pitavastatin and Ischemic-Attack--Transient

Periprocedural ischemic stroke is one problem associated with carotid artery stenting (CAS). This study was designed to assess whether preoperative statin therapy reduces the risk of periprocedural ischemic complications with CAS.. In this prospective study at 11 centers, patients with carotid artery stenosis (symptomatic ≥50%, asymptomatic ≥80%) and a high risk of carotid endarterectomy but without previous statin treatments were divided into two groups by low-density lipoprotein cholesterol (LDL-C) levels. With LDL-C ≥120 mg/dl, the pitavastatin-treated (PS) group received pitavastatin at 4 mg/day. With LDL-C <120 mg/dl, the non-PS group received no statin therapy. After 4 weeks, both groups underwent CAS. Frequencies of new ipsilateral ischemic lesions on diffusion-weighted imaging within 72 h after CAS and cerebrovascular events (transient ischemic attack, stroke, or death) within 30 days were assessed.. Among the 80 patients enrolled, 61 patients (PS group, n = 31; non-PS group, n = 30) fulfilled the inclusion criteria. New ipsilateral ischemic lesions were identified in 8 of 31 patients (25.8%) in the PS group and 16 of 30 patients (53.3%) in the non-PS group (P = 0.028). Cerebrovascular events occurred in 0 patients in the PS group and in 3 of 30 patients (10.0%) in the non-PS group (P = 0.071). Multivariate analyses demonstrated the pitavastatin treatment (β = 0.74, 95% confidence interval 0.070-1.48, P = 0.042) to be an independent factor for decreasing post-CAS ischemic lesions.. Pretreatment with pitavastatin significantly reduced the frequency of periprocedural ischemic complications with CAS.

Topics: Aged; Carotid Stenosis; Diffusion Magnetic Resonance Imaging; Endarterectomy, Carotid; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Ischemic Attack, Transient; Japan; Lipoproteins, LDL; Male; Prospective Studies; Quinolines; Risk Factors; Stents; Stroke; Treatment Outcome

1. We investigated the immunohistochemical alterations of BDNF, NGF, HSP 70 and ubiquitin in the hippocampus 1 h to 14 days after transient cerebral ischemia in gerbils. We also examined the effect of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor pitavastatin against the changes of BDNF, NGF, HSP 70 and ubiquitin in the hippocampus after cerebral ischemia in the hippocampus after ischemia. 2. The transient cerebral ischemia was carried out by clamping the carotid arteries with aneurismal clips for 5 min. 3. In the present study, the alteration of HSP 70 and ubiquitin immunoreactivity in the hippocampal CA1 sector was more pronounced than that of BDNF and NGF immunoreactivity after transient cerebral ischemia. In double-labeled immunostainings, BDNF, NGF and ubiquitin immunostaining was observed both in GFAP-positive astrocytes and MRF-1-positive microglia in the hippocampal CA1 sector after ischemia. Furthermore, prophylactic treatment with pitavastatin prevented the damage of neurons with neurotrophic factor and stress proteins in the hippocampal CA1 sector after ischemia. 4. These findings suggest that the expression of stress protein including HSP 70 and ubiquitin may play a key role in the protection against the hippocampal CA1 neuronal damage after transient cerebral ischemia in comparison with the expression of neurotrophic factor such as BDNF and NGF. The present findings also suggest that the glial BDNF, NGF and ubiquitin may play some role for helping surviving neurons after ischemia. Furthermore, our present study indicates that prophylactic treatment with pitavastatin can prevent the damage of neurons with neurotrophic factor and stress proteins in the hippocampal CA1 sector after transient cerebral ischemia. Thus our study provides further valuable information for the pathogenesis after transient cerebral ischemia.

