Structure-nongenomic neuroprotection relationship of estrogens and estrogen-derived compounds

Nongenomic estrogen signaling pathways involve extranuclear estrogen receptors or function independently from estrogen receptors. These pathways participate in neuroprotection elicited by the hormone. Additional nongenomic neuroprotective effects are attributable to antioxidant and antiinflammatory actions of estrogens. Numerous chemical modifications to afford neuroprotective compounds from estrogens while eliminating estrogenicity and maintaining or enhancing nongenomic neuroprotection have been described. This review highlights recent structure-activity studies that revealed the importance of antioxidant effects for neuroprotective estrogen analogues and derivatives.     

beta-estradiol, dehydroepiandrosterone, and dehydroepiandrosterone sulfate protect against N-methyl-D-aspartate-induced neurotoxicity in rat hippocampal neurons by different mechanisms

We examined neuroprotective effects of beta-estradiol, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEA-S) against N-methyl-D-aspartate (NMDA)-induced neurotoxicity in primary cultured rat hippocampal neurons. All three steroids demonstrated neuroprotective effects. Time-course studies revealed that steroid cotreatment for only 15 min at the same time as exposure to NMDA, but neither pretreatment nor addition of steroids for 24 h after NMDA-mediated neuroprotective effects. This indicates that short-term actions of these steroids are critical for this process. Acute treatment with beta-estradiol dose dependently inhibited NMDA-induced intracellular Ca(2+) increases, which strongly correlated with its neuroprotective effect via L-type voltage-gated calcium channels. Acute treatment with DHEA, but not with DHEA-S, significantly inhibited nitric oxide (NO) production and Ca(2+)-sensitive NO synthase (NOS) activity caused by NMDA stimulation. An NOS inhibitor, N(G)-monomethyl-L-arginine acetate was also protective against NMDA-induced neurotoxicity. These data indicate that beta-estradiol may exert neuroprotective effects mainly by reducing Ca(2+) increases but that DHEA may act by inhibiting NOS activity. Treatment with the sigma-1 receptor (Sig-1R) antagonists rimcazole or BD1063 (1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine dihydrochloride) partially, but significantly, reversed the neuroprotective effect of DHEA-S against NMDA-induced neurotoxicity, whereas muscimol, a GABA-A-receptor agonist, did not. This suggests that the neuroprotective effect of DHEA-S may be mediated via Sig-1R, at least in part. Together, our data suggest that the neurosteroid family members beta-estradiol, DHEA, and DHEA-S exert neuroprotective effects through different nongenomic mechanisms.     

Argon: Neuroprotection in in vitro models of cerebral ischemia and traumatic brain injury

Introduction

Recently, it has been shown in several experimental settings that the noble gases xenon and helium have neuroprotective properties. In this study we tested the hypothesis that the noble gas argon has a neuroprotective potential as well. Since traumatic brain injury and stroke are widespread and generate an enormous economic and social burden, we investigated the possible neuroprotective effect in in vitro models of traumatic brain injury and cerebral ischemia.

Methods

Organotypic hippocampal slice cultures from mice pups were subjected to either oxygen-glucose deprivation or to a focal mechanical trauma and subsequently treated with three different concentrations (25, 50 and 74%) of argon immediately after trauma or with a two-or-three-hour delay. After 72 hours of incubation tissue injury assessment was performed using propidium iodide, a staining agent that becomes fluorescent when it diffuses into damaged cells via disintegrated cell membranes.

Results

We could show argon's neuroprotective effects at different concentrations when applied directly after oxygen-glucose deprivation or trauma. Even three hours after application, argon was still neuroprotective.

Conclusions

Argon showed a neuroprotective effect in both in vitro models of oxygen-glucose deprivation and traumatic brain injury. Our promising results justify further in vivo animal research.     

