Neuroprotection of catalpol in transient global ischemia in gerbils

The neuroprotection of catalpol and its mechanism was evaluated in cerebral ischemic model in gerbils. Three groups were designed as sham-operated, ischemia-treated, respectively, with catalpol and saline. Catalpol was injected intraperitoneally immediately after reperfusion and repeatedly at 12, 24, 48 and 72 h with the dose of 5.0 mg/kg. The neuroprotection was estimated by the indexes of behavior and histology. Behavioral testing was performed in Y-maze and the survival neurons in CA1 subfield were counted under a microscope after behavioral testing. In addition, apoptosis induced by ischemia was also examined by using the terminal deoxynucleotidyl transferase-mediated UTP nick end labeling method. It was shown that catalpol significantly attenuated apoptosis, rescued hippocampal CA1 neurons and reduced cognitive impairment. In order to make clear the mechanism of catalpol's neuroprotection, the activities of endogenous antioxidants and nitric oxide synthase together with the content of lipid peroxide in cortex and hippocampus were assayed. The results proved that catalpol significantly reduced the content of lipid peroxide, increased the activity of glutathione peroxidase and decreased the activity of nitric oxide synthase. All these suggested that catalpol was a potential neuroprotective agent and its neuroprotective effects were achieved at least partly by promoting endogenous antioxidant enzymatic activities and reducing the formation of nitric oxide.     

Neuroprotection by the inhibition of apoptosis

Accumulating evidence strongly suggests that apoptosis contributes to neuronal cell death in a variety of neurodegenerative contexts. Activation of the cysteine protease caspase-3 appears to be a key event in the execution of apoptosis in the central nervous system (CNS). As a result, mice null for caspase-3 display considerable neuronal expansion usually resulting in death by the second week of life. At present, 14 caspase family members have been identified and subdivided into three subgroups on the basis of preference for specific tetrapeptide motifs using a positional scanning combinatorial substrate library. Caspase-3 is a group II member (2, 3, 7) categorized by an absolute substrate requirement for aspartic acid in the P4 position of the scissile bond. The preferred cleavage motif (DExD) for group II caspases is found in many structural, metabolic and repair proteins essential for cellular homeostasis. Consistent with the proposal that apoptosis plays a central in role human neurodegenerative disease, caspase-3 activation has recently been observed in stroke, spinal cord trauma, head injury and Alzheimer's disease. Indeed, peptide-based caspase inhibitors prevent neuronal loss in animal models of head injury and stroke suggesting that these compounds may be the forerunners of non-peptide small molecules that halt apoptosis processes implicated in these neurodegenerative disorders. A clear link between an hereditary neurodegenerative disorder and failed caspase inhibition has recently been proposed for spinal muscular atrophy (SMA). In severe SMA, the neuronal specific inhibitor of apoptosis (IAP) family member known as NAIP is often dysfunctional due to missense and truncation mutations. IAPs such as NAIP potently block the enzymatic activity of group II caspases (3 and 7) suggesting that NAIP mutations may permit unopposed developmental apoptosis to occur in sensory and motor systems resulting in lethal muscular atrophy. Conversely, adenovirally-mediated overexpression of NAIP or the X-linked IAP called XIAP reduces the loss of CA1 hippocampal neurons following transient forebrain ischemia. Taken together, these findings suggest that anti-apoptotic strategies may some day have utility in the treatment of neurodegenerative disease. The present review will summarize some of the recent evidence suggesting that apoptosis inhibitors may become a practical therapeutic approach for both acute and chronic neurodegenerative conditions.     

Neuroprotection in stroke by complement inhibition and immunoglobulin therapy

Activation of the complement system occurs in a variety of neuroinflammatory diseases and neurodegenerative processes of the CNS. Studies in the last decade have demonstrated that essentially all of the activation components and receptors of the complement system are produced by astrocytes, microglia, and neurons. There is also rapidly growing evidence to indicate an active role of the complement system in cerebral ischemic injury. In addition to direct cell damage, regional cerebral ischemia and reperfusion (I/R) induces an inflammatory response involving complement activation and generation of active fragments, such as C3a and C5a anaphylatoxins, C3b, C4b, and iC3b. The use of specific inhibitors to block complement activation or their mediators such as C5a, can reduce local tissue injury after I/R. Consistent with therapeutic approaches that have been successful in models of autoimmune disorders, many of the same complement inhibition strategies are proving effective in animal models of cerebral I/R injury. One new form of therapy, which is less specific in its targeting of complement than monodrug administration, is the use of immunoglobulins. Intravenous immunoglobulin (IVIG) has the potential to inhibit multiple components of inflammation, including complement fragments, pro-inflammatory cytokine production and leukocyte cell adhesion. Thus, IVIG may directly protect neurons, reduce activation of intrinsic inflammatory cells (microglia) and inhibit transendothelial infiltration of leukocytes into the brain parenchyma following an ischemic stroke. The striking neuroprotective actions of IVIG in animal models of ischemic stroke suggest a potential therapeutic potential that merits consideration for clinical trials in stroke patients.     

