Intra-arterial administration of cell-based biological agents for ischemic stroke therapy

Introduction: Ischemic stroke is becoming a primary cause of disability and death worldwide. To date, therapeutic options remain limited focusing on mechanical thrombolysis or administration of thrombolytic agents. However, these therapies do not promote neuroprotection and neuro-restoration of the ischemic area of the brain.

Areas covered: This review highlights the option of minimal invasive, intra-arterial, administration of biological agents for stroke therapy. The authors provide an update of all available studies, discuss issues that influence outcomes and describe future perspectives which aim to improve clinical outcomes. New therapeutic options based on cellular and molecular interactions following an ischemic brain event, will be highlighted.

Expert opinion: Intra-arterial administration of biological agents during trans-catheter thrombolysis or thrombectomy could limit neuronal cell death and facilitate regeneration or neurogenesis following ischemic brain injury. Despite the initial progress, further meticulous studies are needed in order to establish the clinical use of stem cell-induced neuroprotection and neuroregeneration.     

Reviving through human hippocampal newborn neurons

Recent contradictory data has renewed discussion regarding the existence of adult hippocampal neurogenesis (AHN) in humans, i.e., the continued production of new neurons in the brain after birth. The present review revisits the debate of AHN in humans from a historical point of view in the face of contradictory evidence, analyzing the methods employed to investigate this phenomenon. Thus, to date, of the 57 studies performed in humans that we reviewed, 84% (48) concluded in favor of the presence of newborn neurons in the human adult hippocampus. Besides quality of the tissue (such as postmortem intervals below 26 hours as well as tissue conservation and fixation), considerations for assessing and quantify AHN in the human brain require the use of stereology and toxicological analyses of clinical data of the patient.     

去势后大鼠海马结构一氧化氮合酶阳性神经元的变化

目的：观察去势后大鼠海马结构一氧化氮合酶（NOS）阳性神经元的变化。方法：用黄递酶组织化学染色方法观察切除双侧卵巢后雌后SD大鼠海马结构NOS阳性神经元的形态，分布的变化，并进行计算机图像分析。结果：去势后海马结构NOS阳性神经元分布变化有区域差异性；NOS阳性神经元在下托、海马（CA）一区邻近下托的部分、CA三区、CA四区（CA4）和齿状回（DG）数目明显减少，而在CA二区数目明显明显增多，CA4和DG的NOS阳性神经元平均密度降低，胞体的平均周长和平均截面积都明显减少。结论：雌激素可能通过影响海马结构NOS的表达来影响学习和记忆。     

Ineffectiveness of organic calcium channel blockers in antagonizing long-term potentiation

Evidence has accumulated suggesting that the presence of calcium is critical for development of hippocampal long-term potentiation (LTP). However, there is a paucity of information about whether calcium's role in LTP is pre- or postsynaptic. In the present study, we examined the effectiveness of nitrendipine, verapamil, flunarizine and the benzodiazepine diazepam in: blocking voltage-dependent calcium channels; blocking synaptic transmission; and preventing development of LTP. Using the in vitro slice preparation, we obtained intracellular and extracellular recordings from guinea pig hippocampal CA1 pyramidal cells. At the cellular level, all 4 drugs were ineffective in blocking voltage-dependent calcium spikes (TTX resistant) and the calcium-dependent afterhyperpolarization. Verapamil and diazepam appeared to antagonize synaptic transmission, as reflected in smaller population spike amplitudes. Development of long-term potentiation was not affected by the presence of verapamil, flunarizine and diazepam. Nitrendipine appeared to reduce the percentage of slices exhibiting LTP; however, ethanol, the vehicle used to dissolve nitrendipine, was shown in separate experiments to reduce the percentage of slices exhibiting LTP. These results suggest that neither the organic calcium channel blockers--nitrendipine, verapamil, and flunarizine--nor micromolar concentrations of diazepam are potent blockers of extrasynaptic voltage-sensitive calcium channels in hippocampus. They thus cannot be used to demonstrate a specific pre- or postsynaptic calcium role in LTP.     

Changes of Unit Discharge of the Medullary Respiratory Neurons during Apnea

Changes of the neuronal discharge of 128 medullary respiratory unitswere recorded and studied during the period of expiratory apnea induced reflexlyby intracarotid sinus injection of sodium citrate in rabbits.Generally,theneuronal discharge of inspiratory units began,stopped and recovered at the sametime with those of the phrenic nerve.But,about 5% the phase-spanninginspiratory units near the obex showed a different time course with the dischargeof the phrenic nerve.They fired continuously in a low frequency while thephrenic nerve was quiet.When increasing progressively and approaching to acertain level,the firing rate increased abruptly and at the same time phrenic nervebegan to fire.So it seemed that they acted as the pacemaker of inspiration.Comparison of the cycle-triggered histograms(CTH)of these inspiratory unitswith those of phrenic nerve showed clearly the above mentioned phasicrelationship.They started firing before the phrenic nerve,but they reached theirmaximal rate and then declined and stopped quite in accordance with the phrenicnerve.It is,therefore,reasonable to assume that the central mechanism of theswitch from expiratory apnea to inspiration may originate from this kind ofneurons.Most of the expiratory units show tonic discharges during the period of apneawith a higher discharge rate than normal and then the rate decreases just beforerecovery of phrenic firing.In addition,small portion of the expiratory units weredepressed as the phrenic discharge ceased.The function of these two differentkinds of neurons in the mechanism of development of respiratory rhythm is,apparently,different.     

