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    12 August 2014, Volume 9 Issue 15 Previous Issue    Next Issue
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    Driving neural regeneration through the mammalian target of rapamycin
    Kenneth Maiese
    2014, 9 (15):  1413-1417.  doi: 10.4103/1673-5374.139453
    Abstract ( 273 )   PDF (170KB) ( 914 )   Save

    Neurodegenerative disorders affect more than 30 million individuals throughout the world and lead to significant disability as well as death. These statistics will increase almost exponentially as the lifespan and age of individuals increase globally and individuals become more susceptible to acute disorders such as stroke as well as chronic diseases that involve cognitive loss, Alzheimer’s disease, and Parkinson’s disease. Current therapies for such disorders are effective only for a small subset of individuals or provide symptomatic relief but do not alter disease progression. One exciting therapeutic approach that may turn the tide for addressing neurodegenerative disorders involves the mammalian target of rapamycin (mTOR). mTOR is a component of the protein complexes mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) that are ubiquitous throughout the body and control multiple functions such as gene transcription, metabolism, cell survival, and cell senescence. mTOR through its relationship with phosphoinositide 3-kinase (PI 3-K) and protein kinase B (Akt) and multiple downstream signaling pathways such as p70 ribosomal S6 kinase (p70S6K) and proline rich Akt substrate 40 kDa (PRAS40) promotes neuronal cell regeneration through stem cell renewal and oversees critical pathways such as apoptosis, autophagy, and necroptosis to foster protection against neurodegenerative disorders. Targeting by mTOR of specific pathways that drive long-term potentiation, synaptic plasticity, and β-amyloid toxicity may offer new strategies for disorders such as stroke and Alzheimer’s disease. Overall, mTOR is an essential neuroprotective pathway but must be carefully targeted to maximize clinical efficacy and eliminate any clinical toxic side effects.

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    Molecular mechanisms of the suppression of axon regeneration by KLF transcription factors
    Akintomide Apara, Jeffrey L. Goldberg
    2014, 9 (15):  1418-1421.  doi: 10.4103/1673-5374.139454
    Abstract ( 234 )   PDF (188KB) ( 724 )   Save

    Molecular mechanisms of the Kru?ppel-like family of transcription factors (KLFs) have been studied more in proliferating cells than in post-mitotic cells such as neurons. We recently found that KLFs regulate intrinsic axon growth ability in central nervous system (CNS) neurons including retinal ganglion cells, and hippocampal and cortical neurons. With at least 15 of 17 KLF family members expressed in neurons and at least 5 structurally unique subfamilies, it is important to determine how this complex family functions in neurons to regulate the intricate genetic programs of axon growth and regeneration. By characterizing the molecular mechanisms of the KLF family in the nervous system, including binding partners and gene targets, and comparing them to defined mechanisms defined outside the nervous system, we may better understand how KLFs regulate neurite growth and axon regeneration.

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    Give progesterone a chance
    Florencia Labombarda, Daniel Garcia-Ovejero
    2014, 9 (15):  1422-1424.  doi: 10.4103/1673-5374.139456
    Abstract ( 246 )   PDF (153KB) ( 662 )   Save

    There is currently no standard pharmacological treatment for spinal cord injury. Here, we suggest that progesterone, a steroid hormone, may be a promising therapeutical candidate as it is already for traumatic brain injury, where it has reached phase II clinical trials. We rely on previous works showing anti-inflammatory, neuroprotective and promyelinating roles for progesterone after spinal cord injury and in our recent paper, in which we demonstrate that progesterone diminishes lesion, preserves white matter integrity and improves locomotor recovery in a clinically relevant model of spinal cord lesion.

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    The role of DJ-1 in the oxidative stress cell death cascade after stroke
    Paolina Pantcheva, Maya Elias, Kelsey Duncan, Cesar V. Borlongan, Naoki Tajiri, Yuji Kaneko
    2014, 9 (15):  1430-1433.  doi: 10.4103/1673-5374.139458
    Abstract ( 270 )   PDF (492KB) ( 940 )   Save

    Oxidative stress is closely associated with secondary cell death in many disorders of the central nervous system including stroke, Parkinson’s disease, Alzheimer’s disease. Among many aberrant oxidative stress-associated proteins, DJ-1 has been associated with the oxidative stress cell death cascade primarily in Parkinson’s disease. Although principally expressed in the cytoplasm and nucleus, DJ-1 can be secreted into the serum under pathological condition. Recently, a close pathological association between DJ-1 and oxidative stress in stroke has been implicated. To this end, we and others have demonstrated the important role of mitochondria in neuroprotection for stroke by demonstrating that the translocation of DJ-1 in the mitochondria could potentially mitigate mitochondrial injury. Here, we discuss our recent findings testing the hypothesis that DJ-1 not only functions as a form of intracellular protection from oxidative stress, but that it also utilizes paracrine and/or autocrine cues in order to accomplish extracellular signaling between neighboring neuronal cells, resulting in neuroprotection. This article highlights recent evidence supporting the status of DJ-1 as key anti-oxidative stress therapeutic target for stroke.