Neuroprotection in HIV-positive drug users: implications for antioxidant therapy

Impaired neuroprotection resulting from oxidative stress has been implicated in neurodegeneration in a number of pathologic conditions of the brain, including both subcortical and cortical type dementias. Production of excessive oxidative stress, moreover, can lead to elevated levels of certain proinflammatory cytokines that are considered to be contributing factors to neuronal injury and are evident in HIV-related dementia as well as in other neurodegenerative conditions. Inhibitors of oxidative damage could thus be promising therapeutic agents for preventing progressive nerve cell death and slowing the advance of neurodegenerative disease. The potential of antioxidant therapy to provide neuroprotection is substantiated by studies demonstrating reduced oxidative stress with supplementation and lower risk for cognitive impairment with higher plasma antioxidant levels.     

Immunological mechanisms in glaucoma

Glaucoma is one of the most frequent causes of blindness worldwide. The elevated intraocular pressure does not explain glaucoma in all patients but can be considered as a risk factor of the disease. There are some evidences that autoimmune mechanisms may be involved in this disorder. This review attempts to demonstrate the findings about autoimmune mechanisms in glaucoma patients. Consistent up- and down-regulations in the autoantibody profiles against ocular antigens are present in glaucoma patients. These changes in natural autoimmunity could be found in independent study populations and might be a promising tool for glaucoma detection.     

GDNF基因修饰的NSCs移植对暂时性缺血性脑卒中大鼠的神经保护作用研究

目的　探讨移植胶质细胞源性神经营养因子（glial cell line derived neurotrophic factor,GDNF）基因修饰的神经干细胞（neural stem cells,NSCs）对暂时性缺血性脑卒中大鼠的神经保护。 方法　用GDNF重组腺病毒载体转染新生大鼠NSCs（GDNF/NSCs）,分化培养7 d后,行免疫细胞化学染色检测微管相关蛋白2（MAP2）。采用改良的插线法制作暂时性脑缺血再灌注模型,3 d后经脑室分别移植生理盐水、NSCs和GDNF/NSCs。于再灌注后1、2、3、5、7周末处死大鼠,行免疫组织化学染色观察移植细胞在脑内的神经元分化及星形胶质细胞在缺血区形成胶质界膜情况,行Luxol fast blue（LFB）染色显示神经纤维损伤情况。 结果　GDNF/NSCs体外分化为MAP2+细胞的比例显著高于NSCs的分化。移植细胞在脑内分化为MAP2+细胞,于再灌注第5周分化达高峰,GDNF/NSCs组于再灌注第3~7周,其MAP2+细胞显著高于NSCs组。各组缺血区由星形胶质细胞形成的血管胶质界膜存在不同程度的破坏,其连续性中断。对照组在各个时间点,血管胶质界膜损伤严重,完整性差,两细胞移植组,其胶质界膜随时间延长逐渐完整,GDNF/NSCs组早于NSCs组完善对胶质界膜的修复。此外,GDNF/NSCs组的神经纤维损伤修复优于NSCs组。 结论　GDNF/NSCs比NSCs对暂时性缺血性脑卒中大鼠模型有更好的神经保护作用,可能是与GDNF提高了NSCs在脑内的神经元分化,增强了NSCs对胶质界膜及神经纤维修复有关。     

