HIV neuropathogenesis and therapeutic strategies

Abstract Human immunodeficiency virus (HIV)-l neuropathogenesis can be divided into three important components: (i) virus entry into the nervous system; (ii) the role of viral proteins and/or cellular products in neural tissue damage; and (iii) the mechanisms of neuronal injury/death. Both blood derived macrophages or trafficking HIV-1 infected T-lymphocytes have been implicated in viral entry to the central nervous system (CNS). The major cell type harboring productive HIV-1 infection in the nervous system is the perivascular macrophage/ microglia. The HIV-1 infection of brain astrocytes, restricted to the expression of regulatory gene products, may cause astrocyte dysfunction and contribute to neuronal injury or to disruption of the blood-brain barrier (BBB). Studies of cerebrospinal fluid and postmortem tissues reveal chronic inflammation/immune activation in the nervous system during the later stages of HIV-1 infection associated with disruption of BBB integrity. Blood-brain barrier damage may underlie the white matter pallor described in HIV-1 infection and could result in further entry into the CNS of toxic viral or cellular products, or additional HIV-1 infected cells. The HIV infected and activated macrophages/microglia produce excessive amounts of pro-inflammatory cytokines, including tumor necrosis factor alpha, and platelet activating factor. These products are directly toxic to human neurons in vitro. The HIV-1 envelope glycoprotein, gp 120 may stimulate the release of toxic factors from brain macrophages. Blocking N-methyl-D-aspartate (NMDA; or AMPA) glutamate receptors can antagonize candidate toxins of both viral and cellular origin. It has been postulated that (weak) excitotoxicity leads to oxidative stress in neurons and ultimately to apoptosis. Neuronal apoptosis occurs in the brains of both children and adults with HIV-1 infection. This understanding of HIV neuropathogenesis implies that therapeutic strategies should include: (i) anti-retroviral medications to decrease systemic and CNS virus load, and possibly to prevent perinatal transmission of HIV; (ii) anti-inflammatory compounds to decrease the chronic immune activation in microglia and allow the restoration of BBB integrity; and (iii) neuroprotective compounds to reduce neuronal injury and apoptotic death.     

Chlormethiazole, dizocilpine and haloperidol prevent the degeneration of serotonergic nerve terminals induced by administration of MDMA (‘Ecstasy’) to rats

An investigation has been made into the effect of 3,4-methylenedioxymethamphetamine (MDMA or ‘Ecstasy’) administration on the concentration of 5-hydroxytryptamine (5-HT), uptake of [³H]5-HT and [³H]paroxetine binding in rat cerebral cortex tissue. Four days after 2 injections of MDMA (20 mg/kg i.p., 6 hr apart) the concentrations of 5-HT and its metabolite 5-HIAA were reduced by 60%. The binding of [³H]paroxetine to the presynaptic 5-HT transporter was decreased and high affinity uptake of [³H]5-HT was reduced by a similar amount, indicating neurodegeneration of 5-HT terminals. Pretreatment with chlormethiazole (100 mg/kg i.p.), 10 min before each MDMA injection prevented the decrease in both [³H]parotextine binding and uptake of [³H]5-HT. The loss in 5-HT and 5-HIAA content was also attenuated. Pretreatment with dizocilpine (1 mg/kg i.p.) or haloperidol (2 mg/kg i.p.) also prevented the MDMA-induced loss of [³H]paroxetine binding and attenuated the loss of 5-HT and 5-HIAA content. All three compounds also decreased the degree of hyperthermia that follows MDMA administration, although previous studies suggest that the long term neurodegeneration is not associated with the acute hyperthermic response. These data support the findings of others that MDMA injection produces degeneration of 5-HT nerve terminals in the cortex, confirm that chlormethiazole, dizocilpine and haloperidol attenuate MDMA-induced neurotoxic loss of 5-HT and demonstrate for the first time that these compounds prevent the neurodegeneration of 5-HT nerve terminals that follows MDMA administration.     

