouse and analyzed the behavioral phenotypes. We found that Vps13b mutant mice showed reduced activity in open field test and significantly shorter latency to fall in the rotarod test, suggesting that the mutants have motor deficits. In addition, we found that Vps13b mutant mice showed deficits in spatial learning in the hidden platform version of the Morris water maze. The Vps13b mutant mice were normal in other behaviors such as anxiety-like behaviors, working memory and social behaviors. Our results suggest that Vps13b mutant mice may recapitulate key clinical symptoms in Cohen syndrome such as intellectual disability and hypotonia. Vps13b mutant mice may serve as a useful model to investigate the pathophysiology of VPS13B-associated disorders.
Animals ; Autism Spectrum Disorder ; Cognition Disorders ; Exons ; Humans ; Intellectual Disability ; Learning Disorders ; Memory, Short-Term ; Mice ; Models, Animal ; Muscle Hypotonia ; Phenotype ; Rotarod Performance Test ; Social Behavior ; Spatial Learning ; Water

OBJECTIVE: To evaluate the effects of electric cortical stimulation (ECS) and transcranial direct current stimulation (tDCS) on motor and cognitive function recovery and brain plasticity in focal traumatic brain injury (TBI) of rats model. METHODS: Forty rats were pre-trained to perform a single pellet reaching task (SPRT), rotarod test (RRT), and Y-maze test for 14 days, then a focal TBI was induced by a weight drop model on the motor cortex. All rats were randomly assigned to one of the three groups: anodal ECS (50 Hz and 194 μs) (ECS group), tDCS (0.1 mA, 50 Hz and 200 μs) (tDCS group), and no stimulation as a control group. Four-week stimulation, including rehabilitation, was started 3 days after the operation. SPRT, RRT, and Y-maze were measured from day 1 to day 28 after the TBI was induced. Histopathological and immunohistochemistry staining evaluations were performed at 4 weeks. RESULTS: SPRT was improved from day 7 to day 26 in ECS, and from day 8 to day 26 in tDCS compared to the control group (p < 0.05). SPRT of ECS group was significantly improved on days 3, 8, 9, and 17 compared to the tDCS group. Y-maze was improved from day 8 to day 16 in ECS, and on days 6, 12, and 16 in the tDCS group compared to the control group (p < 0.05). Y-maze of the ECS group was significantly improved on day 9 to day 15 compared to the tDCS group. The c-Fos protein expression was better in the ECS group and the tDCS group compared to the control group. CONCLUSION: Electric stimulation in rats modified with a focal TBI is effective for motor recovery and brain plasticity. ECS induced faster behavioral and cognitive improvements compared to tDCS during the recovery period of rats with a focal TBI.
Animals ; Brain ; Brain Injuries* ; Cognition ; Electric Stimulation ; Immunohistochemistry ; Motor Cortex ; Plastics ; Rats* ; Recovery of Function ; Rehabilitation ; Rotarod Performance Test ; Transcranial Direct Current Stimulation*

OBJECTIVE: The current study aimed to elucidate the effect of vanillin on behavioral changes, oxidative stress, and histopathological changes induced by potassium bromate (KBrO3), an environmental pollutant, in the cerebellum of adult mice. METHODS: The animals were divided into four groups: group 1 served as a control, group 2 received KBrO3, group 3 received KBrO3 and vanillin, and group 4 received only vanillin. We then measured behavioral changes, oxidative stress, and molecular and histological changes in the cerebellum. RESULTS: We observed significant behavioral changes in KBrO3-exposed mice. When investigating redox homeostasis in the cerebellum, we found that mice treated with KBrO3 had increased lipid peroxidation and protein oxidation in the cerebellum. These effects were accompanied by decreased Na+-K+ and Mg2+ ATPase activity and antioxidant enzyme gene expression when compared to the control group. Additionally, there was a significant increase in cytokine gene expression in KBrO3-treated mice. Microscopy revealed that KBrO3 intoxication resulted in numerous degenerative changes in the cerebellum that were substantially ameliorated by vanillin supplementation. Co-administration of vanillin blocked the biochemical and molecular anomalies induced by KBrO3. CONCLUSION Our results demonstrate that vanillin is a potential therapeutic agent for oxidative stress associated with neurodegenerative diseases.
Animals ; Antioxidants ; metabolism ; Behavior, Animal ; drug effects ; Benzaldehydes ; pharmacology ; Bromates ; toxicity ; Cerebellum ; drug effects ; metabolism ; pathology ; Cytokines ; genetics ; metabolism ; Environmental Pollutants ; toxicity ; Gene Expression ; drug effects ; Lipid Peroxidation ; drug effects ; Mice ; Oxidative Stress ; drug effects ; Rotarod Performance Test