Neuroprotection by (-)-deprenyl and related compounds

There is an increasing number of data by in vitro and in vivo experiments, indicating that (-)-deprenyl is neuroprotective to dopamine neurons, even though detailed mechanism remains to be clarified. In this paper neuroprotection by (-)-deprenyl and structurally related compounds was examined in concern with the suppression of apoptosis induced by a reactive oxygen species, peroxynitrite generated from SIN-1. The apoptotic DNA damage was quantitatively determined using dopaminergic SH-SYSY cells and by a single cell gel electrophoresis (comet) assay. DNA damage induced by peroxynitrite was proved to be apoptotic by prevention of the damage by cycloheximide or actinomycin-D. (-)-Deprenyl and other propargylamines protected the cells from apoptosis in a dose-dependent way. (-)-Deprenyl protected the cells even after it was washed out, suggesting that it may initiate the intracellular process to repress the apoptotic death program. The study on the structure-activity relationship of (-)-deprenyl analogues revealed that a N-propargyl residue with adequate size of hydrophobic structure is essentially required for the anti-apoptotic activity. These results suggest that (-)-deprenyl and related compounds may protect neurons from apoptosis and be applicable to delay the deterioration of neurons during advancing ageing and in neurodegenerative disorders.     

Neuroprotection against staurosporine by metalloporphyrins independent of antioxidant capability

Metalloporphyrin catalytic antioxidants are remarkably useful in protecting cells and tissues in a wide array of disease models, attributed primarily to functioning as superoxide dismutase (SOD) mimetics or by scavenging other reactive oxygen species (ROS). However, we recently showed that neuroprotection against Ca²⁺-dependent excitotoxic insults did not correlate with antioxidant strength or capability [25], raising the question of whether scavenging of ROS underlies neuroprotection in other types of neuronal injury. The protein kinase inhibitor staurosporine causes neuronal demise primarily by apoptosis. Neuroprotection from staurosporine by a limited number of metalloporphyrin antioxidants has previously been attributed to antioxidant action. In the current study, a wide array of anionic and cationic metalloporphyrins and porphyrins, ranging in antioxidant strength or capability, provided protection against staurosporine in cortical neuron and cerebellar granule neuron (CGN) culture. Neuroprotection did not correlate with antioxidant strength or capability. In CGN but not cortical neuron cultures, NMDA receptor antagonists also prevented neurotoxicity, so metalloporphyrins may also target this secondary mode of death induced by staurosporine. Neuroprotection observed with antioxidant-inactive controls raises the possibility of an additional, or perhaps alternative, mechanism by antioxidant analogs not involving ROS scavenging.     

Neuroprotection by neuropeptide Y in cell and animal models of Parkinson's disease

This study was aimed to investigate the potential neuroprotective effect of neuropeptide Y (NPY) on the survival of dopaminergic cells in both in vitro and in animal models of Parkinson's disease (PD). NPY protected human SH-SY5Y dopaminergic neuroblastoma cells from 6-hydroxydopamine-induced toxicity. In rat and mice models of PD, striatal injection of NPY preserved the nigrostriatal dopamine pathway from degeneration as evidenced by quantification of (1) tyrosine hydroxylase (TH)-positive cells in the substantia nigra pars compacta, levels of (2) striatal tyrosine hydroxylase and dopamine transporter, (3) dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) as well as (4) rotational behavior. NPY had no neuroprotective effects in mice treated with Y(2) receptor antagonist or in transgenic mice deficient for Y(2) receptor suggesting that NPY effects are mediated through this receptor. Stimulation of Y(2) receptor by NPY triggered the activation of both the ERK1/2 and Akt pathways but did not modify levels of brain derived neurotrophic factor (BDNF) or glial cell line-derived neurotrophic factor. These results open new perspectives in neuroprotective therapies using NPY and suggest potential beneficial effects in PD.     

Neuroprotection by nitric oxide against hydroxyl radical-induced nigral neurotoxicity

We investigated the effects of nitric oxide on an in vitro and in vivo generation of hydroxyl radicals, and in vivo neurotoxicity caused by intranigral infusion of ferrous citrate in rats. The formation of hydroxyl radicals in vitro, without exogenous hydrogen peroxide, was dose-dependent. Some nitric oxide donors (e.g. sodium nitroprusside) stimulated, while others (nitroglycerin, diethylamine/nitric oxide, nitric oxide in Ringer's solution) suppressed hydroxyl radical generation in vitro. A significant increase in extra-cellular hydroxyl radicals was detected in a brain microdialysis study. Intranigral infusion of ferrous citrate caused long-lasting lipid peroxidation and dopamine depletion in the ipsilateral nigral region and striatum, respectively. Sub-acute dopamine depletion in the striatum was positively correlated with acute lipid peroxidation in substantia nigra. Intranigral administration of nitric oxide did not affect striatal dopamine. Interestingly, nitric oxide in Ringer's protected nigral neurones against the oxidative injury. The results demonstrate that a regional increase in the levels of iron can result in hydroxyl radical generation and lipid peroxidation leading to neurotoxicity. It also demonstrates that exogenous nitric oxide can act as hydroxyl radical scavenger and protect neurones from oxidative injury.     

