The Novel Neuroprotective Compound KMS99220 Has an Early Anti-neuroinflammatory Effect via AMPK and HO-1, Independent of Nrf2

We have previously reported a novel synthetic compound KMS99220 that prevented degeneration of the nigral dopaminergic neurons and the associated motor deficits, suggesting a neuroprotective therapeutic utility for Parkinson's disease. Microglia are closely associated with neuroinflammation, which plays a key role in the pathogenesis of neurodegenerative diseases. In this study, we investigated the effects of KMS99220 on the signaling involving AMP-activated protein kinase (AMPK) and heme oxygenase-1 (HO-1), the enzymes thought to regulate inflammation. KMS99220 was shown to elevate the enzyme activity of purified AMPK, and phosphorylation of cellular AMPK in BV2 microglia. It increased the level of HO-1, and this was attenuated by AMPK inhibitors. KMS99220 lowered phosphorylation of IκB, nuclear translocation of NFκB, induction of inducible nitric oxide synthase, and generation of nitric oxide in BV2 cells that had been challenged with lipopolysaccharide. This anti-inflammatory response involved HO-1, because both its pharmacological inhibition and knockdown of its expression abolished the response. The AMPK inhibitors also reversed the anti-inflammatory effects of KMS99220. The induction of HO-1 by KMS99220 occurred within 1 h, and this appeared not to involve the transcription factor Nrf2, because Nrf2 knockdown did not affect the compound's HO-1 inducing- and anti-inflammatory effects in this time window. These findings indicated that KMS99220 leads to AMPK-induced HO-1 expression in microglia, which in turn plays an important role in early anti-inflammatory signaling. Together with its neuroprotective property, KMS99220 may serve as a feasible therapeutic agent against neuroinflammation and neurodegeneration.

A Case of Clopidogrel-Induced Thrombocytopenia

No abstract available.

Kearns-Sayre Syndrome with a Large Deletion in Mitochondrial DNA

Mitochondrial DNA (mtDNA) deletions have been found in a majority of patients with Kearns-Sayre syndrome (KSS). The proband, a 14-year-old male, presented with retinitis pigmentosa, bilateral ptosis with an external opthalmoplegia, and ragged-red fibers in his biceps. The common 5-kb deleted mtDNA was identified in the patient by a long template PCR and DNA sequencing analysis. The deletion was located within the 8469-1344 position and a 13-kb direct repeat sequence was shown in the junction.

Nerve Regeneration After Autogenous Nerve Graft Using Perfabricated Adiponeural and Myoneural Flap: An Experimental Study

Most of the peripheral nerve injuries from crushing or compressive forces are accompanied by surrounding soft tissue injuries. As a result, poor vascularity due to fibrosis and sacr formation compromises regeneration of the grafted nerve. Vascularized nerve graft shows superior regeneration to that of a non-vascularized one. However, the human body provides few donor sites of vascularized nerve graft clinically. We presumed that the prefabricated myoneural or adiponeural flap, which include fabricated nerves wrapped with surrounding vascularized muscle or adipose tissue flap, influences superiorly on the regeneration of grafted nerve because that surrounding vasculatity indirectly enhances the vascularity of the grafted nerve itself. Thirty adult male Sprague-Dawley rats were divided into three groups: 1) conventional reversed autogenous graft of the femoral nerve alone(n=10); 2) nerve graft entubulated with abdominal adipose tissue flap with a pedicle of inferior epigastric artery(n=10); 3) nerve graft entubulated with adductor muscle flap with a pedicle of the first muscular branch of the femoral artery(n=10). At three months postoperatively, grafted nerves were examined by electrophysiologic study to check amplitudes and motor nerve conduction velocities, as well as histopathologic study for evaluation of regenerated nerve cells, fibrosis and neo-vascularization. Consquently, nerve regeneration was found in all three groups. Both the myoneural and adiponeural flap groups had better improved results of nerve regeneration compared to that of the conventional nerve graft group. The result of myoneural flap group was superior to that of the adiponeural flap group. The myoneural flap group showed minimal fibrosis and less prominent neovascularization around moderately regenerated nerves. The adiponeural flap group showed more severe perineural and endoneural fibrosis, as well as vascular proliferation around focal regenerated nerves. The results of myoneural flap group proved to be statistically significant. We concluded that it is possible to use nerve graft entubulated with a vascularized muscle flap (myoneural flap) as a substitute for vascularized nerve graft.

Neuropathological Changes in the Subnucleus of Amygdala in Alzhemer Disease

In this study the quantitative changes of the SP (senile plaque) and NFT (neurofibrillary tangle) in the subnucleus of amygdaloid nucleus were analyzed. All patients (83 cases) were diagnosed clinically and confirmed pathologically as Alzheimer disease. The results were: 1) The SP was most prominenentlv observed in the basomedial sub'nucleus region but NFT was in the lateral subnuclei. 2) There were positive Rank Correlation of pathologic degree between the amygdaloidal subnuclei and neocortex except accessory basal subnuclei. 3)Lateral subnucleus had no Rank Correlation between its SP & NFT.

The Effect of High-dose Intravenous Steroid("pulse") Therapy in Neurologic Disease-Preliminary Report

High dose intravenous methyl prednisolone was administered to patients with multiple sclerosis (4), transverse myelitis (6), and arachnoiditis (I). Almost complete remission was noted in 5 cases (4 with transverse myelitis and one with multiple sclerosis) and partial improvement in 3 patients (2 with multiple sclerosis and I with arachnoiditis ) within 3 days after therapy. The benefits of this therapy, however, was not that dramatic when started late after the onset of neurologic deficits.