Tatsuaki Watanabe

Histamine levels and clonic convulsions of electrically-induced seizure in mice: the effects of α-fluoromethylhistidine and metoprine

SummaryThe purpose of this study was to investigate the possible role of the central histaminergic neuron system in electrically-induced seizure in mice. For this purpose, we examined the effects of intraperitoneal (i. p.) injections of histaminergic agents, such as l-histidine, metoprine, and α-fluoromethylhistidine (FMH), on electrically-induced seizure. l-Histidine decreased the duration of clonic convulsion in electrically-induced seizure, but not affected that of tonic convulsion. This effect of l-histidine was antagonized by pretreatment with FMH, indicating that it was due to histamine formed by decarboxylation of l-histidine in the central nervous system. The anticonvulsive effect of l-histidine was also reduced by the H1-antagonist pyrilamine, but not by the H2-antagonist zolantidine, indicating that the effect on electrically-induced seizure is mediated through central H1-receptors. Metoprine, which increased the histamine levels in the cerebral cortex, diencephalon and midbrain of mice, decreased the duration of clonic convulsions dose-dependently. Conversely, FMH, which decreased the brain histamine levels, increased the duration of clonic convulsions. Good inverse correlations were found between the duration of clonic convulsions and brain histamine levels, especially in the diencephalon: the histamine levels were inversely proportional to the duration of clonic convulsions. No correlation was found between the duration of tonic convulsions and brain histamine levels. These results suggest that the histaminergic neuron system is important in inhibition of the duration of clonic convulsion on electrically induced seizure in mice.

Effects of histamine agents on methamphetamine-induced stereotyped behavior and behavioral sensitization in rats

Abstract In this study, effects of histamine (HA) agents on methamphetamine (METH)-induced stereotyped behavior and behavioral sensitization were examined in rats. Pretreatment with a precursor of HA, L-histidine (750 mg/kg), significantly inhibited the METH (3 mg/kg)-induced stereotyped behavior, whereas pretreatment with an inhibitor of HA synthesis, α-fluoromethylhistidine (FMH) (100 mg/kg), an H1 antagonist pyrilamine (5 mg/kg) or an H2 antagonist zolantidine (5 mg/kg) enhanced it. The inhibitory effect of L-histidine on METH-induced stereotyped behavior was significantly blocked by coadministration of pyrilamine and zolantidine, indicating that the effect is mediated through H1 and H2 receptors. Moreover, chronic treatment with METH (3 mg/kg) significantly enhanced stereotyped behavior at the rechallenge with METH (1 mg/kg). Chronic treatment with L-histidine (750 mg/kg) plus METH inhibited the METH-induced argumentation of stereotyped behavior, while that with FMH (100 mg/kg), pyrilamine (5 mg/kg) or zolantidine (5 mg/kg) potentiated it. These findings suggest that the HA neuron system has an inhibitory role in METH-induced stereotyped behavior and behavioral sensitization.

Angiogenesis Inhibitor Vasohibin-1 Enhances Stress Resistance of Endothelial Cells via Induction of SOD2 and SIRT1

Vasohibin-1 (VASH1) is isolated as an endothelial cell (EC)-produced angiogenesis inhibitor. We questioned whether VASH1 plays any role besides angiogenesis inhibition, knocked-down or overexpressed VASH1 in ECs, and examined the changes of EC property. Knock-down of VASH1 induced premature senescence of ECs, and those ECs were easily killed by cellular stresses. In contrast, overexpression of VASH1 made ECs resistant to premature senescence and cell death caused by cellular stresses. The synthesis of VASH1 was regulated by HuR-mediated post-transcriptional regulation. We sought to define the underlying mechanism. VASH1 increased the expression of (superoxide dismutase 2) SOD2, an enzyme known to quench reactive oxygen species (ROS). Simultaneously, VASH1 augmented the synthesis of sirtuin 1 (SIRT1), an anti-aging protein, which improved stress tolerance. Paraquat generates ROS and causes organ damage when administered in vivo. More VASH1 (+/−) mice died due to acute lung injury caused by paraquat. Intratracheal administration of an adenovirus vector encoding human VASH1 augmented SOD2 and SIRT1 expression in the lungs and prevented acute lung injury caused by paraquat. Thus, VASH1 is a critical factor that improves the stress tolerance of ECs via the induction of SOD2 and SIRT1.