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    Perspectives on the neural connectivity of the fornix in the human brain
    Sung Ho Jang, Hyeok Gyu Kwon
    2014, 9 (15):  1434-1436.  doi: 10.4103/1673-5374.139459
    Abstract ( 405 )   PDF (394KB) ( 703 )   Save

    The fornix is involved in the transfer of information on episodic memory as a part of the Papez circuit. Diffusion tensor imaging enables to estimate the neural connectivity of the fornix. The anterior fornical body has high connectivity with the anterior commissure, and brain areas relevant to cholinergic nuclei (septal forebrain region and brainstem) and memory function (medial temporal lobe). In the normal subjects, by contrast, the posterior fornical body has connectivity with the cerebral cortex and brainstem through the splenium of the corpus callosum. We believe that knowledge of the neural connectivity of the fornix would be helpful in investigation of the neural network associated with memory and recovery mechanisms following injury of the fornix

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    Optimal therapeutic dose and time window of picroside II in cerebral ischemic injury
    Guangyi Liu, Li Zhao, Tingting Wang, Meizeng Zhang, Haitao Pei
    2014, 9 (15):  1437-1445.  doi: 10.4103/1673-5374.139460
    Abstract ( 208 )   PDF (1170KB) ( 731 )   Save

    A preliminary study from our research group showed that picroside II inhibited neuronal apoptosis in ischemic penumbra, reduced ischemic volume, and improved neurobehavioral function in rats with cerebral ischemia. The aim of the present study was to validate the neuroprotective effects of picroside II and optimize its therapeutic time window and dose in a rat model of cerebral ischemia. We found that picroside II inhibited cell apoptosis and reduced the expression of neuron-specific enolase, a marker of neuronal damage, in rats after cerebral ischemic injury. The optimal treatment time after ischemic injury and dose were determined, respectively, as follows: (1) 2.0 hours and 10 mg/kg according to the results of toluidine blue staining; (2) 1.5 hours and 10 mg/kg according to early apoptotic ratio by flow cytometry; (3) 2.0 hours and 10 mg/kg according to immunohistochemical and western blot analysis; and (4) 1.5 hours and 10 mg/kg according to reverse transcription polymerase chain reaction. The present findings suggest that an intraperitoneal injection of 10 mg/kg picroside II 1.5–2.0 hours after cerebral ischemic injury in rats is the optimal dose and time for therapeutic benefit.

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    Neuroprotective effect of pretreatment with ganoderma lucidum in cerebral ischemia/reperfusion injury in rat hippocampus
    Wangxin Zhang, Qiuling Zhang, Wen Deng, Yalu Li, Guoqing Xing, Xianjun Shi, Yifeng Du
    2014, 9 (15):  1446-1452.  doi: 10.4103/1673-5374.139461
    Abstract ( 207 )   PDF (764KB) ( 1020 )   Save

    Ganoderma lucidum is a traditional Chinese medicine, which has been shown to have both anti-oxidative and anti-inflammatory effects, and noticeably decreases both the infarct area and neuronal apoptosis of the ischemic cortex. This study aimed to investigate the protective effects and mechanisms of pretreatment with ganoderma lucidum (by intragastric administration) in cerebral ischemia/reperfusion injury in rats. Our results showed that pretreatment with ganoderma lucidum for 3 and 7 days reduced neuronal loss in the hippocampus, diminished the content of malondialdehyde in the hippocampus and serum, decreased the levels of tumor necrosis factor-α and interleukin-8 in the hippocampus, and increased the activity of superoxide dismutase in the hippocampus and serum. These results suggest that pretreatment with ganoderma lucidum was protective against cerebral ischemia/reperfusion injury through its anti-oxidative and anti-inflammatory actions.

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    Pretreatment with Danhong injection protects the brain against ischemia-reperfusion injury
    Shaoxia Wang, Hong Guo, Xumei Wang, Lijuan Chai, Limin Hu, Tao Zhao, Buchang Zhao, Xiaoxu Tan, Feifei Jia
    2014, 9 (15):  1453-1459.  doi: 10.4103/1673-5374.139462
    Abstract ( 258 )   PDF (565KB) ( 986 )   Save

