Systemic overexpression of the alpha 1B-adrenergic receptor in mice: an animal model of epilepsy

PURPOSE: A lack of selective alpha1-adrenergic receptor (alpha1-ARs) agonists and antagonists has made it difficult to clarify the precise function of these receptors in the CNS. We recently generated transgenic mice that overexpress either wild-type or a constitutively active mutant alpha 1B-AR in tissues that normally express the receptor. Both wild-type and mutant mice showed an age-progressive neurodegeneration with locomotor impairment and probable stress-induced motor events, which can be partially reversed by alpha 1-AR antagonists. We hypothesized that the wild-type and mutant mice may exhibit spontaneous epileptogenicity as compared with normal (nontransgenic) mice. METHODS: Normal, wild-type, and mutant mice were studied. Twenty mice (1 year old) underwent prolonged video-EEG monitoring over a 4-week period. Raw EEG data were blindly analyzed by visual inspection for the presence of interictal and ictal epileptic activities. RESULTS: During the acute postoperative period (< or = 3 days), both wild-type (26.1 +/- 8.07 spikes/day) and mutant mice (116.87 +/- 55.13) exhibited more frequent interictal spikes than did normal mice (2.17 +/- 0.75; p value, <0.05), but all three groups showed EEG and clinical seizures. During the later monitoring periods (>3 days), wild-type and mutant mice showed more frequent interictal spikes (15.44 +/- 4.07; p < 0.01; and 6.05 +/- 2.46; p < 0.05, respectively) as compared with normal mice (0.41 +/- 0.41), but only mutant mice had spontaneous clinical seizures (means +/- SEM). CONCLUSIONS: The selective overexpression of the alpha 1B-AR is associated with increased in vivo spontaneous interictal epileptogenicity and EEG/behavioral seizures. These results suggest a possible role (direct or indirect) for the alpha 1B-ARs in the development and expression of epileptogenicity.     

Pathogenic Potential of Eomesodermin-Expressing T-Helper Cells in Neurodegenerative Diseases

Eomesodermin-expressing (Eomes⁺) T-helper (Th) cells show cytotoxic characteristics in secondary progressive multiple sclerosis. We found that Eomes⁺ Th cell frequency was increased in the peripheral blood of amyotrophic lateral sclerosis and Alzheimer's disease patients. Furthermore, granzyme B production by Th cells from such patients was high compared with controls. A high frequency of Eomes⁺ Th cells was observed in the initial (acutely progressive) stage of amyotrophic lateral sclerosis, and a positive correlation between Eomes⁺ Th cell frequency and cognitive decline was observed in Alzheimer's disease patients. Therefore, Eomes⁺ Th cells may be involved in the pathology of amyotrophic lateral sclerosis and Alzheimer's disease. ANN NEUROL 2024;95:1093–1098     

Intraoperative dorsal language network mapping by using single‐pulse electrical stimulation

The preservation of language function during brain surgery still poses a challenge. No intraoperative methods have been established to monitor the language network reliably. We aimed to establish intraoperative language network monitoring by means of cortico‐cortical evoked potentials (CCEPs). Subjects were six patients with tumors located close to the arcuate fasciculus (AF) in the language‐dominant left hemisphere. Under general anesthesia, the anterior perisylvian language area (AL) was first defined by the CCEP connectivity patterns between the ventrolateral frontal and temporoparietal area, and also by presurgical neuroimaging findings. We then monitored the integrity of the language network by stimulating AL and by recording CCEPs from the posterior perisylvian language area (PL) consecutively during both general anesthesia and awake condition. High‐frequency electrical stimulation (ES) performed during awake craniotomy confirmed language function at AL in all six patients. Despite an amplitude decline (≤32%) in two patients, CCEP monitoring successfully prevented persistent language impairment. After tumor removal, single‐pulse ES was applied to the white matter tract beneath the floor of the removal cavity in five patients, in order to trace its connections into the language cortices. In three patients in whom high‐frequency ES of the white matter produced naming impairment, this “eloquent” subcortical site directly connected AL and PL, judging from the latencies and distributions of cortico‐ and subcortico‐cortical evoked potentials. In conclusion, this study provided the direct evidence that AL, PL, and AF constitute the dorsal language network. Intraoperative CCEP monitoring is clinically useful for evaluating the integrity of the language network. Hum Brain Mapp 35:4345–4361, 2014. © 2014 Wiley Periodicals, Inc .     