Angular bundle kindling is accelerated in rats with a genetic predisposition to acoustic stimulus-induced seizures

Limbic kindling was examined in genetically epilepsy-prone (GEPR) and non-epileptic control rats. The early stage of kindling development was accelerated in both groups of GEPR rats compared to controls. Later stages of kindling were accelerated in GEPR-9 but not GEPR-3 rats. These results indicate that GEPR rats have an enhanced susceptibility to limbic kindling and suggest that limbic brain alterations may contribute to acceleration of the early stage kindling development in GEPR rats.     

Formation of Neurons in the Sexually Dimorphic Anteroventral Periventricular Nucleus of the Preoptic Area of the Rat: Effects of Prenatal Treatment with Testosterone Propionate

An examination was made of neurogenesis in the anteroventral periventricular nucleus (AVPv) of the preoptic area of the rat using bromodeoxyuridine (BrdU), a thymidine analog, and a BrdU-specific antibody. Cells in the AVPv of adult rats were labeled with the antibody when BrdU was injected into pregnant rats once during day 13 to 18 of gestation, but not during day 10 to 12 nor 19 to 20 of gestation nor on postnatal day 1, indicating that neurogenesis of the AVPv occurs during a limited period from day 13 to 18 of gestation. Next, to examine the effects of androgen on neurogenesis, BrdU was injected once on day 15 into pregnant rats that also received injections of testosterone propionate (TP). The number of BrdU-labeled cells in the AVPv was similar in control female and male fetuses and female fetuses from pregnant rats that received daily injections of TP during days 14 to 16, when fetuses were examined on day 17 of gestation. These results suggest that the neurogenesis that was recognized by labeling with BrdU was not affected by the treatment with TP. On day 21 of gestation, BrdU-labeled cells in the AVPv of control male fetuses and female fetuses that received TP during days 14 to 18 were fewer in number than those in female fetuses of the control group, whereas treatments with TP during days 14 to 16 and during days 17 to 18 did not cause any significant decrease in number of BrdU-labeled cells. These findings support the hypothesis that elimination of a population of cells, for example, by cell death as described previously, is enhanced in male fetuses and in female fetuses treated with TP repetitively.     

Rapid effect of stress concentration corticosterone on glutamate receptor and its subtype NMDA receptor activity in cultured hippocampal neurons

Objective: To study the rapid effect of glucocorticoids (GCs) on NMDA receptor activity in hippocampal neurons in stress and to elucidate its underlying probable membrane mechanisms. Methods: Whole-cell patch-clamp recording was used to assess the effect of stress concentration corticosterone (B) on the responses of cultured hippocampal neurons to glutamate and NMDA (N-methy-D-asparatic acid). To make clear the target of B, intracellular dialysis of B(10μmol/L)through patch pipette and extracellular application of bovine serum albumin-conjugated corticosterone (B-BSA, 10μmol/L)were carried out to observe their influence on peak amplitude of NMDA-evoked current. Results: B had a rapid, reversible and inhibitory effect on peak amplitude of GLU-or NMDA-evoked current in cultured hippoeampal neurons. Furthermore, B-BSA had the inhibitory effect on INMDA as that of B, but intraeeUularly dialyzed B had no significant effect on INMDA. Conclusion: These results suggest that under the condition of stress, GCs may rapidly, negatively regulate excitatory synaptic receptors-glutamate receptors (GluRs), especially NMDA receptor (NMDAR) in central nervous system, which is mediated by rapid membrane mechanisms, but not by classical, genomic mechanisms.     

神经保护剂鸡尾酒疗法对海马神经元氧糖剥离（OGD）后神经元凋亡及抗凋亡蛋白Bcl一2表达的影响

目的：探讨不同类型神经保护剂联合应用即鸡尾酒（cocktail）疗法是否较单一神经保护剂对海马神经元培养氧糖剥离（OGD）后有更好的保护作用。方法：采用海马神经元培养氧糖剥离（OGD）模型，分为1，6-二磷酸果糖（FDP）组、MK-801组、N-乙酰半胱氨酸（NAC）组、cocktail组和对照组，观察神经元凋亡及抗凋亡蛋白Bcl-2表达情况。结果：cocktail组神经元凋亡减少，Bcl-2表达增多，与单-用药各组相比有显著性差异（P＜0．05）。结论：神经保护剂cocktail疗法对神经元缺血保护作用较单一用药明显增强。