    Danhong injection (DHI), a Chinese Materia Medica standardized product extracted from Radix Salviae miltiorrhizae and Flos Carthami tinctorii, is widely used in China for treating acute ischemic stroke. In the present study, we explored the neuroprotective efficacy of DHI in a rat model of temporary middle cerebral artery occlusion, and evaluated the potential mechanisms underlying its effects. Pretreatment with DHI (0.9 and 1.8 mL/kg) resulted in a significantly smaller infarct volume and better neurological scores than pretreatment with saline. Furthermore, DHI significantly reduced the permeability of the blood-brain barrier, increased occludin protein expression and decreased neutrophil infiltration, as well as profoundly suppressing the upregulation of matrix metallopeptidase-9 expression seen in rats that had received vehicle. Matrix metallopeptidase-2 expression was not affected by ischemia or DHI. Moreover, DHI (1.8 mL/kg) administered 3 hours after the onset of ischemia also improved neurological scores and reduced infarct size. Our results indicate that the neuroprotective efficacy of DHI in a rat model of cerebral ischemia-reperfusion injury is mediated by a protective effect on the blood-brain barrier and the reversal of neutrophil infiltration.

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    A feasible strategy for focal cerebral ischemia-reperfusion injury: remote ischemic postconditioning
    Qiang Liu, Shengnian Zhou, Yaodong Wang, Fang Qi, Yuan Song, Siwei Long
    2014, 9 (15):  1460-1463.  doi: 10.4103/1673-5374.139463
    Abstract ( 292 )   PDF (304KB) ( 646 )   Save

    It is difficult to control the degree of ischemic postconditioning in the brain and other ischemia-sensitive organs. Remote ischemic postconditioning could protect some ischemia-sensitive organs through measures on terminal organs. In this study, a focal cerebral ischemia-reperfusion injury model was established using three cycles of remote ischemic postconditioning, each cycle consisted of 10-minute occlusion of the femoral artery and 10-minute opening. The results showed that, remote ischemic postconditioning significantly decreased the percentage of the infarct area and attenuated brain edema. In addition, inflammatory nuclear factor-κB expression was significantly lower, while anti-apoptotic Bcl-2 expression was significantly elevated in the cerebral cortex on the ischemic side. Our findings indicate that remote ischemic postconditioning attenuates focal cerebral ischemia/reperfusion injury, and that the neuroprotective mechanism is mediated by an anti-apoptotic effect and reduction of the inflammatory response.

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    Integration of animal behaviors under stresses with different time courses
    Lun Zheng, Xigeng Zheng
    2014, 9 (15):  1464-1473.  doi: 10.4103/1673-5374.139464
    Abstract ( 313 )   PDF (1209KB) ( 1031 )   Save

    We used animal models of “forced swim stress” and “chronic unpredictable stress”, and tried to reveal whether a passive coping style of high flotation behavior in forced swim stress predicts anhedonia behavior after chronic unpredictable stress, and whether the dopamine system regulates floating and anhedonia behaviors. Our results confirmed that depression-prone rats use “floating behavior” as a coping strategy in forced swim stress and more readily suffer from anhedonia during chronic unpredictable stress. Intraperitoneal injection or nucleus accumbens microinjection of the dopamine 2/3 receptor subtype agonist ropinirole reduced floating behaviors in depression-prone animals, but increased sucrose preference in rats showing anhedonia. These data indicate that floating behavior is a defensive mode that is preferred by susceptible individuals under conditions of acute stress. Simultaneously, these animals more readily experienced anhedonia under long-term stress; that is, they were more readily affected by depression. Our results suggest that dopamine 2/3 receptor subtypes in the nucleus accumbens play an important role in floating behaviors and anhedonia.

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    Changes in brain activation in stroke patients after mental practice and physical exercise: a functional MRI study
    Hua Liu, Luping Song, Tong Zhang
    2014, 9 (15):  1474-1484.  doi: 10.4103/1673-5374.139465
    Abstract ( 300 )   PDF (1405KB) ( 947 )   Save

    Mental practice is a new rehabilitation method that refers to the mental rehearsal of motor imagery content with the goal of improving motor performance. However, the relationship between activated regions and motor recovery after mental practice training is not well understood. In this study, 15 patients who suffered a first-ever subcortical stroke with neurological deficits affecting the right hand, but no significant cognitive impairment were recruited. 10 patients underwent mental practice combined with physical practice training, and 5 patients only underwent physical practice training. We observed brain activation regions after 4 weeks of training, and explored the correlation of activation changes with functional recovery of the affected hands. The results showed that, after 4 weeks of mental practice combined with physical training, the Fugl-Meyer assessment score for the affected right hand was significantly increased than that after 4 weeks of practice training alone. Functional MRI showed enhanced activation in the left primary somatosensory cortex, attenuated activation intensity in the right primary motor cortex, and enhanced right cerebellar activation observed during the motor imagery task using the affected right hand after mental practice training. The changes in brain cortical activity were related to functional recovery of the hand. Experimental findings indicate that cortical and cerebellar functional reorganization following mental practice contributed to the improvement of hand function.

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