Phosphodiesterase III inhibition promotes differentiation and survival of oligodendrocyte progenitors and enhances regeneration of ischemic white matter lesions in the adult mammalian brain.

Vascular dementia is caused by blockage of blood supply to the brain, which causes ischemia and subsequent lesions primarily in the white matter, a key characteristic of the disease. In this study, we used a chronic cerebral hypoperfusion rat model to show that the regeneration of white matter damaged by hypoperfusion is enhanced by inhibiting phosphodiesterase III. A rat model of chronic cerebral hypoperfusion was prepared by bilateral common carotid artery ligation. Performance at the Morris water-maze task, immunohistochemistry for bromodeoxyuridine, as well as serial neuronal and glial markers were analyzed until 28 days after hypoperfusion. There was a significant increase in the number of oligodendrocyte progenitor cells in the brains of patients with vascular dementia as well as in rats with cerebral hypoperfusion. The oligodendrocyte progenitor cells subsequently underwent cell death and the number of oligodendrocytes decreased. In the rat model, treatment with a phosphodiesterase III inhibitor prevented cell death, markedly increased the mature oligodendrocytes, and promoted restoration of white matter and recovery of cognitive decline. These effects were cancelled by using protein kinase A/C inhibitor in the phosphodiesterase III inhibitor group. The results of our study indicate that the mammalian brain white matter tissue has the capacity to regenerate after ischemic injury.

Clustering of risk factors increases the incidence of echolucent carotid plaque in stroke patients.

BACKGROUND: The purpose of this study was to assess the influence of clusters of risk factors on the incidence of echolucent carotid plaque in stroke patients. METHODS: A retrospective analysis of 413 stroke patients who had undergone carotid ultrasonography was performed. High-resolution B-mode ultrasonography was used to evaluate the characteristics of carotid plaque. We investigated the relationships between the incidence of echolucent carotid plaque and clustering of risk factors (hypertension, diabetes mellitus and hyperlipidemia) and stroke subtypes and transient ischemic attack (TIA). RESULTS: Echolucent plaques were present in 10.5% of patients free of risk factors, in 18.8% with a single risk factor (NS), in 27.7% with two risk factors (p <0.01) and in 50.0% with three risk factors (p <0.001), and were significantly more common in patients with multiple risk factors (odds ratio 1.79; 95% CI, 1.05-3.06; p = 0.045). Echolucent plaques were observed in 41.2% of patients with atherothrombotic infarction, in 17.6% with lacunar infarction, in 11.5% with cardioembolic stroke, and in 25.0% with TIA, and were significantly more common in patients with atherothrombotic infarction than in those with lacunar infarction or cardioembolic stroke (p<0.001), or in those with TIA (p <0.05). CONCLUSIONS: The clustering of risk factors increased the incidence of echolucent carotid plaque. Patients with multiple risk factors were at increased risk of echolucent plaque, and these had a significant relationship with atherothrombotic infarction compared with other stroke subtypes and TIA.

Cilostazol protects against brain white matter damage and cognitive impairment in a rat model of chronic cerebral hypoperfusion.

BACKGROUND AND PURPOSE: White matter lesions contribute to cognitive impairment in poststroke patients. The present study was designed to assess the neuroprotective mechanisms of cilostazol, a potent inhibitor of type III phosphodiesterase, through signaling pathways that lead to activation of transcription factor cAMP-responsive element binding protein (CREB) phosphorylation using rat chronic cerebral hypoperfusion model. METHODS: Rats underwent bilateral common carotid artery ligation. They were divided into the cilostazol group (n=80) and the vehicle (control) group (n=80). Performance at the Morris water maze task and immunohistochemistry for 4-hydroxy-2-nonenal (HNE), glutathione-S-transferase-pi (GST-pi), ionized calcium-binding adaptor molecule 1, phosphorylated CREB (p-CREB), Bcl-2, and cyclooxygenase-2 (COX-2) were analyzed at baseline and at 3, 7, 14, 21, and 28 days after hypoperfusion. RESULT: Cilostazol significantly improved spatial learning memory (6.8+/-2.3 seconds; P<0.05) at 7 days after hypoperfusion. Cilostazol markedly suppressed accumulation of HNE-modified protein and loss of GST-pi-positive oligodendrocytes in the cerebral white matter during the early period after hypoperfusion (P<0.05). Cilostazol upregulated p-CREB and Bcl-2 (P<0.05), increased COX-2 expression, and reduced microglial activation in the early period of hypoperfusion. CONCLUSIONS: Our results indicate that cilostazol exerts a brain-protective effect through the CREB phosphorylation pathway leading to upregulation of Bcl-2 and COX-2 expressions and suggest that cilostazol is potentially useful for the treatment of cognitive impairment in poststroke patients.

[An 80-year-old woman with progressive stroke, who had rheumatoid arthritis and antiphospholipid syndrome].

We report an 80-year-old woman who had rheumatoid arthritis and antiphospholipid syndrome. She was treated for rheumatoid arthritis since her thirties. At 76 years of age, she was diagnosed antiphospholipid syndrome serologically. She felt It. limb weakness and dysarthria and was admitted to the hospital on July 18, 2003. The brain MRI showed T2 hyperintensity signal on the rt. pre-central lobe. She was treated by the argatroban, edaravone, glycerol, and aspirin. However, she became bedridden and fed by NG-tube because her symptoms progressed in spite of the therapy. Progression of stroke stopped by adding heparin at last. After that, she repeated pneumonia. She was found dead on the bed August 2, 2003. The patient was discussed in a CPC. The chief discussant arrived at a conclusion that the cause of infarction was angitis due to rheumatoid arthritis. Other possibilities were multiple thrombus due to antiphospholipid syndrome, amyloid angiopathy, and atherosclerotic infarction. Post-mortem study revealed sputum obstruction in her bronchus, string deposition in her organs. The brain showed infarction on the rt. pre-central lobe. There were multiple thrombus in the leptomeningeal artery, but few atherosclerotic changes of the small arteries. Amyloid didn't deposit in the brain artery and the parenchyma. Pathologist concluded that her infarction was induced with multiple thrombus due to antiphospholipid syndrome.