Both the antioxidant and D3 agonist actions of pramipexole mediate its neuroprotective actions in mesencephalic cultures

Pramipexole (PPX) is a full intrinsic activity, direct-acting dopamine (DA) agonist possessing 7-fold higher affinity for D3 than for D2 receptors. It also is a potent antioxidant. PPX was previously shown to be neuroprotective because it dose dependently attenuated the DA neuron loss produced by levodopa in mesencephalic cultures. Several different drugs with properties similar to PPX were studied here to better understand the mechanism or mechanisms responsible for this neuroprotective effect. The D3-preferring agonist 7-hydroxy-diphenylaminotetralin (7-OH-DPAT) and the D3 antagonist U99194, respectively, increased and decreased the neuroprotective effects of PPX in a dose-dependent fashion. Addition of the selective D2 agonist U95666 or the D2/D3 antagonists domperidone or raclopride did not affect PPX's neuroprotective effect. Interestingly, 7-OH-DPAT by itself did not attenuate the DA neuron loss produced by levodopa. However, when 7-OH-DPAT was combined with a low dose of the antioxidants U101033E or alpha-tocopherol, the toxic effects of levodopa were attenuated. Similar results were observed when the D3-preferring agonist PD128, 907 was studied. In addition, media conditioned by exposure of mesencephalic cultures incubated with all D3-preferring agonists studied was shown to enhance the growth of DA neurons in freshly harvested recipient cultures implicating a D3-mediated trophic activity in the neuroprotective effect. These data suggest that PPX's neuroprotective actions in the levodopa toxicity model are a consequence of its combined actions as a D3 receptor agonist and an antioxidant.     

粉防己碱对培养皮层神经元NMDA兴奋毒性损伤的保护作用

目的研究粉防己碱（Tet）对神经细胞兴奋性氨基酸N-甲基-D-天冬氨酸（NMDA）损伤的保护作用。方法采用原代培养的大鼠皮层神经细胞模型，给予NMDA直接损伤，加入不同浓度的粉防己碱，测定神经细胞损伤MTT变化。结果粉防己碱对兴奋性氨基酸损伤保护作用在10^-8～10^-6mmol／L范围内存在非剂量线性相关。结论Tet通过多靶点对神经元兴奋损伤产生拮抗作用，离体细胞模型中5×10^-7mol／L浓度具有最佳的保护效果。     

氯胺酮对培养胎鼠皮层神经元NMDA兴奋毒性损伤的保护作用

目的研究氯胺酮对培养神经细胞兴奋性氨基酸N-甲基-D-天冬氨酸(NMDA)损伤的保护作用。方法采用原代培养的胎鼠皮层神经细胞模型,给予NMDA直接损伤,加入不同浓度的氯胺酮,测定神经细胞损伤后噻唑蓝(MTT)变化。结果氯胺酮在50～1000μmol/L范围内存在对兴奋性氨基酸损伤的保护作用,非剂量线性相关。结论氯胺酮对神经元NMDA兴奋毒性损伤产生拮抗作用,离体细胞模型中1×102-3μmol/L浓度左右具有保护效果。     

Neuroprotective efficacy and therapeutic window of the high-affinity N-methyl-D-aspartate antagonist conantokin-G: in vitro (primary cerebellar neurons) and in vivo (rat model of transient focal brain ischemia) studies

Conantokin-G (Con-G), a 17-amino-acid peptide derived from marine snails and a potent N-methyl-D-aspartate (NMDA) antagonist, was evaluated for its neuroprotective properties in vitro and in vivo. In primary cerebellar neurons, Con-G was shown to decrease excitotoxic calcium responses to NMDA and to exhibit differential neuroprotection potencies against hypoxia/hypoglycemia-, NMDA-, glutamate-, or veratridine-induced injury. Using the intraluminal filament method of middle cerebral artery occlusion as an in vivo rat model of transient focal brain ischemia, the neuroprotective dose-response effect of Con-G administration beginning 30 min postocclusion was evaluated after 2 h of ischemia and 22 h of reperfusion. In the core region of injury, an 89% reduction in brain infarction was measured with significant neurological and electroencephalographic recovery at the maximal dose tested (2 nmol), although mild sedation was noted. Lower doses of Con-G (0.001-0.5 nmol) were significantly neuroprotective without causing sedation. Postinjury time course experiments demonstrated a therapeutic window out to at least 4 to 8 h from the start of the injury, providing a 47% reduction in core injury. The neuroprotective effect of Con-G (0. 5 nmol) was also evaluated after 72 h of injury, where a 54% reduction in core brain infarction was measured. Critically, in both recovery models (i.e., 24 and 72 h), the reduction in brain infarction was associated with significant improvements in neurological and electroencephalographic recovery. These data provide evidence for the potent and highly efficacious effect of Con-G as a neuroprotective agent, with an excellent therapeutic window for the potential intervention against ischemic/excitotoxic brain injury.     