Topics: Animals; Brain-Derived Neurotrophic Factor; Enzyme Inhibitors; Gerbillinae; Hippocampus; HSP70 Heat-Shock Proteins; Immunohistochemistry; Ischemic Attack, Transient; Male; Nerve Growth Factor; Neuroprotective Agents; Quinolines; Ubiquitin

We investigated the immunohistochemical alterations of the transcription nuclear factor kappa-B (NF-kappaB) and transcription factor p53 in the hippocampus after transient cerebral ischemia in gerbils. We also examined the effect of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pitavastatin against the alterations of NF-kappaB, p53 and neuronal nuclei in the hippocampus after ischemia. Severe neuronal damage was observed in the hippocampal CA1 neurons 5 and 14 days after ischemia. In the present study, the increase of NF-kappaB immunoreactivity in glial cells and p53 immunoreactivity in neurons preceded neuronal damage in the hippocampal CA1 sector after ischemia. Thereafter, NF-kappaB immunoreactivity was induced highly in reactive astrocytes and microglia of the hippocampal CA1 sector where severe neuronal damage was observed. Our immunohistochemical study showed that pitavastatin prevented the alterations of NF-kappaB and p53 in the hippocampal CA1 sector 5 days after transient ischemia. Furthermore, our results with neuronal nuclei immunostaining indicate that pitavastatin dose-dependently prevented the neuronal cell death in the hippocampal CA1 sector 5 days after transient cerebral ischemia. These results suggest that the up-regulations of NF-kappaB in glia and p53 in neurons can cause neuronal cell death after ischemia. Our findings also support the hypothesis that NF-kappaB- and/or p53-mediated neuronal cell death is prevented through decreasing oxidative stress by pitavastatin. Thus, NF-kappaB and p53 may provide an attractive target for the development of novel therapeutic approaches for brain stroke.

Topics: Animals; Apoptosis; Astrocytes; Enzyme Inhibitors; Gerbillinae; Hippocampus; Immunohistochemistry; Ischemic Attack, Transient; Male; Microglia; Nerve Tissue Proteins; Oxidative Stress; Quinolines; Transcription Factor RelA; Tumor Suppressor Protein p53

We investigated the immunohistochemical alterations of parvalbumin (PV)-expressing interneurons in the hippocampus after transient cerebral ischemia in gerbils in comparison with neuronal nitric oxide synthase (nNOS)-expressing interneurons. We also examined the effect of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pitavastatin against the damage of neurons and interneurons in the hippocampus after cerebral ischemia. Severe neuronal damage was observed in the hippocampal CA1 pyramidal neurons 5 and 14 days after ischemia. The PV immunoreactivity was unchanged up to 2 days after ischemia. At 5 and 14 days after ischemia, in contrast, a conspicuous reduction of PV immunoreactivity was observed in interneurons of the hippocampal CA1 sector. Furthermore, a significant decrease of PV immunoreactivity was found in interneurons of the hippocampal CA3 sector. No damage of nNOS-immunopositive interneurons was detected in the gerbil hippocampus up to 1 day after ischemia. Thereafter, a decrease of nNOS immunoreactive interneurons was found in the hippocampal CA1 sector up to 14 days after ischemia. Pitavastatin significantly prevented the neuronal cell loss in the hippocampal CA1 sector 5 days after ischemia. Our immunohistochemical study also showed that pitavastatin prevented significant decrease of PV- and nNOS-positive interneurons in the hippocampus after ischemia. Double-labeled immunostainings showed that PV immunoreactivity was not found in nNOS-immunopositive interneurons of the brain. The present study demonstrates that cerebral ischemia can cause a loss of both PV- and nNOS-immunoreactive interneurons in the hippocampal CA1 sector. Our findings also show that the damage to nNOS-immunopositive interneurons may precede the neuronal cell loss in the hippocampal CA1 sector after ischemia and nNOS-positive interneurons may play some role in the pathogenesis of cerebral ischemic diseases. Furthermore, our present study indicates that pitavastatin can prevent the damage of interneurons in the hippocampus after cerebral ischemia. Thus, our study provides valuable information for the pathogenesis after cerebral ischemia.

