An Autopsy Case of Amyotrophic Lateral Sclerosis with Diaphragm Pacing.

Respiratory insufficiency is a critical problem in amyotrophic lateral sclerosis (ALS) patients. We herein present the case of an autopsied patient with sporadic ALS who underwent diaphragm pacing (DP). The pathology showed several localized adhesions with a markedly atrophied diaphragm. A marked loss of motor neurons with Bunina bodies and phosphorylated TDP-43 positive inclusions was found in the spinal cord and primary motor cortex. Mild hyalinization and a few multinucleated giant cells were present around the electrode tracks in the diaphragm. However, no infiltration of inflammatory cells was detected. Our findings suggest that full-time DP might not cause severe damage to adjacent diaphragm tissue.

A novel small molecule, N-(4-(2-pyridyl)(1,3-thiazol-2-yl))-2-(2,4,6-trimethylphenoxy) acetamide, selectively protects against oxidative stress-induced cell death by activating the Nrf2-ARE pathway: therapeutic implications for ALS.

Antioxidant defense is crucial in restoring cellular redox homeostasis. Recent findings have suggested that oxidative stress plays pivotal roles in the pathogenesis of many neurodegenerative diseases. Thus, an anti-oxidative stress remedy might be a promising means for the treatment of such disorders. In this study, we employed a novel ligand-based virtual screening system and identified a novel small molecule, N-(4-(2-pyridyl)(1,3-thiazol-2-yl))-2-(2,4,6-trimethylphenoxy) acetamide (CPN-9), which selectively suppressed oxidative stress-induced cell death in a cell-type-independent manner. CPN-9 upregulates NF-E2-related factor 2 (Nrf2), a key transcriptional regulator of the expression of phase II detoxification enzymes and antioxidant proteins, and Nrf2-regulated factors such as heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutamate-cysteine ligase modifier subunit (GCLM). The CPN-9-mediated upregulation of HO-1, NQO1, and GCLM was abolished by Nrf2 knockdown. Moreover, the antioxidant N-acetylcysteine reduced the protective effect of CPN-9 against oxidative stress-induced cell death with concomitant diminishing of Nrf2 nuclear translocation. These results indicate that CPN-9 exerts its activity via the reactive oxygen species-dependent activation of the Nrf2 signaling pathway in cultured cells. It is noteworthy that the postonset systemic administration of CPN-9 to a transgenic ALS mouse model carrying the H46R mutation in the human Cu/Zn superoxide dismutase (SOD1) gene sustained motor functions and delayed disease progression after onset. Collectively, CPN-9 is a novel Nrf2 activator and a neuroprotective candidate for the treatment of neurodegenerative diseases, including ALS.

Antiplatelet effects of a Kampo medicine, Orengedokuto.

INTRODUCTION: Orengedokuto, a Kampo medicine, is used to treat patients with hypertension and cerebrovascular disease in Japan. One of its effects is thought to be antiplatelet action, but the mechanisms involved are unclear. Therefore, we investigated the effects of Orengedokuto on platelet aggregation and activation. METHODS: Platelet aggregation was determined by measuring light transmission (optical density [OD]) and light scattering intensity. Platelet activation was assessed by flow-cytometric determination of PAC-1+ and CD62P+ platelets. For the in vitro study, blood samples were obtained from 45 patients with cerebral infarction (chronic stage) and 27 magnetic resonance imaging-proven control subjects. Furthermore, Orengedokuto was administered to 10 patients with cerebral infarction for up to 12 months, and its effects on platelet aggregation and activation were evaluated. RESULTS: Orengedokuto dose-dependently inhibited agonist-induced platelet aggregation. In vitro, the OD% (mean +/- SD) after stimulation with 2 mumol/L adenosine diphosphate was decreased from 54.4 +/- 21.0 to 16.0 +/- 14.2 (P < .01) in patients, and from 56.8 +/- 26.9 to 19.8 +/- 18.9 (P < .01) in control subjects (1000 mug/mL Orengedokuto). Similarly, the OD% after 0.5 mug/mL collagen stimulation was decreased from 98.3 +/- 37.0 to 24.8 +/- 27.9 (P < .01) in patients, and from 79.2 +/- 13.8 to 21.5 +/- 21.9 (P < .01) in the control subjects. In the clinical study, platelet aggregation was also significantly decreased (P < .05). Agonist-induced platelet activation was not significantly inhibited by Orengedokuto in vitro, but spontaneous platelet activation in patients after oral administration was reduced from 31.0 +/- 18.3 to 14.2 +/- 8.7 (PAC-1+) and from 11.3 +/- 7.8 to 5.1 +/- 3.9 (CD62+) (P < .05). CONCLUSION: Our results demonstrated inhibitory activity of Orengedokuto on both platelet aggregation and activation at a clinically relevant dose.