Repairing brain after stroke: a review on post-ischemic neurogenesis

Stroke is devastating as currently no therapies are available that can prevent stroke-induced neurological dysfunction in humans. With the recent observations that acute insults to adult brain stimulate new neuronal formation in various species of animals, optimism is building for a possible regeneration of stroke-damaged brain. This article reviewed the advances in the understanding of the molecular mechanisms of the various steps of neurogenesis with an emphasis on the endogenous mediators and exogenous promoters of neural progenitor proliferation, migration and survival in the post-ischemic adult brain.     

Ischemic post-conditioning protects brain and reduces inflammation in a rat model of focal cerebral ischemia/reperfusion

Ischemic post-conditioning (Post-cond) is a phenomenon in which intermittent interruptions of blood flow in the early phase of reperfusion can protect organ from ischemia/reperfusion (I/R) injury. Recent studies demonstrated ischemic Post-cond reduced infarct size in cerebral I/R injury. However, the molecular mechanisms underlying this phenomenon are not completely understood. As inflammation is known to be detrimental to the neurological outcome during the acute phase after stroke, we investigated whether ischemic Post-cond played its protective role in preventing post-ischemic inflammation in the rat middle cerebral artery occlusion model. Rats were treated with ischemic Post-cond after 60 min of occlusion (beginning of reperfusion). The infarct volume and myeloperoxidase activity were assessed at 24 h. The lipid peroxidation levels was evaluated by malondialdehyde assay and the expressions of interleukin-1β, tumor necrosis factor-α, and intercellular adhesion molecule 1 were studied by RT-PCR or western blotting. Ischemic Post-cond decreased myeloperoxidase activity and expressions of interleukin-1β, tumor necrosis factor-α, and intercellular adhesion molecule 1. Ischemic Post-cond also reduced infarct volume and lipid peroxidation levels. These findings indicated that ischemic Post-cond may be a promising neuroprotective approach for focal cerebral I/R injury and it is achieved, at least in part, by the inhibition of inflammation.     

All’s well that transcribes well: Non-coding RNAs and post-stroke brain damage

The mammalian genome is replete with various classes of non-coding (nc) RNA genes. Many of them actively transcribe, and their relevance to CNS diseases is just beginning to be understood. CNS is one of the organs in the body that shows very high ncRNAs activity. Recent studies demonstrated that cerebral ischemia rapidly changes the expression profiles of different classes of ncRNAs: including microRNA, long noncoding RNA and piwi-interacting RNA. Several studies further showed that post-ischemic neuronal death and/or plasticity/regeneration can be altered by modulating specific microRNAs. These studies are of interest for therapeutic development as they may contribute to identifying new ncRNA targets that can be modulated to prevent secondary brain damage after stroke.     

植物环境响应启动子的诱导元件及转录因子

光、温度、水分等环境因素影响植物的生长发育,植物可以通过启动子中顺式作用元件与转录因子的相互协调作用,对这些信号产生响应,调控基因表达。本文综述了光、温度、水分诱导表达启动子中的顺式作用元件及相关转录因子研究的最新进展,从分子水平上探讨了环境因子诱导的基因表达调控,对研究植物适应环境的机制具有一定的意义。     

Plant sigma factors and their role in plastid transcription

Plant sigma factors determine the promoter specificity of the major RNA polymerase of plastids and thus regulate the first level of plastome gene expression. In plants, sigma factors are encoded by a small family of nuclear genes, and it is not yet clear if the family members are functionally redundant or each paralog plays a particular role. The review presents the analysis of the information on plant sigma factors obtained since their discovery a decade ago and focuses on similarities and differences in structure and functions of various paralogs. Special attention is paid to their interaction with promoters, the regulation of their expression, and their role in the development of a whole plant. The analysis suggests that though plant sigma factors are basically similar, at least some of them perform distinct functions. Finally, the work presents the scheme of this gene family evolution in higher plants.     

Reduction of cellular damage induced by cerebral ischemia in rats

A model of incomplete cerebral ischemia involving bilateral ligation of the common carotid arteries in rats, was used to examine the potential of a Chinese herbal preparation and of nifedipine to reduce cell damage following cerebral ischemia. The herbal preparation contained ginsengosides and extracts ofPanax notoginseng, Ligusticum chuanxiong Hort.,Carthamus tinctorius L. andSalvia militorrhiza Bge. Histological evidence of cell damage and the formation of peroxidation products were both reduced in rats pretreated with the herbal preparation or with nifedipine. It has been suggested that the free radical reaction is involved in tissue damage, particularly in the pathological neurocyte injury of cerebral ischemia. The results show that in this model of incomplete cerebral ischemia, the degree of lipid peroxidation can be lowered by the pretreatment with Chinese herbs containing ginsengosides or with nifedipine. These drugs maybe beneficial in the treatment of cerebral ischemia in humans.Special issue dedicated to Dr. Lawrence Austin.     

