Current Neurovascular Research - Volume 10, Issue 1, 2013

Migration, proliferation and apoptosis of vascular smooth muscle cells (VSMCs) have recently been identified as important processes in a variety of human vascular diseases, including atherosclerosis, arterial injury, and restenosis after angioplasty. These processes are regulated by interactions between the local cell-cell and cytokine environment. Cytokine induced apoptosis inhibitor (CIAPIN1) is a novel antiapoptotic molecule and plays a vitally important role in malignant phenotypes of cancers. However, the effect of CIAPIN1 on VSMCs has not been reported. In the present study, we constructed the adenovirus encoding CIAPIN1 siRNA and transduced it into VSMCs. The results demonstrated that CIAPIN1 siRNA inhibited proliferation, migration and promotes apoptosis of VSMCs by regulating Bcl-2 and Bax. Our results suggest that CIAPIN1 siRNA might play the key role in VSMC biological function and provide the new therapeutic strategy for vascular diseases.

Hereditary spinocerebellar ataxia (SCA) is a devastating, incurable disease. Stem-cell-based therapies represent new promise for clinical research in neurology. The objectives of this study were to assess the feasibility, efficacy, and potential toxicity of human umbilical cord mesenchymal stem cells (UCMSCs) therapy in patients with SCA. Sixteen genomically diagnosed SCA patients were enrolled and received intravenous and intrathecal infusion of UCMSCs. Clinical, laboratory, and radiographic evaluations were conducted to assess the safety of UCMSC therapy. Efficacy was evaluated by the Berg Balance Scale (BBS) and International Cooperative Ataxia Rating Scale (ICARS) scores. Among the 16 cases, there were no serious transplant-related adverse events happened in 12 months follow-up. The majority of patients showed improved BBS and ICARS scores continuing for at least 6 months which indicated UCMSC therapy could alleviate SCA symptoms. This study suggested that UCMSC transplantation was safe and might delay the progression of SCA. This may represent a new therapeutic strategy for SCA and other genetic neurological diseases.

Preconditioning-induced ischemic tolerance is one of the most important mechanisms, responsible for the increased brain resistance after stroke. Recent studies over the past years have provided interesting insights into the molecular mechanisms of this neuroprotective phenomenon. In this research, we attempted to see changes in the expression of group I and II metabotropic glutamate receptors (mGluR I and II) following intermittent hyperoxia preconditioning. Rats were divided into five groups (hyperoxia-intact, hyperoxia-MCAO, room air-intact, room air- MCAO, room air-sham). Hyperoxia groups were exposed to 95% inspired O2 for 4 h/day and 6 consecutive days. Oxygen level in room air groups was %21. 48 hours after pretreatment, MCAO-operated groups were subjected to focal cerebral ischemia for 60 min. 24 hours after reperfusion, neurologic deficit score (NDS) and brain infarct volume (IV) were evaluated in MCAO-operated subgroups. Sham-operated and intact groups were used to assess expression of group I and II mGluR and glutathione (GSH) levels of core, penumbra and subcortex regions. The results of this study showed that preconditioning with intermittent HO decreased NDS and IV, increased GSH levels in subcortex, and upregulated mGluRs I and II significantly. Although additional studies will be required to further elucidate precise mechanism(s) of ischemic tolerance, it seems that intermittent HO may exert its protective effects in part through upregulation of mGluR I and II.

More than 110 million individuals will suffer from cognitive loss worldwide by the year 2050 with a majority of individuals presenting with Alzheimer's disease (AD). Yet, successful treatments for etiologies that involve β.-amyloid (Aβ.) toxicity in AD remain elusive and await novel avenues for drug development. Here we show that Wnt1 inducible signaling pathway protein 1 (WISP1/CCN4) controls the post-translational phosphorylation of Akt1, p70S6K, and AMP activated protein kinase (AMPK) to the extent that tuberous sclerosis complex 2 (TSC2) (Ser1387) phosphorylation, a target of AMPK, is decreased and TSC2 (Thr1462) phosphorylation, a target of Akt1, is increased. The ability of WISP1 to limit TSC2 activity allows WISP1 to increase the activity of p70S6K, since gene silencing of TSC2 further enhances WISP1 phosphorylation of p70S6K. However, a minimal level of TSC2 activity is necessary to modulate WISP1 cytoprotection that may require modulation of mTOR activity, since gene knockdown of TSC2 impairs the ability of WISP1 to protect microglia against apoptotic membrane phosphatidylserine (PS) exposure, nuclear DNA degradation, mitochondrial membrane depolarization, and cytochrome c release during Aβ. exposure.

We examined the temporal profiles of changes in the expressions of tight junction proteins (TJPs; namely, claudin-5, occludin, and ZO-1) after focal cerebral ischemia/reperfusion in mice. We also examined the effects of delayed treatment with tissue plasminogen activator (tPA) on the expressions of TJPs and angiopoietin (Ang) -1/2/Tie2. Mice subjected to a 6-h filamental middle cerebral artery (MCA) occlusion were treated with tPA (10 mg/kg, intravenously, just after the start of reperfusion) or vehicle. The expressions of TJPs were significantly decreased in the early phase of ischemia/reperfusion, and then gradually recovered. A delayed treatment with tPA decreased the expressions of TJPs when examined at 42 h after reperfusion. In contrast, delayed tPA treatment markedly increased Ang-2, but not Ang-1 expression, when examined at 30 h after reperfusion. Treatment with tPA at 300 μg/ml also significantly decreased Ang- 2, but not Tie2 expression, in an in vitro monolayer model generated using human brain microvascular endothelial cells subjected to serum-deprivation. These findings suggest that delayed tPA treatment prevents recovery of TJPs following focal cerebral ischemia/reperfusion, partially via upregulation of Ang-2.