大豆异黄酮对雌性大鼠缺血脑组织的保护作用

目的 探讨大豆异黄酮对去势雌性SD大鼠永久性局灶性脑缺血组织的神经保护作用。方法 雌性SD大鼠双侧卵巢切除后，随机分成大豆异黄酮组和对照组。异黄酮组(HISO)灌胃给予120mg/kg的大豆异黄酮，对照组以等剂量的溶剂灌胃。1月后各实验组均采用线栓法建立右侧永久性大脑中动脉阻断模型。缺血24h后立即断头取脑，冠状切片，应用免疫组化法检测不同实验组大鼠缺血侧C-fos表达的情况。TUNEL法原位检测细胞凋亡。结果 大豆异黄酮组与对照组相比，缺血侧C-fos表达阳性细胞数明显减少；凋亡细胞数明显减少。结论 大豆异黄酮具有类雌激素的作用，它对缺血性脑损伤具有保护作用，而减弱大脑缺血边缘区的C-fos表达及神经细胞凋亡可能是它发挥神经保护作用的机制。     

Neuroprotective effect of estrogen after chronic spinal cord injury in ovariectomized rats

BACKGROUND: At present, there is still lack of effective drugs for chronic spinal cord injury, whereas it is found recently that estrogen has a neuroprotective effect on brain and spinal cord injuries. OBJECTIVE: To observe the effect of estrogen on the apoptosis of nerve cells after gradual chronic spinal cord injury in ovariectomized rats. DESIGN: A randomized controlled animal trial. SETTING: Institute of Orthopaedics, the Second Hospital of Lanzhou University. MATERIALS: Sixty-five female Wistar rats of common degree, weighing 220–250 g, were provided by the experimental animal center of Lanzhou University. The rats were randomly divided into sham-operated group (n =5), estrogen-treated group (n =30) and saline control group (n =30), and the latter two groups were observed at 1, 3, 7, 14, 28 and 60 days respectively, and 5 rats for each time point. METHODS: All the rats were treated with bilateral oophorectomy 2 weeks before the experiment. T10 vertebral lamina was revolved into using plastic screw. The spinal canal impingement was not induced initially. After that, the original incision was opened to expose the screw every 7–10 days. MAIN OUTCOME MEASURES: The apoptosis and Caspase-3 positive cells in the damaged spinal cord were detected using terminal deoxynucleotidal transferase-mediated dUTP-biotin nick end labeling (TUNEL) method and Caspase-3 immunohistochemical staining at 1, 3, 7, 14, 28 and 60 days after chronic spinal cord injury respectively. RESULTS: Totally 65 rats were used, and the deleted ones during the experiment were supplemented by others. Changes of Caspase-3 expression after spinal cord injury: In the sham-operated group, only a small amount of Caspase-3 proteins were observed in the rat spinal cord, mainly located in motor neurons of spinal cord anterior horn. In the estrogen-treated group and saline control group, positive cells expressed occasionally at 1 day postoperatively, began to increase obviously at 7 days after injury, strongly expressed at 14 and 28 days, but decreased at 60 days, mainly located in the neurons of spinal cord gray matter anterior horn, and they expressed fewer in the motor neurons and white matter of ventral horn, and there were obvious differences between the estrogen-treated group and saline control group at 7, 14, 28 and 60 days (P < 0.05). CONCLUSION: Estrogen can reduce the apoptosis of nerve cells and promote the recovery of neurological function following gradual chronic spinal cord injury.     

"同病异治"原则与中医缺血脑保护药物干预策略

溶栓治疗和神经保护治疗是缺血性脑卒中的两大药物干预策略,其中广义的神经保护治疗包括神经保护和神经修复两种方法,而目前存在的中西医结合缺血性脑卒中的药物干预策略可能也存在多层次、分阶段干预的特点,体现了祖国医学"同病异治"的原则,我们认为现有的缺血脑保护方法主要针对缺血性脑卒中的不同发展阶段,而神经修复的研究,尤其是中医药促进神经干细胞再生的研究,可能蕴涵着巨大的发展潜力和无限商机.     