多巴胺在缺血性脑损伤中作用机制的研究进展

多巴胺是哺乳动物脑内重要的儿茶酚胺灰神经递质,但在某些病理条件下可引起神经毒性作用。近年来研究表明,ＤＡ在缺血性脑损伤中有重要作用。缺血时ＤＡ的酶促氧化和自身氧化导致自由基的产生被认为是ＤＡ神经毒性的主要原因,但这一观点尚需进一步探讨。     

Cold-inducible RNA-binding protein mediates neuroinflammation in cerebral ischemia

Background

Neuroinflammation is a key cascade after cerebral ischemia. Excessive production of proinflammatory mediators in ischemia exacerbates brain injury. Cold-inducible RNA-binding protein (CIRP) is a newly discovered proinflammatory mediator that can be released into the circulation during hemorrhage or septic shock. Here, we examine the involvement of CIRP in brain injury during ischemic stroke.

Methods

Stroke was induced by middle cerebral artery occlusion (MCAO). In vitro hypoxia was conducted in a hypoxia chamber containing 1% oxygen. CIRP and tumor necrosis factor-α (TNF-α) levels were assessed by RT-PCR and Western blot analysis.

Results

CIRP is elevated along with an upregulation of TNF-α expression in mouse brain after MCAO. In CIRP-deficient mice, the brain infarct volume, induction of TNF-α, and activation of microglia are markedly reduced after MCAO. Using microglial BV2 cells, we demonstrate that hypoxia induces the expression, translocation, and release of CIRP, which is associated with an increase of TNF-α levels. Addition of recombinant murine (rm) CIRP directly induces TNF-α release from BV2 cells and such induction is inhibited by neutralizing antisera to CIRP. Moreover, rmCIRP activates the NF-κB signaling pathway in BV2 cells. The conditioned medium from BV2 cells exposed to hypoxia triggers the apoptotic cascade by increasing caspase activity and decreasing Bcl-2 expression in neural SH-SY5Y cells, which is inhibited by antisera to CIRP.

Conclusion

Extracellular CIRP is a detrimental factor in stimulating inflammation to cause neuronal damage in cerebral ischemia.

General significance

Development of an anti-CIRP therapy may benefit patients with brain ischemia.     

Continuous oral administration of atorvastatin ameliorates brain damage after transient focal ischemia in rats

Aims

Pre-treatment with statins is known to ameliorate ischemic brain damage after experimental stroke, and is independent of cholesterol levels. We undertook pre- vs post-ischemic treatment with atorvastatin after focal cerebral ischemia in rats.

Main methods

Male Sprague–Dawley rats underwent transient 90-min middle cerebral artery occlusion (MCAO). Atorvastatin (20 mg/kg/day) or vehicle was administered orally. Rats were divided into vehicle-treated, atorvastatin pre-treatment, atorvastatin post-treatment, and atorvastatin continuous-treatment groups. In the pre-treatment, rats were given atorvastatin or vehicle for 7 days before MCAO. In the post-treatment, rats received atorvastatin or vehicle for 7 days after MCAO. Measurement of infarct volume, as well as neurological and immunohistochemical assessments, were done 24 h and 7 days after reperfusion.

Key findings

Each atorvastatin-treated group demonstrated significant reductions in infarct and edema volumes compared with the vehicle-treated group 24 h after reperfusion. Seven days after reperfusion, infarct volumes in the post-treatment group and continuous-treatment group (but not the pre-treatment group) were significantly smaller than in the vehicle-treated group. Only the continuous-treatment group had significantly improved neurological scores 7 days after reperfusion compared with the vehicle group. Post-treatment and continuous-treatment groups had significantly decreased lipid peroxidation, oxidative DNA damage, microglial activation, expression of tumor necrosis factor-alpha, and neuronal damage in the cortical ischemic boundary area after 7 days of reperfusion.

Significance

These results suggest that continuous oral administration (avoiding withdrawal) with statins after stroke may reduce the extent of post-ischemic brain damage and improve neurological outcome by inhibiting oxidative stress and inflammatory responses.