Topics: Animals; Cell Count; Disease Models, Animal; Enzyme Inhibitors; Gerbillinae; Hippocampus; Immunohistochemistry; Interneurons; Ischemic Attack, Transient; Male; Nitric Oxide Synthase Type I; Parvalbumins; Quinolines; Time Factors

We investigated the immunohistochemical alterations of S100beta-, S100-, glial fibrillary acidic protein (GFAP)- and isolectin B4-positive cells in the hippocampus after 5 min of transient cerebral ischaemia in gerbils. We also examined the effect of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor pitavastatin against neuronal damage in the hippocampal CA1 sector after ischaemia.. Severe neuronal damage was observed in the hippocampal CA1 pyramidal neurons from 5 days after ischaemia. GFAP-positive cells increased gradually in the hippocampus from 5 days after ischaemia. Five and 14 days after ischaemia, significant increases in the number of GFAP-positive cells and isolectin B4-positive cells were observed in the hippocampal CA1 and CA3 sector. Mild increases in the number of S100 and S100beta-positive cells were observed in the hippocampal CA1 sector from 1 h to 2 days after ischaemia. Thereafter, S100beta-positive cells increased in the hippocampal CA1 sector after ischaemia, whereas S100-positive cells decreased in this region. In our double-labelled immunostainings, S100 and S100beta immunoreactivity was found in GFAP-positive astrocytes, but not in isolectin B4-positive microglia. Pharmacological study showed that HMG-CoA reductase inhibitor, pitavastatin, can protect against the hippocampal CA1 neuronal damage after ischaemia. This drug also prevented increases in the number of GFAP-positive astrocytes, isolectin B4-positive microglia, S100-positive astrocytes and S100beta-positive astrocytes after ischaemia.. The present study demonstrates that pitavastatin can decrease the neuronal damage of hippocampal CA1 sector after ischaemia. This beneficial effect may be, at least in part, mediated by inhibiting the expression of astrocytic activation in the hippocampus at the acute phase after ischaemia. Thus the modulation of astrocytic activation may offer a novel therapeutic strategy of ischaemic brain damage.

Topics: Animals; Astrocytes; Gerbillinae; Glial Fibrillary Acidic Protein; Hippocampus; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunohistochemistry; Ischemic Attack, Transient; Lectins; Male; Microglia; Neurons; Quinolines; S100 Proteins

Pitavastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, is a potent cholesterol-lowering drug that reduces the risk of myocardial infarction and stoke. In this study, we examined its neuroprotective effects against hippocampal CA1 neuronal damage following transient cerebral ischemia in gerbils. Forebrain ischemia was induced by occlusion of bilateral common carotid arteries for 5 min. Pitavastatin, at a dose of 3, 10 or 30 mg/kg, was administered orally twice a day for 5 consecutive days and transient cerebral ischemia was induced in mice 1 h after the last treatment with pitavastatin. Histopathological observations showed that neuronal damage to the hippocampal CA1 neurons, which was observed 5 days after ischemia in animals, was prevented by pitavastatin treatment. Immunohistochemical staining for copper/zinc superoxide dismutase (SOD) and manganese SOD decreased in the hippocampal CA1 sector of gerbils 2 days after ischemia when histological neuronal destruction was not yet found, but was clearly observed in pitavastatin-treated animals. These results indicate that pitavastatin can protect dose-dependently against ischemia-induced neuronal damage and that the mechanism of the neuroprotection may be related to the preservation of SODs, especially copper/zinc-SOD. This in part explains how pitavastatin therapy, which targets free radicals, has beneficial effects against disorders including ischemic stroke.

Topics: Animals; Cerebral Infarction; Disease Models, Animal; Dose-Response Relationship, Drug; Free Radical Scavengers; Free Radicals; Gerbillinae; Hippocampus; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunohistochemistry; Ischemic Attack, Transient; Male; Nerve Degeneration; Neuroprotective Agents; Oxidative Stress; Quinolines; Superoxide Dismutase