PURPOSE: Traumatic brain injury (TBI) is a significant cause of morbidity and mortality worldwide. Severity of the initial insult is one of the most significant factors affecting outcome following TBI. In order to investigate the mechanisms of cellular injury and develop novel therapeutic strategies for TBI, we designed a standardized animal TBI model and evaluated histological and functional outcomes according to the degree of impact severity. METHODS: Male adult C57Bl/6 mice underwent controlled cortical impact (CCI) at varying depths of deflection (1.0-2.0 mm). We performed hematoxylin and eosin staining at 7 days after recovery from TBI. Neurobehavioral characterization after TBI was analyzed by the Barnes maze test, passive avoidance test, open field test, rotarod test, tail suspension test, and light/dark test. RESULTS: We observed a graded injury response according to the degree of deflection depths tested (diameter, 3 mm; velocity, 3 m/s; and duration, 500 ms) compared to sham controls. In the Barnes maze test, the severe TBI (2 mm depth) group showed reduced spatial memory as compared with the sham and mild TBI (1 mm depth) groups at 7 days after TBI. There was a significant difference in the results of the open field test and light/dark test among the three groups. CONCLUSION: Our findings demonstrate that the graded injury responses following TBI resulted in differential histopathological and behavioral outcomes in a mouse experimental CCI model. Thus, a model of CCI with histologic/behavioral outcome analysis may offer a reliable and convenient design for preclinical TBI research involving mice.
Adult* ; Animals ; Brain Injuries* ; Eosine Yellowish-(YS) ; Hematoxylin ; Hindlimb Suspension ; Humans ; Male ; Mice* ; Mortality ; Neurobehavioral Manifestations ; Rotarod Performance Test ; Spatial Memory

OBJECTIVE: The purpose of this study was to evaluate the effects of localized brain cooling on blood-brain barrier (BBB) permeability following transient middle cerebral artery occlusion (tMCAO) in rats, by using dynamic contrast-enhanced (DCE)-MRI. MATERIALS AND METHODS: Thirty rats were divided into 3 groups of 10 rats each: control group, localized cold-saline (20℃) infusion group, and localized warm-saline (37℃) infusion group. The left middle cerebral artery (MCA) was occluded for 1 hour in anesthetized rats, followed by 3 hours of reperfusion. In the localized saline infusion group, 6 mL of cold or warm saline was infused through the hollow filament for 10 minutes after MCA occlusion. DCE-MRI investigations were performed after 3 hours and 24 hours of reperfusion. Pharmacokinetic parameters of the extended Tofts-Kety model were calculated for each DCE-MRI. In addition, rotarod testing was performed before tMCAO, and on days 1-9 after tMCAO. Myeloperoxidase (MPO) immunohisto-chemistry was performed to identify infiltrating neutrophils associated with the inflammatory response in the rat brain. RESULTS: Permeability parameters showed no statistical significance between cold and warm saline infusion groups after 3-hour reperfusion 0.09 ± 0.01 min-1 vs. 0.07 ± 0.02 min-1, p = 0.661 for K(trans); 0.30 ± 0.05 min-1 vs. 0.37 ± 0.11 min-1, p = 0.394 for kep, respectively. Behavioral testing revealed no significant difference among the three groups. However, the percentage of MPO-positive cells in the cold-saline group was significantly lower than those in the control and warm-saline groups (p < 0.05). CONCLUSION: Localized brain cooling (20℃) does not confer a benefit to inhibit the increase in BBB permeability that follows transient cerebral ischemia and reperfusion in an animal model, as compared with localized warm-saline (37℃) infusion group.
Animals ; Behavior Rating Scale ; Blood-Brain Barrier* ; Brain* ; Infarction, Middle Cerebral Artery* ; Ischemia ; Ischemic Attack, Transient ; Magnetic Resonance Imaging* ; Middle Cerebral Artery* ; Models, Animal ; Neutrophils ; Permeability* ; Peroxidase ; Rats* ; Reperfusion ; Rotarod Performance Test