HLA in primary open-angle glaucoma

Histocompatibility antigen typing was carried out in 50 Caucasian patients with primary open-angle glaucoma (POAG) and 50 Caucasian ocular-normotensive subjects. HLA-A 3 was present in 46%, B7 in 52%, B12 in 50%, and either B7 or B12 in 88% of p,tients with POAG. These prevalences in POAG patients were significantly greater than in ocular-normotensive subjects (p less than 0.01, p less than 0.0005, p less than 0.001, and p less than less than 0.0005, respectively). The prevalences of A 3-B 7, A 3-B 12 and either combination were also significantly greater in POAG patients than in the ocular normotensives (p less than 0.005, p less than 0.005, and p less than 0.0005, respectively). HLA-BW 35 was noted to be in deficit in Caucasian POAG patients (8%) as compared to Caucasian ocular normotensives (32%; p less than 0.01).     

Cyclic nucleotides in experimental glaucoma

Research Institute of General Pathology and Pathological Physiology, Academy of Medical Sciences of the USSR, Moscow. Academician V. P. Filatov Odessa Research Institute of Eye Diseases and Tissue Therapy. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 106, No. 10, pp. 419–421, October, 1988.     

Neuroprotection by the multitarget iron chelator M30 on age-related alterations in mice

Based on a multimodal drug design paradigm, we have synthesized a multifunctional non-toxic, brain permeable iron chelating compound, M30, possessing the neuroprotective N-propargyl moiety of the anti-Parkinsonian drug, monoamine oxidase (MAO)-B inhibitor, rasagiline and the antioxidant-iron chelator moiety of an 8-hydroxyquinoline derivative of the iron chelator, VK28. Here, we report that a chronic systemic treatment of aged mice with M30 (1 and 5 mg/kg; 4 times weekly for 6 months), had a significant positive impact on neuropsychiatry functions and cognitive age-related impairment. M30 significantly reduced cerebral iron accumulation as demonstrated by Perl's staining, accompanied by a marked decrease in cerebral β-amyloid plaques. In addition, our results demonstrate that M30 caused a significant inhibition of both MAO-A and -B activities in the cerebellum of aged mice, compared with vehicle-treated aged control mice. In summary, the present study indicates that the novel MAO inhibitor/iron chelating drug, M30, acting against multiple brain targets could reverse age-associated memory impairment and provide a potential treatment against the progression of neurodegeneration in ageing.     

Neuroprotection and Remyelination after Autoimmune Demyelination in Mice that Inducibly Overexpress CXCL1

In rodents, the chemokine CXCL1 both induces the proliferation and inhibits the migration of oligodendrocyte precursor cells. We previously reported that in multiple sclerosis, the same chemokine is expressed by hypertrophic astrocytes, which associate with oligodendrocytes that express the receptor CXCR2. To investigate whether chemokines influence repair after autoimmune demyelination, we generated GFAP-rtTA × β-Gal-TRE-CXCL1 double-transgenic (Tg) mice that inducibly overexpress CXCL1 under the control of the astrocyte-specific gene, glial fibrillary acidic protein. Experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, was induced in these animals (and controls) by the subcutaneous injection of myelin oligodendrocyte glycoprotein, and after disease onset, CXCL1 production was initiated by the intraperitoneal injection of doxycycline. Double-Tg animals displayed a milder course of disease compared with both single (CXCL1 or glial fibrillary acidic protein)-Tg and wild-type controls. Pathologies were similar in all groups during the acute stage of disease. During the chronic disease phase, both inflammation and demyelination were diminished in double-Tg mice and Wallerian degeneration was markedly decreased. Remyelination was strikingly more prominent in double-Tg mice, together with an apparent increased number of oligodendrocytes. Moreover, cell proliferation, indicated by BrdU incorporation within the central nervous system, was more widespread in the white matter of double-Tg animals. These findings suggest a neuroprotective role for CXCL1 during the course of autoimmune demyelination.