Modulation of glial cell signaling by adenosine and pharmacological reinforcement

In view of the increasing evidence that a pathological glial activation plays a significant role in the development of neurodegenerative diseases, we investigated the underlying molecular signaling as a possible target for a pharmacological therapy. Here, we are particularly focusing on the endogenous modulation of the Ca²⁺ and cyclic nucleotide-dependent signaling by the nucleoside adenosine and its reinforcement by the xanthine derivative propentofylline (PPF). As an experimental model, we used cultured rat microglial cells and astrocytes that are immature, show a high proliferation rate, and resemble in several aspects pathologically activated glial cells. A prolonged increase of the cellular cAMP level favored the differentiation of cultured astrocytes and associated properties required for the physiological nerve cell function. On the other hand, a strengthening of the cyclic nucleotide-dependent signaling inhibited potentially neurotoxic properties of cultured microglial cells. Similar effects were obtained by treatment with propentofylline, which mimicked modulatory adenosine effects and increased the intracellular level of cAMP and cGMP. Such a pharmacological glial cell conditioning, obtained by modifying the strength and the timing of these second messengers, may provide a therapy of neurodegenerative diseases in which a pathological activation of microglial cells and astrocytes is discussed to play a pathogenic role.     

杜仲化学成分、药理作用和临床应用研究进展

杜仲Eucommia ulmoides是我国特有的珍稀濒危二类保护植物,其皮、叶、雄花和种子均具有药用价值和食用价值。化学成分研究发现杜仲不同部位（皮、叶、雄花、种子）主要有木脂素类、环烯醚萜类、黄酮类、苯丙素类、萜类和甾体类等成分,具有抗骨质疏松、抗炎、神经保护、降血压、降血糖、调血脂、免疫调节、抗菌、抗病毒等药理作用,广泛应用在医药、保健食品、饲料添加剂及日化用品等多个领域。通过对2000年1月—2022年12月在中国知网（CNKI）和PubMed数据库中发表的杜仲文献进行检索,共检索到相关文献1772篇,其中有效文献188篇。综述了杜仲在化学成分、药理作用、临床研究和开发应用方面的研究进展,为后续杜仲的临床应用及相关产品开发提供参考。     

硫酸镁减轻缺血再灌注性兔脑损伤作用的实验研究

目的 :探讨硫酸镁对缺血再灌注兔脑损伤的作用。方法 :15只兔随机均分至 :对照组、缺血组和缺血+硫酸镁处理组。阻断兔脑血管 6分钟 ,诱导全脑缺血。缺血再灌注 3天后 ,分别用HE染色和TUNEL染色 ,检测海马CA1 区神经元密度和凋亡神经元密度。结果 :缺血 +硫酸镁处理组海马CA1 区正常神经元密度为 140 .5 2±16 .2 3个 mm ,显著高于缺血组 (P <0 .0 1) ;缺血神经元密度为 2 4.18± 3 .16个 mm ,显著低于缺血组 (P <0 .0 1) ;凋亡神经元密度为 18.40± 8.0 8个 mm ,显著低于缺血组 (P <0 .0 1)。结论 :硫酸镁具有减轻兔缺血再灌注性全脑损伤的作用 ,其作用机制可能同抑制缺血后神经元凋亡有关     

Effects of ciliary neurotrophic factor on excitotoxicity and calcium-ionophore A23187-induced cell death in cultured embryonic striatal neurons

Ciliary neurotrophic factor (CNTF) has a protective effect on the striatum in animal models of Huntington's disease. However, the mechanism through which it exerts its effect is not clear. In this study, we show that there is a concentration-dependent direct protective effect of CNTF against N-methyl-D-aspartate-mediated excitotoxicity on striatal neurons in vitro. The CNTF has to be added more than half an hour before the insult for the effect to occur and its effect is eliminated by the presence of the protein synthesis inhibitor cycloheximide. This suggests that the protective mechanism of CNTF does not involve acute interference with the glutamate receptors, but probably requires gene/protein expression. We have also shown that the effect of CNTF against glutamate-induced excitotoxicity is dependent on the concentration of glutamate with a protective effect more evident at a low grade excitotoxic insult. Finally, we saw no effect of CNTF on calcium ionophore A23187-induced toxicity in striatal cultures, indicating that the growth factor does not promote survival by enhancing general defenses against raised intracellular levels of calcium.