Caffeic acid phenethyl ester (CAPE), derived from honeybee hives, is a bioactive compound with strong antioxidant activity. This study was designed to test the neuroprotective effect of CAPE in 3-nitropropionic acid (3NP)-induced striatal neurotoxicity, a chemical model of Huntington's disease (HD). Initially, to test CAPE's antioxidant activity, a 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid (ABTS) antioxidant assay was employed, and CAPE showed a strong direct radical-scavenging eff ect. In addition, CAPE provided protection from 3NP-induced neuronal cell death in cultured striatal neurons. Based on these observations, the in vivo therapeutic potential of CAPE in 3NP-induced HD was tested. For this purpose, male C57BL/6 mice were repeatedly given 3NP to induce HD-like pathogenesis, and 30 mg/kg of CAPE or vehicle (5% dimethyl sulfoxide and 95% peanut oil) was administered daily. CAPE did not cause changes in body weight, but it reduced mortality by 29%. In addition, compared to the vehicle-treated group, robustly reduced striatal damage was observed in the CAPE-treated animals, and the 3NP-induced behavioral defi cits on the rotarod test were signifi cantly rescued after the CAPE treatment. Furthermore, immunohistochemical data showed that immunoreactivity to glial fibrillary acidic protein (GFAP) and CD45, markers for astrocyte and microglia activation, respectively, were strikingly reduced. Combined, these data unequivocally indicate that CAPE has a strong antioxidant eff ect and can be used as a potential therapeutic agent against HD.
Animals ; Astrocytes ; Body Weight ; Cell Death ; Dimethyl Sulfoxide ; Glial Fibrillary Acidic Protein ; Humans ; Huntington Disease ; Male ; Mice ; Microglia ; Models, Chemical ; Mortality ; Neurons ; Neuroprotective Agents* ; Rotarod Performance Test ; Urticaria

OBJECTIVEThe aim of this study was to assess the effects of yttrium nitrate on neurobehavioral development in Sprague-Dawley rats.

METHODSDams were orally exposed to 0, 5, 15, or 45 mg/kg daily of yttrium nitrate from gestation day (GD) 6 to postnatal day (PND) 21. Body weight and food consumption were monitored weekly. Neurobehavior was assessed by developmental landmarks and reflexes, motor activity, hot plate, Rota-rod and cognitive tests. Additionally, brain weights were measured on PND 21 and 70.

RESULTSNo significant difference was noted among all groups for maternal body weight and food consumption. All yttrium-exposed offspring showed an increase in body weight on PND 21; however, no significant difference in body weight for exposed pups versus controls was observed 2 weeks or more after the yttrium solution was discontinued. The groups given 5 mg/kg daily decreased significantly in the duration of female forelime grip strength and ambulation on PND 13. There was no significant difference between yttrium-exposed offspring and controls with respect to other behavioral ontogeny parameters and postnatal behavioral test results.

CONCLUSIONExposure of rats to yttrium nitrate in concentrations up to 45 mg/kg daily had no adverse effects on their neurobehavioral development.

Animals ; Dose-Response Relationship, Drug ; Environmental Pollutants ; toxicity ; Female ; Food Safety ; Male ; Maze Learning ; drug effects ; Motor Activity ; drug effects ; Pain Measurement ; drug effects ; Pregnancy ; Prenatal Exposure Delayed Effects ; chemically induced ; physiopathology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Risk Assessment ; Rotarod Performance Test ; Yttrium ; toxicity