The nuclear factor erythroid 2-related factor 2 activator oltipraz attenuates chronic hypoxia-induced cardiopulmonary alterations in mice.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator that activates many antioxidant enzymes. Oxidative stress, which accumulates in diseased lungs associated with pulmonary hypertension (PH), is thought to be responsible for the progression of cardiopulmonary changes. To test whether Nrf2 activation would exert therapeutic efficacy against cardiopulmonary changes in a hypoxia-induced PH model, wild-type (WT) and Nrf2-deficient mice as well as Kelch-like ECH associating protein 1 (Keap1) (negative regulator of Nrf2) knockdown mutant mice were exposed to hypobaric hypoxia for 3 weeks. This chronic hypoxia exacerbated right ventricular systolic pressure, right ventricular hypertrophy (RVH), and pulmonary vascular remodeling in the WT mice. These pathological changes were associated with aberrant accumulation of Tenascin-C, a disease-indicative extracellular glycoprotein. Simultaneous administration of oltipraz, a potent Nrf2 activator, significantly attenuated RVH and pulmonary vascular remodeling and concomitantly ameliorated Tenascin-C accumulation in the hypoxic mice. Hypoxia-exposed Nrf2-deficient mice developed more pronounced RVH than WT mice, whereas hypoxia-exposed Keap1-knockdown mice showed less RVH and pulmonary vascular remodeling than WT mice, underscoring the beneficial potency of Nrf2 activity against PH. We also demonstrated that expression of the Nrf2-regulated antioxidant enzymes was decreased in a patient with chronic obstructive pulmonary disease associated with PH. The decreased antioxidant enzymes may underlie the pathogenesis of cardiopulmonary changes in the patient with chronic obstructive pulmonary disease and PH. The pharmacologically or genetically induced Nrf2 activity clearly decreased RVH and pulmonary vascular remodeling in the hypoxic PH model. The efficacy of oltipraz highlights a promising therapeutic potency of Nrf2 activators for the prevention of PH in patients with hypoxemic lung disease.

Opioid μ-deficient CXBK mouse and the role of μ1-receptors in electrically induced convulsions

Abstract Studies were made on the role of μ1-receptors on electrically induced convulsions in mice. A relatively selective μ1-agonist, DAGO ([ d -Ala 2 -N- methyl-Phe 4 - Gly-ol]-enkephalin ) decreased the durations of tonic and clonic convulsions in C57BL/6 mice, but not in opioid μ-deficient CXBK mice, indicating that the activation of μ1-rreceptors had an anticonvulsive effect on these convulsions in mice. The selective μ1-antagonists naloxonazine and naltrexonazine promoted the clonic phase of electrically induced convulsion in C57BL/6 mice. Moreover, the duration of the clonic phase was longer in μ-deficient CXBK mice than in C57BL/6 mice. These data for CXBK mice confirmed, at least some proconvulsant effects of μ1-antagonists in C57BL/6 mice. Thus, blockade of μ1-receptors has a proconvulsant effect, and μ1-receptors have at least some protective role against electrically induced convulsions.

A potent anti-angiogenic factor, vasohibin-1, ameliorates experimental bronchiolitis obliterans.

BACKGROUND Bronchiolitis obliterans (BO) is a major cause of morbidity and mortality after lung transplantation. BO is pathologically characterized by neovascularized fibro-obliteration of the allograft airway. A recent study has shown that aberrant angiogenesis during fibro-obliteration contributes to the pathogenesis of BO. Vasohibin-1 (VASH1) has been isolated as a vascular endothelial growth factor-inducible gene in endothelial cells (ECs) that inhibits migration and proliferation of ECs and exhibits anti-angiogenic activity in vivo. PURPOSE This study examines whether VASH1 inhibits fibro-obliteration of the allograft in a murine intrapulmonary tracheal transplantation model. METHOD Tracheal allografts of BALB/c mouse were transplanted into the left lung of recipient C57BL/6J mouse. We performed gene transfer to the recipient lungs using an adenovirus vector encoding human VASH1 (Ad-VASH1) or beta- garactosidase (Ad-LacZ) as the control. Tracheal allografts were harvested and pathological on days 21 and 28. RESULT Ad-VASH1 treatment reduced the vascular area on day 21 (4.6% versus 13.0%, P = .037) and day 28 (5.4% versus 13.4%, P = .022) compared with the control group. This was accompanied by significantly inhibited luminal obliteration of the tracheal allografts in the animals transferred with Ad-VASH1 compared with the control (69% versus 93%, P = .028) on day 21. We were not able to observe this effect on day 28 (92% versus 97%, P = .48). CONCLUSION Transgene expression of VASH1 in the recipient lung significantly attenuated luminal obliteration of the tracheal allograft; this was associated with significantly reduced aberrant angiogenesis in the fibro-obliterative tissue in a murine model intrapulmonary tracheal transplantation.

