Therapeutic approaches to the treatment of Alzheimer's disease

Alzheimer's disease is the most common cause of progressive decline of cognitive function in aged humans and is characterized by the presence of numerous senile plaques and neurofibrillary tangles accompanied by neuronal loss. The only treatment currently available for the disease is pharmacotherapy with acetylcholinesterase inhibitors, a palliative strategy aimed at the temporary improvement of cognitive function. Other strategies with disease-modifying potential may include the use of antiinflammatory drugs, estrogen replacement therapy and antioxidants. Recent progress in understanding the molecular and cellular pathophysiology of Alzheimer's disease has suggested possible pharmacological interventions that could modify the development and progress of the disease (disease-modifying therapy), such as treatment with secretase inhibitors, transition metal chelators, HMG-CoA reductase inhibitors and amyloid-b immunization. Inhibitors of tau hyperphosphorylation may also modulate the development and progress of the disease.     

Transient cochlear ischemia causes delayed cell death in the organ of Corti: an experimental study in gerbils

To elucidate whether ischemia-reperfusion can cause delayed cell death in the cochlea, the effects of transient cochlear ischemia on hearing and on neuronal structures in the cochlea were studied in Mongolian gerbils. Ischemia was induced by bilaterally occluding the vertebral arteries for 5 minutes in gerbils, which lack posterior cerebral communicating arteries. In gerbils, the labyrinthine arteries are fed solely by the vertebral arteries. Occlusion of the vertebral arteries caused a remarkable increase in the threshold of compound action potentials (CAPs), which recovered over the following day. However, 7 days after the onset of reperfusion, the threshold began to increase again. Morphologic changes in the hair cell stereocilia were revealed by electron microscopy. The number of nuclear collapses was counted in cells stained for DNA and F-actin to evaluate the degree of cell death in the organ of Corti. Changes in spiral ganglion cell (SGC) neuron number were detected, whether or not progressive neuronal death occurred in the SGC. These studies showed that sporadic fusion of hair cells and the disappearance of hair cell stereocilia did not begin until 4 days after ischemia. On subsequent days, the loss of hair cells, especially inner hair cells (IHCs), and the degeneration of SGC neurons became apparent. Ten days after ischemia, the mean percentage cell loss of IHCs was 6.4% in the basal turn, 6.4% in the second turn, and 0.8% in the apical turn, respectively, and the number of SGC neurons had decreased to 89% of preischemic status. These results indicate that transient ischemia causes delayed hearing loss and cell death in the cochlea by day 7 after ischemia.     

Demyelination associated with HSV-1-induced facial paralysis

In 1995, we developed an animal model of transient homolateral facial nerve paralysis by inoculating Herpes simplex virus type 1 (HSV-1) into the auricle of mice. This study examined the mechanism of facial nerve paralysis in this model histopathologically. Using the immunofluorescence technique with anti-HSV-1 antibody, the time course of viral spread and the site of viral replication were investigated over the entire course of the facial nerve. Furthermore, viral replication and nerve degeneration at the site of viral replication were observed by electron microscopy. On the 7th day after inoculation, facial paralysis was observed in more than 60% of mice. Immunofluorescence study revealed HSV-1 in the geniculate ganglion, the descending root, and the facial nucleus at this stage. On the 9th day, the descending root in the sections stained with osmium looked pale, because prominent demyelination had occurred in this region; electron micrographs showed many degenerated oligodendrocytes and large naked axons. In contrast, the facial nucleus neurons showed no remarkable degeneration, despite HSV-1 particles in their cytoplasm. From these findings, we concluded that facial nerve paralysis in this model is caused mainly by facial nerve demyelination in the descending root.     

Centrifugal lipodystrophy presenting with serpiginous erythema and alopecia

We describe serpiginous erythema with alopecia developing on the scalp of a 10-year-old boy during follow-up of centrifugal lipodystrophy. Because the clinical and histopathologic features of these lesions were identical to those of centrifugal lipodystrophy, we conclude that involvement of a hairy region by this disorder could cause alopecia and that the hair loss might be an indirect effect of interstitial inflammatory infiltrates around the hair follicles and in the subcutaneous fat.     

Role of tissue plasminogen activator in the rewarding effect of morphine]

Tissue plasminogen activator (tPA) is a serine protease that catalyzes the conversion of plasminogen (plg) to plasmin. The tPA-plasmin system plays a role in synaptic plasticity and remodeling. In this review, we focused on the role of tPA-plasmin system in the rewarding effect of morphine. A single morphine treatment induced tPA mRNA and protein expression in a naloxone-sensitive manner, which was associated with an increase in the enzyme activity in the nucleus accumbens (NAc). The acute effect of morphine in inducing tPA expression was diminished after repeated administration. No differences were observed in the morphine-induced antinociceptive effect between wild-type and tPA knockout (tPA-/-) mice. Morphine-induced conditioned place preference and hyperlocomotion were significantly reduced in tPA-/- and pLg-/- mice, being accompanied by a loss of morphine-induced dopamine release in the NAc. Microinjection of either exogenous tPA or plasmin into the NAc significantly potentiated morphine-induced dopamine release in the NAc of ICR mice. In contrast, plasminogen activator inhibitor-1 (PAI-1) dose-dependently reduced morphine-induced dopamine release. Furthermore, the defect of morphine-induced dopamine release and hyperlocomotion in tPA-/- mice was reversed by microinjections of either exogenous tPA or plasmin into the NAc. Our findings demonstrate a novel function of the tPA-plasmin system in regulating dopamine release in the NAc, which is involved in the morphine reward.     

Delayed facial palsy after middle-ear surgery due to reactivation of varicella-zoster virus

Viral reactivation is thought to be an important cause of post-operative facial palsy of delayed onset. We present an unusual case of Ramsay-Hunt syndrome that occurred as a consequence of middle-ear surgery by triggering varicella-zoster virus reactivation. As a pathognomonic auricular eruption was not seen, the patient was initially misdiagnosed as iatrogenic facial palsy. Clinical features, diagnosis and management are discussed.