Hemodynamic disturbance in cerebral blood flow (CBF) is common in both Alzheimer's disease (AD) and vascular dementia (VaD).The aim of this study is to investigate the different patterns of regional cerebral blood flow (rCBF) change and cerebrovascular reactivity (CVR) in these two types of dementia. Mean flow velocity (MFV) of middle cerebral artery and rCBF were measured by Transcranial Doppler ultrasound (TCD) and arterial spin-labeling (ASL) magnetic resonance, separately. CVR was evaluated by MFV or rCBF change in response to 5% CO2 inhalation. The ASL results showed that, rCBF was significantly lower in both the bilateral frontal and temporal lobes in AD group and lower in left frontal and temporal white matter in patients with VaD. CVR calculated by rCBF was impaired more severely in bilateral frontal cortices in AD. Conversely, TCD tests failed to demonstrate significant difference in MFV and CVR between the two groups. It is concluded that the different patterns detected by ASL in resting rCBF change and cerebrovascular reactivity in response to carbogen inhalation may serve as a potential marker to distinguish AD and VaD.

As a member of the secreted extracellular matrix associated proteins of the CCN family, Wnt1 inducible signaling pathway protein 1 (WISP1/CCN4) is garnering increased attention not only as a potent proliferative entity, but also as a robust cytoprotective agent during toxic insults. Here we demonstrate that WISP1 prevents forkhead transcription factor FoxO3a mediated caspase 1 and caspase 3 apoptotic cell death in primary neurons during oxidant stress. Phosphoinositide 3-kinase (PI 3-K) and protein kinase B (Akt1) are necessary for WISP1 to foster posttranslational phosphorylation of FoxO3a and sequester FoxO3a in the cytoplasm of neurons with protein 14-3-3. Through an autoregulatory loop, WISP1 also minimizes deacytelation of FoxO3a, prevents caspase 1 and 3 activation, and promotes an effective neuroprotective level of SIRT1 activity through SIRT1 nuclear trafficking and prevention of SIRT1 caspase degradation. Elucidation of the critical pathways of WISP1 that determine neuronal cell survival during oxidative stress may offer novel therapeutic avenues for neurodegenerative disorders.

N-methyl-D-aspartate receptors (NMDA-Rs) activation has been implicated in various forms of synaptic plasticity depending on the receptor subtypes involved. However, the contribution of NR2A and NR2B subunits in glycine-induced long-term potentiation (LTP) of miniature excitatory postsynaptic currents (mEPSCs) in layer II/III pyramidal neurons of the rat visual cortex remains unclear. The present study used whole-cell patch-clamp recordings in vitro to investigate the role of NR2A-containing and NR2B-containing NMDA-Rs in glycine-induced LTP in visual cortical slices from 13-15 day old rats. We found that glycine-induced LTP of mEPSCs was readily induced in layer II/III pyramidal neurons of the rat visual cortex with glycine. D-APV, a selective NMDA-R antagonist, blocked the glycineinduced LTP. Moreover, the selective NR2B-containing NMDA-R antagonists (Ro 25-6981) displayed no influence on the glycine-induced LTP. However, Zn2+, a voltage-independent NR2A-containing NMDA-R antagonist, prevented glycine-induced LTP. These results suggest that the glycine-induced LTP in layer II/III pyramidal neurons of the rat visual cortex is NMDA-R-dependent and requires NR2A-containing NMDA-Rs, not NR2B-containing NMDA-Rs.

The pathogenesis of Alzheimer's disease (AD) is complex, and only a minority of cases appears to be primarily genetic. A relationship between genetic and acquired vascular factors in AD has been hypothesized. Many vascular risk factors for AD, such as atherosclerosis, stroke and cardiac disease in the aging individual, could result in cerebrovascular dysfunction. A major vascular susceptibility factor gene is the apolipoprotein E gene, found to be associated with sporadic late-onset AD cases. Oxidative damage and mitochondrial dysfunction have been also implicated in the pathogenesis of AD, but the question as to whether they are involved in the onset and progression of the pathology or rather represent a consequence of neurodegeneration is still debated. Recent evidence suggests that chronic hypoperfusion may trigger mitochondrial dysfunction in vascular cells which, in turn, may enhance the production of reactive oxygen species. In this short review we revise the link between vascular factors and mitochondrial dysfunction in AD pathogenesis.

Nitric oxide, derived from nitric oxide synthase (NOS), plays an important role in regulating sympathetic nerve activity. Neuronal NOS (nNOS) is expressed throughout the central and peripheral nervous system. nNOS has a sympathoinhibitory effect under physiological conditions by acting on different sites of the nervous system, including the paraventricular nucleus, the nucleus of the solitary tract, the rostral ventrolateral medulla, the carotid body and nerves in the kidney. nNOS is sympathoinhibitory in a range of diseases including chronic heart failure, chronic renal failure, hypertension and diabetes. nNOS is believed to mediate sympathoinhibitory effects induced by a range of signaling pathways including those promoted by angiotensin-converting enzyme 2 over-expression; statin therapy; angiotensin II type 1 receptor blockers; exercise training; tumor necrosis factor-α blockade; superoxide dismutase mimetics; and estrogen replacement therapy. Increase in nNOS can increase sympathoinhibitory γ-aminobutyric acid activity and decrease sympathoexcitatory angiotensin II signaling and glutamate activity. nNOS may have sympathoexcitatory effects in some circumstances such as chronic heart failure induced by prolonged high salt treatment. The effectiveness of nNOS upregulation in treating sympathetic overactive conditions including chronic heart failure needs to be further investigated.