Calpain inhibitor attenuated optic nerve damage in acute optic neuritis in rats.
Calpain inhibitor attenuated optic nerve damage in acute optic neuritis in rats.
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DOI：
10.1111/jnc.12064
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发表时间：
2013-01
影响因子：
4.7
通讯作者：
Banik NL
中科院分区：
文献类型：
--
作者：
Das A;Guyton MK;Smith A;Wallace G 4th;McDowell ML;Matzelle DD;Ray SK;Banik NL
视神经炎是一种急性炎症性自身免疫性中枢神经系统脱髓鞘疾病，常见于多发性硬化症。在大多数MS患者中，ON是由视神经损伤导致视觉功能障碍引起的早期诊断标志。在Lewis大鼠诱发实验性自身免疫性脑脊髓炎(EAE)后，可以研究MS和ON的各种特征。视神经中的炎症和细胞死亡，以及随后对视网膜中视网膜神经节细胞的损害，被认为与视觉功能障碍有关。因此，表征导致EAE动物视觉功能障碍的病理生理变化可能有助于开发治疗干预的新靶点。我们用和不用钙蛋白酶抑制剂钙肽(CP)治疗EAE动物。我们的研究表明，在疾病的临床症状(OCS)诱发EAE后，钙激活的中性蛋白水解酶Calain在视神经中表达上调，这些变化在CP治疗后被减弱。这些减少与炎症(细胞因子、诱导型一氧化氮合酶、环氧合酶-2、核因子-κB)和小胶质细胞(即激活的小胶质细胞)的减少有关。我们观察到，Calain抑制减少了星形胶质细胞(反应性星形胶质细胞)和水通道蛋白4(AQP4)的表达。Th1/Th2细胞因子产生的平衡以及Th1相关的CCR5和CXCR3趋化因子受体的表达影响许多病理过程，在神经元损伤中既起到致病作用，又起到保护作用。我们的数据表明，CP抑制了细胞因子失衡。此外，CP还可降低Bax/bcl2比值、TBID、PARP-1的产生、Calain和Caspase的表达和活性，以及核小体DNA片段化。结果表明，CP可减少EAE大鼠视神经脱髓鞘[髓鞘碱性蛋白(MBP)丢失]和轴突损伤[增加去磷酸化神经丝蛋白(de-NFP)]，并促进细胞内神经保护通路。因此，这些数据表明，Calain参与了疾病的炎症和神经退行性变，可能是治疗EAE和MS的一个有前途的靶点。
Optic neuritis (ON), which is an acute inflammatory autoimmune demyelinating disease of the central nervous system (CNS), often occurs in multiple sclerosis (MS). ON is an early diagnostic sign in most MS patients caused by damage to the optic nerve leading to visual dysfunction. Various features of both MS and ON can be studied following induction of experimental autoimmune encephalomyelitis (EAE), an animal model of MS, in Lewis rats. Inflammation and cell death in the optic nerve, with subsequent damage to the retinal ganglion cells in the retina, are thought to correlate with visual dysfunction. Thus, characterizing the pathophysiological changes that lead to visual dysfunction in EAE animals may help develop novel targets for therapeutic intervention. We treated EAE animals with and without the calpain inhibitor calpeptin (CP). Our studies demonstrated that the Ca2+-activated neutral protease calpain was upregulated in the optic nerve following induction of EAE at the onset of clinical signs (OCS) of the disease and these changes were attenuated following treatment with CP. These reductions correlated with decreases in inflammation (cytokines, iNOS, COX-2, NF-κB), and microgliosis (i.e. activated microglia). We observed that calpain inhibition reduced astrogliosis (reactive astroglia) and expression of aquaporin 4 (AQP4). The balance of Th1/Th2 cytokine production and also expression of the Th1-related CCR5 and CXCR3 chemokine receptors influence many pathological processes and play both causative and protective roles in neuron damage. Our data indicated that CP suppressed cytokine imbalances. Also, Bax:Bcl-2 ratio, production of tBid, PARP-1, expression and activities of calpain and caspases, and internucleosomal DNA fragmentation were attenuated after treatment with CP. Our results demonstrated that CP decreased demyelination [loss of myelin basic protein (MBP)] and axonal damage [increase in dephosphorylated neurofilament protein (de-NFP), and also promoted intracellular neuroprotective pathways in optic nerve in EAE rats. Thus, these data suggest that calpain is involved in inflammatory as well as in neurodegenerative aspects of the disease and may be a promising target for treating ON in EAE and MS.
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影响因子：
9.1
作者：
Kennedy, KJ;Karpus, WJ
通讯作者：
Karpus, WJ
影响因子：
3
作者：
Das, Arabinda;Guyton, M. Kelly;Banik, Naren L.
通讯作者：
Banik, Naren L.
DOI：
10.1196/annals.1344.005
发表时间：
2005-01-01
期刊：
NEUROPROTECTIVE AGENTS
影响因子：
--
作者：
Guyton, MK;Sribnick, EA;Banik, NL
通讯作者：
Banik, NL
影响因子：
158.5
作者：
BECK, RW;CLEARY, PA;ATWELL, CW
通讯作者：
ATWELL, CW
MOG 特异性 TCR 转基因小鼠自发性自身免疫性视神经炎引起的视网膜神经节细胞损伤
影响因子：
3.3
作者：
Guan, Yangtai;Shindler, Kenneth S.;Rostami, A. M.
通讯作者：
Rostami, A. M.