Superoxide dismutase-like immunoreactivity in spheroids in Hallervorden-Spatz disease

Iron accumulation in the basal ganglia and spheroid formation are pathological hallmarks of Hallervorden-Spatz disease (HS). Since an overaccumulation of iron (iron thesaurosis) that exceeds the binding capacity of ferritin could cause oxidative damage, we studied the possible role of oxidative stress in the pathogenesis of HS. The basal ganglia and spinal cord from patients with HS were investigated at autopsy, using histochemistry for iron and immunohistochemistry for Cu/Zn superoxide dismutase (SOD1), Mn superoxide dismutase (SOD2) and ferritin. SOD1-like immunoreactivity (IR), SOD2-IR and ferritin-IR occurred frequently in spheroids observed in the basal ganglia, and associated iron accumulation indicated the possible existence of increased oxidative stress in HS patients. Spheroids in the spinal cord showed intense SOD1-IR and SOD2-IR in HS, in sharp contrast with the occasional weak SOD1-IR and SOD2-IR observed in spheroids from patients with amyotrophic lateral sclerosis (ALS). Neither increased ferritin-IR nor iron accumulation were observed in spinal spheroids from HS and ALS patients. These data may suggest that, at least in the spinal cord, SOD1-IR and SOD2-IR in spheroids in HS patients do not result from oxidative stress directly related to iron accumulation. Received: 15 March 1996 / Revised accepted: 15 July 1996     

Effect of inhaled beclomethasone dipropionate on peroxynitrite inhibitory activity in induced sputum from asthmatic patients

STUDY OBJECTIVES: We recently found that peroxynitrite inhibitory activity in induced sputum was significantly lower in asthmatic patients than in normal control subjects. Current guidelines recommend inhaled corticosteroids as first-line control therapy in asthma. Therefore, this study was designed to examine the effect of inhaled beclomethasone dipropionate (BDP) on peroxynitrite inhibitory activity in induced sputum from asthmatic patients. DESIGN: Interventional study. SETTING: University hospital. PATIENTS: Twenty-one asthmatic patients and 10 age-matched, normal control subjects. INTERVENTIONS: Inflammatory indexes in induced sputum were examined in all study subjects, and peroxynitrite inhibitory activity was also assayed by monitoring rhodamine formation. For 8 weeks after the first sputum induction, BDP 400 microg bid, was administered to all asthmatic patients and sputum induction was repeated. MEASUREMENTS AND RESULTS: Nitrite and nitrate levels in induced sputum were significantly higher in asthmatic patients (1,121 micro mol/L [SD, 205 micro mol/L], p < 0.0001) than in normal control subjects (642 micromol/L [SD, 137 micromol/L]). In contrast, peroxynitrite inhibitory activity in induced sputum was significantly lower in asthmatic patients (50.0% [SD, 25.7%], p < 0.0001) than in normal control subjects (93.0% [SD, 3.6%]). After 8 weeks of BDP therapy, nitrite and nitrate levels were significantly decreased (847 micromol/L [SD, 143 micromol/L], p < 0.0001) and peroxynitrite inhibitory activity was increased (73.9% [SD, 19.2%], p = 0.0005). Moreover, the increase in peroxynitrite inhibitory activity from before to after BDP therapy was significantly correlated with decrease in nitrite and nitrate levels (r = 0.79, p = 0.0004). We also found the significant relationship between increase in peroxynitrite inhibitory activity in induced sputum and increase in FEV(1) percentage of predicted after BDP therapy (r = 0.68, p = 0.0023). CONCLUSIONS: Large amounts of peroxynitrite, which are exaggerated in acute asthma attacks, might overwhelm endogenous antioxidant defenses. However, inhaled corticosteroid therapy enhanced antioxidant activity against peroxynitrite, and therefore might reduce the susceptibility to peroxynitrite-induced injury in asthmatic airways.     

