Role Of Neuron-restrictive Silencer Factor Research Articles

Knockdown of NRSF Alleviates Ischemic Brain Injury and Microvasculature Defects in Diabetic MCAO Mice.

Diabetes is one of the well-established risk factors of stroke and is associated with a poor outcome in patients with stroke. Previous studies have shown that the expression of neuron restrictive silencer factor (NRSF) is elevated in diabetes as well as ischemic stroke. However, the role of NRSF in regulating an outcome of diabetic ischemic stroke has not been completely understood. Here, we hypothesized that diabetes-induced NRSF elevation can aggravate brain injury and cognition impairment in ischemic stroke. The diabetic ischemic stroke mice model was established by 8 weeks of high-fat-diet feeding and 5 days of streptozotocin injection followed by 30 min of middle cerebral artery occlusion (MCAO). We found that diabetes enhanced the MCAO-induced elevation of NRSF in the hippocampus in accompany with an elevation of its corepressors, HDAC1, and mSin3A, and decrease of β-TrCP. By using histological/immunofluorescence staining and neurobehavioral testing, our results showed that the brain damage and learning/memory impairment were aggravated in diabetic ischemic mice but significantly attenuated after stereotaxic injection of NRSF-shRNA. Meanwhile, by performing whole-brain clearing with PEGASOS, microvascular reconstruction, western blotting, and ELISA, we found that NRSF-shRNA markedly alleviated the vasculature disorders and rescued the suppression of NRP-1, VEGF, and VEGFR2 in the hippocampus of diabetic ischemic mice. Therefore, our results demonstrated for the first time that the elevation of hippocampal NRSF plays an important role in alleviating brain injury and cognitive disabilities in diabetic ischemic mice, potentially via the reduction of NRP-1/VEGF signaling.

Role of neuron-restrictive silencer factor in spinal cord in remifentanil-induced hyperalgesia in a mouse model of incisional pain

Objective To evaluate the role of neuron-restrictive silencer factor （NRSF） in the spinal cord in remifentanil-induced hyperalgesia in a mouse model of incisional pain （IP） .Methods Fifty-six male Kunming mice were randomly divided into 7 groups （n=8 each）：control group （group C） ,IP group （group I） ,IP ＋remifentanil group （group IR ） , NRSF antisense oligonucleotide group （NAS group ） , IP ＋ NRSF antisense oligonucleotide group （I＋NAS group ） ,IP ＋ remifentanil ＋ NRSF mismatch oligonucleotide group （IR＋NMS group） , and IP ＋ remifentanil ＋ NRSF antisense oligonucleotide group （IR ＋ NAS group ） . Artificial cerebrospinal fluid 5 μl was injected intrathecally once a day for 3 consecutive days in C ,I and IR groups .NRSF antisense oligonucleotide NAS 10μg was injected intrathecally once a day for 3 consecutive days in NAS ,I＋NAS and IR ＋ NAS groups . NRSF mismatch oligonucleotide 10 μg was injected intrathecally once a day for 3 consecutive days in IR＋NMS group .A 1-cm longitudinal incision was made through skin ,fascia and muscle of the plantar aspect of the right hindpaw to establish the model of incisional pain in sevoflurane-anesthetized rats .At 30 min after the last injection ,normal saline 0.4 ml was infused subcutaneously in C and NAS groups ,the model＆nbsp;was established and normal saline 0.4 ml was subcutaneously infused simultaneously in I and I＋NAS groups ,and the model was established and remifentanil 0.04 mg/kg was subcutaneously infused simultaneously in IR ,IR＋NMS and IR＋NAS groups .At 3 days before operation （T0 ） ,4 h before operation （T1 ） and 4 ,12 ,24 and 48 h after operation （T1-5 ） ,mechanical paw withdrawal threshold to von Frey stimuli （PMWT ） and paw withdrawal latency to thermal nociceptive stimulus （PTWL ） were measured .Results Compared with C group ,the PWMT and PWTL were significantly decreased at T2-5 in I ,IR ,I＋NAS ,IR＋NMS and IR＋NAS groups （ P0.05 ） .Compared with I group ,the PWMT and PWTL were significantly decreased at T2-5 in IR and IR＋NMS groups （ P0.05） . Compared with IR group ,no significant change was found in the PWMT and PWTL at each time point in IR＋NMS group （ P〉0.05） ,and the PWMT and PWTL were significantly increased at T2-5 in IR＋NAS group （ P〈0.05） . Conclusion NRSF in the spinal cord is involved in the development and maintenance of hyperalgesia induced by remifentanil in a mouse model of IP . Key words: Repressor proteins; Piperidines; Hyperalgesia; Spinal cord

Ethanol-induced neurodegeneration in NRSF/REST neuronal conditional knockout mice

The transcription regulator, neuron-restrictive silencer factor (NRSF), also known as repressor element-1 silencing transcription factor (REST), plays an important role in neurogenesis and various neuronal diseases such as ischaemia, epilepsy, and Huntington's disease. In these disease processes, neuronal loss is associated with abnormal expression and/or localization of NRSF. Previous studies have demonstrated that NRSF regulates the effect of ethanol on neuronal cells in vitro, however, the role of NRSF in ethanol-induced neuronal cell death remains unclear. We generated nrsf conditional knockout mice using the Cre- loxP system to disrupt neuronal expression of nrsf and its truncated forms. At postnatal day 6, ethanol significantly increased the expression of REST4, a neuron-specific truncated form of NRSF, in the brains of wild type mice, and this effect was diminished in nrsf conditional knockout mice. The apoptotic effect of ethanol was pronounced in multiple brain regions of nrsf conditional mutant mice. These results indicate that NRSF, specifically REST4, may protect the developing brain from ethanol, and provide new evidence that NRSF can be a therapeutic target in foetal alcohol syndrome (FAS).

The role of neuron-restrictive silencer factor in modulating the Sp-1 mediated transactivation of human secretin receptor gene

The role of neuron-restrictive silencer factor in modulating the Sp-1 mediated transactivation of human secretin receptor gene