Distribution and Analysis of Milk Fat Globule and Crescent in Murrah Buffalo and Crossbred Cow

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - India is the largest producer of buffalo milk in the world. Buffalo milk is rich in minerals like calcium and...     

实验性阿尔茨海默模型大鼠海马内病理和PCNAmRNA表达的变化及rLent/NT4-NAP对其的影响

目的探讨实验性阿尔茨海默病模型大鼠脑内海马光镜下的变化和DNA修复蛋白PCNAmRNA表达的变化,进一步探讨神经保护肽慢病毒rLent/NT4-NAP（NAP）对其具有神经保护作用机制。方法选择无菌级雄性大鼠Wister大鼠40只,随机分为对照组,假手术组,阿尔茨海默（AD）模型大鼠组,rLent/NT4-NAP（NAP）组,每组10只。建立Aβ1-40联合应用转移生长因子β1（TGFβ1）注入实验大鼠左侧海马区制备阿尔茨海默动物模型,通过HE染色观察各组大鼠海马区的形态学改变;通过原位杂交的方法检测实验各组大鼠海马区PCNAmRNA表达的变化。结果 HE染色发现痴呆组大鼠左侧海马区神经细胞明显变性、坏死,而NAP组细胞损伤情况较痴呆组大鼠明显减轻;用原位杂交的方法检测痴呆组大鼠左侧海马区神经细胞胞核内PCNAmRNA强阳性表达减少,而NAP组左侧海马区神经细胞胞核内PCNAmRNA表达较痴呆组显著上调与对照组比较无统计学差异。结论 NAP通过诱导DNA修复蛋白PCNA蛋白表达上调,从而促进DNA损伤修复和减少细胞凋亡,对神经细胞有神经保护作用,实现其内源性的保护作用。     

Incidence and Antimicrobial Resistance of Campylobacter and Salmonella from Houseflies (Musca Domestica) in Kitchens,Farms, Hospitals and Slaughter Houses

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - Carriage status of Campylobacter and Salmonella was investigated in houseflies in Shahrekord and Isfahan...     

Taxonomic and Biochemical Composition and Digestive Enzyme Activity of Periphyton and Plankton: A Comparative Study

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - Periphyton grown on sugarcane bundles was analyzed for major digestive enzymes in order to quantify their...     

Neuroprotection in traumatic brain injury: a complex struggle against the biology of nature

PURPOSE OF REVIEW: Translating the efficacy of neuroprotective agents in experimental traumatic brain injury to clinical benefit has proven an extremely complex and, to date, unsuccessful undertaking. The focus of this review is on neuroprotective agents that have recently been evaluated in clinical trials and are currently under clinical evaluation, as well as on those that appear promising and are likely to undergo clinical evaluation in the near future. RECENT FINDINGS: Excitatory neurotransmitter blockage and magnesium have recently been evaluated in phase III clinical trials, but showed no neuroprotective efficacy. Cyclosporin A, erythropoietin, progesterone and bradykinin antagonists are currently under clinical investigation, and appear promising. SUMMARY: Traumatic brain injury is a complex disease, and development of clinically effective neuroprotective agents is a difficult task. Experimental traumatic brain injury has provided numerous promising compounds, but to date these have not been translated into successful clinical trials. Continued research efforts are required to identify and test new neuroprotective agents, to develop a better understanding of the sequential activity of pathophysiologic mechanisms, and to improve the design and analysis of clinical trials, thereby optimizing chances for showing benefit in future clinical trials.     