Increased levels of vascular endothelial growth factor in induced sputum in asthmatic patients

BACKGROUND: Vascular endothelial growth factor (VEGF) is highly expressed in the airway of asthmatic patients. As VEGF increases airway vascular permeability, consequent thickening of the airway wall mucosa may lead to narrowing of the airway lumen. OBJECTIVE: We evaluated the relationship between VEGF levels in induced sputum and eosinophilic inflammatory profiles, and the degree of airway vascular permeability in asthmatic patients and we evaluated the effect of inhaled corticosteroids on VEGF levels in induced sputum. METHODS: Induced sputum specimens were obtained from 28 glucocorticosteroids free asthmatics and 11 healthy control subjects. We examined VEGF levels and airway vascular permeability index in induced sputum. After the initial sputum induction, 21 asthmatics received 8-week inhaled beclomethasone dipropionate (BDP, 800 micro g/day) therapy, then sputum induction was repeated. RESULTS: The VEGF levels in asthmatics were significantly higher than in healthy control subjects (P < 0.0001). The VEGF levels were negatively correlated with forced expiratory volume of 1 s (FEV1, % predicted, r = - 0.68, P < 0.001), the percentage of eosinophils (r = 0.51, P < 0.01) and ECP levels (r = 0.39, P < 0.05). Moreover, the VEGF levels were significantly correlated with airway vascular permeability index (r = 0.61, P < 0.001). After 8-week inhaled BDP therapy, the VEGF levels were significantly decreased compared to pretreatment levels (P < 0.0001) and the VEGF levels were significantly correlated with airway vascular permeability index even in post-treatment asthmatics (r = 0.62, P < 0.01). CONCLUSION: The VEGF levels in induced sputum were increased in asthmatics and its levels were associated with degree of airway narrowing and airway vascular permeability. These findings provide strong evidence that VEGF may play an important role in the pathogenesis of bronchial asthma.     

Neurotoxicity of an endogenous brain amine, 1-benzyl-1,2,3,4-tetrahydroisoquinoline,in organotypic slice co-culture of mesencephalon and striatum

Organotypic slice co-culture of the ventromedial portion of the mesencephalon and striatum was used to evaluate the neurotoxicity of 1-benzyl-1,2,3,4-tetrahydroisoquinoline, an endogenous brain amine related to Parkinson's disease. 1-Benzyl-1,2,3,4-tetrahydroisoquinoline is specifically increased in the cerebrospinal fluid of patients with Parkinson's disease and induces parkinsonian features in the monkey and mouse. Here, it decreased the dopamine content of the cultured mesencephalon in both dose- (10-100 microM) and time- (24 h to 7 days) dependent manners. This result suggests that the neurotoxicity of 1-benzyl-1,2,3,4-tetrahydroisoquinoline is correlated with the overall exposure (concentration multiplied by exposure time). Culture with 100 microM 1-benzyl-1,2,3,4-tetrahydroisoquinoline for 24 h irreversibly reduced the dopamine content. Furthermore, culture with 100 microM 1-benzyl-1,2,3,4-tetrahydroisoquinoline for 10 days caused morphological changes, including cell body shrinkage and distortion of dendritic morphology, in tyrosine hydroxylase-positive cells in the mesencephalon and reduced the number of cells by half. The increase in lactate dehydrogenase activity in the media produced by 1-benzyl-1,2,3,4-tetrahydroisoquinoline was significant in culture of the mesencephalon alone or its co-culture with striatum, but not in cultures of other brain regions. We suggest that 1-benzyl-1,2,3,4-tetrahydroisoquinoline is toxic to tyrosine hydroxylase-positive cells in the ventral mesencephalon and that it is correlated with the integral of the concentration by time of exposure. Thus a low concentration of 1-benzyl-1,2,3,4-tetrahydroisoquinoline may first induce a decrease in the dopamine content then shrinkage of the cell body, followed by the slow death of dopaminergic neurons over a long period. This is the first report that indicates 1-benzyl-1,2,3,4-tetrahydroisoquinoline exerts neurotoxicity at the cellular level, and reveals in part the character of its neurotoxicity.     

Aquaporin-1 and -5 are involved in the invasion and proliferation of soft tissue sarcomas

Background and aim

Recent studies of several carcinomas have reported that aquaporin possesses novel oncogenic properties. The aim of this study was to clarify the involvement of aquaporin-1 and ?5 in the proliferation, invasion and metastasis of soft tissue sarcomas.