脳虚血後神経細胞障害における小胞体ストレスの役割

近年、細胞死の原因として、従来知られていたミトコンドリア障害やDNA障害によるものとは異なる、小胞体機能の破綻（小胞体ストレス）が関与することが明らかになってきた。小胞体ストレスは、アルツハイマー病などの神経変性疾患の神経細胞死メカニズムに関与していることが示唆され、アポトーシスシグナルの新たな発信地として注目を集めている。そこで、脳虚血後神経細胞障害の病態・機序を解明するための一環として、動物脳虚血モデルにおける小胞体ストレスの役割について検討した。砂ネズミ前脳虚血モデルにおける一過性脳虚血誘発海馬CA1野選択的神経細胞死およびマウス中大脳動脈閉塞モデルにおける永久閉塞誘発神経細胞死において小胞体ストレスの関与が認められた。そこで、新規脳卒中治療薬探索のため、小胞体ストレスにより誘導される分子シャペロンBiPの選択的誘導薬（BiP inducer X: BIX）の脳保護作用について検討した。BIXは、砂ネズミ前脳虚血誘発海馬CA1野選択的神経細胞死およびマウス中大脳動脈永久閉塞誘発神経細胞死を抑制した。以上より、脳虚血後神経細胞障害の機序に小胞体ストレス誘導性アポトーシスの関与が示唆され、BiP選択的誘導薬は神経細胞保護作用を有する新規な脳卒中治療薬の候補となる可能性が示唆された。Recent studies have revealed that perturbation of endoplasmic reticulum (ER) functions, which is called ER stress, induces apoptosis. ER stress, which is caused by an accumulation of unfolded proteins in the ER lumen, is associated with neurodegenerative diseases such as Alzheimer disease. The purpose of this study was to provide new insights into the pathogenesis of brain ischemia for development of new therapeutic approaches to ischemic brain diseases. We suggest that ER stress is involved in the CA1-selective neuronal cell death and permanent middle cerebral artery occlusion (MCAO) induced cell death. Furthermore, to investigate a possible role of a selective inducer of BiP (BIX), we evaluated the neuroprotective effects of BIX against acute ischemic neuronal damage. BIX provided significant protection against CA1-selective neuronal cell death and permanent MCAO-induced cell death. In conclusion, ER stress plays an important causal role both in transient and permanent ischemic damage, and drugs which selectively induce BiP may exert a neuroprotective effect and may be a candidate of new therapeutic treatments of stroke

Generation and Characterization of Conditional Heparin-Binding EGF-Like Growth Factor Knockout Mice

Recently, neurotrophic factors and cytokines have been shown to be associated in psychiatric disorders, such as schizophrenia, bipolar disorder, and depression. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the EGF family, serves as a neurotrophic molecular and plays a significant role in the brain. We generated mice in which HB-EGF activity is disrupted specifically in the ventral forebrain. These knockout mice showed (a) behavioral abnormalities similar to those described in psychiatric disorders, which were ameliorated by typical or atypical antipsychotics, (b) altered dopamine and serotonin levels in the brain, (c) decreases in spine density in neurons of the prefrontal cortex, (d) reductions in the protein levels of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor and post-synaptic protein-95 (PSD-95), (e) decreases in the EGF receptor, and in the calcium/calmodulin-dependent protein kinase II (CaMK II) signal cascade. These results suggest the alterations affecting HB-EGF signaling could comprise a contributing factor in psychiatric disorder

Daily dose of metformin caused acute kidney injury with lactic acidosis: a case report

Abstract Background Metformin-induced lactic acidosis with acute kidney injury is rare but well known. Here we report a case of a Japanese patient taking metformin who experienced severe acute renal failure accompanied with significantly elevated metformin plasma concentrations and signs of lactic acidosis. Case presentation A 60-year-old Japanese man with type II diabetes, who was taking metformin (500 mg three times a day) along with several other medications, visited the emergency department with dizziness, malaise, and oliguria. The initial laboratory test results showed elevated levels of serum creatinine and blood urea nitrogen, although his renal function was normal approximately 2 weeks earlier. His lactate level was raised (4.27 mmol/L), and he was diagnosed with lactic acidosis. Considering the low creatinine clearance and elevated urinary albumin/serum creatinine ratio, urinary N-acetyl-β-d-glucosaminidase level, and β2-microglobulin level, the patient was further diagnosed with AKI (in other words, acute tubular necrosis). A renal biopsy performed on day 3 after admission revealed renal tubular epithelium necrosis, supporting this diagnosis. The patient underwent intermittent hemodialysis until he was discharged on day 13. The metformin concentrations on days 3, 5, and 7 were 8.95, 2.58, and 0.16 μg/mL, respectively, which is significantly higher than the maximal steady-state concentration of metformin at the recommended dosage (approximately 1 μg/mL). The calculated pharmacokinetic parameters of metformin suggested poor renal excretion and a low distribution volume at higher metformin levels. Other possible acute kidney injury-causing factors included dehydration, alcohol consumption, and the use of an angiotensin receptor blocker or SGLT2 inhibitor. Conclusions This is the first reported case of acute kidney injury possibly caused by high levels of metformin with lactic acidosis in a patient treated with the recommended metformin dose. Thus, the development of metformin-induced acute kidney injury should be considered for patients with several acute kidney injury risk factors who are taking metformin

Case report of pharmacokinetic analysis of continuous intravenous infusion of fentanyl in a patient with severe burn: burn shock stage complicates pain management

Abstract Background Fentanyl is widely used as an analgesic and sedative for patients with severe burn injuries in intensive care units. However, pharmacokinetic (PK) data for fentanyl, particularly for continuous intravenous infusion during the acute phase of burn injuries, are limited. Here, we report the clinical course and changes in blood fentanyl concentrations during the acute phase in a patient with severe burns treated with continuous intravenous infusion of fentanyl. Case presentation A woman in her 40s, with burns caused by a gas cylinder explosion, was transported to our hospital. The patient had burn wounds on face, neck, shoulders, and all four extremities, with a total burn area of 39.0%. For pain relief, the patient received a continuous infusion of 0.01 mg/mL fentanyl (20–30 µg/h) with a target blood concentration of 1.0–1.5 ng/mL, but continued to suffer from pain due to burning during the acute phase. We measured the blood fentanyl concentrations and found that all concentrations obtained during the acute phase were subtherapeutic. Notably, during the burn shock stage, blood concentrations of fentanyl were 0.50 ng/mL on day 1 and 0.66 ng/mL on day 2, indicating that the blood concentration did not rise sufficiently for the dosage. From days 0 to 2, the patient was administered a massive fluid load for burn shock. After the burn shock stage resolved, fentanyl concentrations gradually approached the target range, and the pain rating scale improved, even though the fentanyl administration rate remained unchanged (30 µg/h). Conclusions Major changes in the fluid volumes of body compartments that occur with large burns might increase the volume of fentanyl distribution, thereby lowering its concentration when a standard dose is administered. Our findings indicate that the PK of fentanyl in patients with severe burns can be substantially affected, especially during the shock phase, implying the importance of titrating analgesics for clinical efficacy in the acute phase