Histamine H1 receptor binding capacities in the amygdalas of the amygdaloid kindled rat.

Abstract: The histamine H1 receptor binding capacity of the amygdalas of amygdaloid kindled rats was studied. In the kindled nonstimulated amygdala, significant decreases in KD and Bmax values compared with those of control amygdala were found 1 week after the last kindled seizure. One month after the last kindled seizure, the decreased KD value was sustained in the kindled nonstimulated amygdala. This decreased Bmax value 1 week after the last kindled seizure in nonstimulated amygdala may partly and transiently contribute to kindled seizure susceptibility. The decreased KD value in nonstimulated amygdala observed until 1 month after the last kindled seizure indicates the long‐lasting increment of binding affinity of the pyrilamine binding site of the histamine H1 receptor in the steady state of kindled seizure susceptibility.

Resection of Apical Lung Carcinoma Involving the Vertebral Artery

We report a patient with left apical lung carcinoma involving the left subclavian artery with the origin of the vertebral artery who had hypoplasia of the right vertebral artery and the bilateral posterior communicating arteries. After induction chemoradiotherapy, a vein graft was used to create a bypass between the left common carotid artery and the vertebral artery, followed by a successful left upper lobectomy with combined resection of the subclavian artery together with the left vertebral artery. Because anatomic variations of vertebral arteries and cerebral arterial circle are known, preoperative evaluation of the cerebral blood flow should be performed and a relevant reconstruction considered.

MOTOR BEHAVIOURAL FUNCTION FOR HISTAMINE-DOPAMINE INTERACTION IN BRAIN

Motor behavioural function for histamine-dopamine interaction in brain K. Onodera, C. Itoh, M. Sato and T. Watanabe Department of Pharmacology, Tohoku University School of Dentistry, Seiryo-machi 4-1, Aoba-ku, Sendai 980-77, Japan, Fax +81 22 263 9867 Department of Psychiatry, Tohoku University School of Medicine, Seiryo-machi 1-1, Sendai, Japan Department of Pharmacology I, Tohoku University School of Medicine, Seiryo-machi 2-1, Sendai, Japan

Medical consultant system for improving lung transplantation opportunities and outcomes in Japan.

Because the shortage of donor organs is especially serious in Japan, since 2002 a unique partnership between transplant consultant physicians and local physicians has been developed to maximize the organ utilization rate. Since 2011, more than 25 lung consultant physicians have been registered to specifically assess donor lungs and provide advice on intensive respiratory care to donors. In this study, we retrospectively reviewed the efficacy of this system for lung transplantation opportunities and outcomes. One hundred eighty-seven brain-dead lung donor candidates were chronologically divided into 3 phases: I (May 1998-November 2006) and II (December 2006-January 2011), before and after medical consultants requested that local physicians administer aggressive bronchial suctioning using bronchoscopy, respectively; and phase III (February 2011-January 2013), after the emergence of lung consultants. The lung utilization rate, Pao2/Fio2 ratio at the first and second brain death examinations and at the tertiary assessment before recovery, and graft survival were analyzed. The lung utilization rate was significantly higher in phases II and III than in phase I. In phases I and II, the Pao2/Fio2 ratio at the tertiary assessment was significantly lower than that at the first or the second brain death examination, whereas it did not worsen with time in phase III. Graft survival was significantly better in phases II and III than in phase I. Graft death due to primary graft dysfunction was significantly more frequent in phase I than in phases II and III. In conclusion, this system is effective in improving lung transplantation opportunities and outcomes.