Neuroprotective effects of LY379268, a selective mGlu2/3 receptor agonist: investigations into possible mechanism of action in vivo

The mechanisms underlying the neuroprotective effects of the group II metabotropic glutamate receptor (mGluR) agonist LY379268 were investigated in a gerbil model of global ischemia. LY379268 (10 mg/kg i.p.) 30 or 60 min after 5-min bilateral carotid artery occlusion (BCAO) attenuated the ischemia-induced hyperactivity and provided protection in the CA1 hippocampal cells. This neuroprotective effect was maintained (P <.001) when histological analysis was performed 14 and 28 days after BCAO. Furthermore, 24- or 48-h pretreatment with LY379268, 10 mg/kg i.p., before 5-min BCAO markedly reduced (P <.001 and P <.05, respectively) the damage to CA1 hippocampal neurons. This result is consistent with the induction of neuroprotective factors or a very long brain half-life. To study the possible induction of neuroprotective factors as contributing to this action of LY379268, brains were examined for expression of neurotrophic factors. Results indicated that LY379268 (10 mg/kg i.p.) failed to alter the expression of transforming growth factor-beta, brain-derived neurotrophic factor, nerve growth factor, and basic fibroblast growth factor in the hippocampal regions of brains taken from gerbils sacrificed at 6, 24, 72, and 120 h postinjection. The new group II mGlu antagonist, LY341495, administered 1 h before 5-min BCAO, attenuated the neuroprotective effect of LY379268 administered 24 h before 5-min BCAO. Complementary pharmacokinetic studies showed that a significant receptor-active concentration persisted in the brain 24 h after LY379268 10 mg/kg i.p. We conclude that group II mGluR occupancy, rather than induction of neuroprotective factors, explains the long-lasting neuroprotective effect of LY379268 in the gerbil model of global ischemia.     

Cultivation and conservation of underutilized medicinal and agricultural plants in India

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - In the current era, the increased demand of healthy food rich in antioxidants, vitamins and minerals and...     

Readability and information density in biomedical research

OBJECTIVE: This study was performed in order to compare the lexicosyntactic readability, and the information density in the informed consent forms used in biomedical research, in comparison with standard scientific texts dedicated to the general population. In addition, we studied whether there is a correlation between information readability and density. METHODS: Fifteen informed consent forms, 6 articles from "Sciences et Avenir" and 6 articles from "Sciences et Vie Junior" were analyzed. The lexicosyntactic readability was calculated using the Flesh score, and the information density using the number of information bits related to the number of words. RESULTS: The lexicosyntactic readability was lower in the informed consent forms (25, 17-32) compared with "Sciences et Avenir" (32, 29-38), but even higher in "Sciences et Vie Junior" (42, 38-57). Conversely, the information density was similar in "Sciences et Vie Junior" (0.24, [0.21-0.27]) and the informed consent forms (0.24, [0.22-0.26]), but higher in "Sciences et Avenir" (0.32, [0.26-0.38]). CONCLUSION: Informed consent forms are less readable, but paradoxically less dense than scientific papers dedicated to the general population. There is no correlation between density and readability.     

Genetic Diversity,Population Structure and Correlation Study in Moringa oleifera Lam. Using ISSR and SRAP Markers

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - Moringa oleifera Lam. is promoted in homestead gardens and is extensively cultivated as an affordable...     

Growth and Proximate Composition of Scenedesmus obliquus and Selenastrum bibraianum Cultured in Different Media and Condition

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - Microalgae are natural producers of various biochemical compounds such as protein, lipid, carotenoids and...     

Isolation and Identification of Culturable Bacteria and Fungi from Mixed Dipterocarp and Mangrove Forests of Brunei Darussalam

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - Unique forests comprise of culturable microbes with unique properties that are of potential biotechnological...     

In vitro Evaluation of Insecticides,Bio-Fungicide and Bio-Fertilizer for Strategic and Eco-Friendly Combinatorial Seed Treatments in Chickpea

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - Use of seed treatments in Integrated Pest Management of major field crops has increased considerably over the...     

Comparative Assessment of UV-B Priming on Vegetative and Reproductive Stages of Oat and Barley

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - Barley and oat were irradiated with elevated UV-B...