Dogma and dreams: experimental lessons for epilepsy mechanism chasers

Epilepsy mechanism chasers face one major difficulty. Since we don’t know how the normal brain works, we can’t start to understand how the diseased brain fails. Most of today’s hypotheses are based on what we think about ‘normal’ brain function, which may lead to misconceptions, as will be developed here. Furthermore, since there are many different types of epilepsies, some mechanisms may only be relevant to some epilepsies. Here, I shall focus on temporal lobe epilepsy (TLE) the most common form of partial epilepsy in adults. TLE is often drug resistant, as are 30–40% of all forms of epilepsies. The failure of drug-treatments most likely reflects our lack of knowledge of the underlying mechanisms.Received 10 January 2005; received after revision 3 March 2005; accepted 23 March 2005     

诺迪康对AD模型大鼠学习记忆及海马AchE、ChAT活性的影响

目的研究诺迪康对阿尔茨海默病(AD)模型大鼠学习记忆及海马胆碱能系统的影响.方法将32只SD大鼠随机分成4组:模型组,安理中组,诺迪康组和正常组.采用双侧海马内注射Aβ-40制作大鼠AD模型,采用Morris水迷宫检测诺迪康对AD大鼠认知功能的影响;通过HE染色观察对AD大鼠的海马神经元形态的影响;采用免疫组化法观察对...     

Regulation of nicotinic acetylcholine receptors by tyrosine kinases in the peripheral and central nervous system: same players, different roles

Nicotinic acetylcholine receptors (nAChRs) exist in many subtypes and are found in the peripheral and central nervous system where they mediate or modulate synaptic transmission. We review how tyrosine phosphorylation and kinases regulate muscle and neuronal nAChRs. Interestingly, although some of the same kinase players interact with the various receptor subtypes, the functional consequences are different. While concerted action of MuSK, Abl- and Src-family kinases (SFKs) regulates the synaptic distribution of nAChRs at the neuromuscular junction, SFKs activate heteromeric neuronal nAChRs in adrenal chromaffin cells, thereby enhancing catecholamine secretion. In contrast, the activity of homomeric neuronal nAChRs, as found in the hippocampus, is negatively regulated by tyrosine phosphorylation and SFKs. It appears that tyrosine kinases provide the means to regulate all nAChRs; but the functional consequences, even those caused by the same kinase family, are specific for each receptor subtype and location. Received 21 February 2006; received after revision 24 July 2006; accepted 30 August 2006     

Transitional function of DG to CA3 in the hippocampus

Using single cell channel model, the transmission features of CA3-DG network in the hippocampus are investigated. The influence of the stimulation on discharge pattern of pyramidal neurons is analyzed, which shows that it starts with period spiking discharges, followed by period-doubling bifurcation to chaos, and period 3 discharge evolving into chaos, and ultimately a period of bursting discharges. By the synaptic model, the CA3-DG network model is constructed, which analyzes the summation of postsynaptic currents in the network, the influence of postsynaptic current on discharge rhythm as well as the mechanism of bursting discharges. The strong capacity of spatiotemporal encoding in the network indicates the features of CA3 network during the information transmission process in the hippocampus. The modeling result with time delay of the synaptic transmission is in accordance with the experimental phenomena of action potential in the hippocampus.     

Effect of stress on choline acetyltransferase activity of the brain and the adrenal of the rat

Choline acetyltransferase (ChAT) activity was determined in cerebral cortex, hypothalamus, hippocampus, cerebellum, medulla oblongata, midbrain and adrenal gland of rats exposed to acute or chronic stress. The exposure of animals to acute immobilization and cold stress (4°C) for one hour resulted in a significant decline of ChAT activity in all brain regions examined except for the medulla oblongata. Moreover, the exposure to acute stress resulted in significant increase of the same enzyme in the adrenal gland. However, chronic exposure of animals to cold stress (4°C) for 7 days resulted in no significant changes of ChAT activity in all tissues examined except for a decline in the midbrain and an increase in the medulla oblongata. The administration of corticosterone (2.0 mg/kg) 1 h prior to sacrificing caused an effect similar to that of acute stress on ChAT activity in all brain regions except for the hypothalamus and the cerebellum. It was concluded from this experiment that stress-induced changes in the ChAT activity of specific brain regions might be mediated by the adrenal steroids.This work was supported by a grant from the National Aeronautics and Space Administration (NSG 2183 and NAG 2-411), a grant from the National Institutes of Health (NIH RR 0811) and a grant from the Division of Research Resources (NIH grant RR 03020).     

Reduction of high affinity glutamate uptake in rat hippocampus by two polyamine-like toxins isolated from the venom of the predatory waspphilanthus triangulum F

Summary Two components of the venom of the predatory waspPhilanthus triangulum F. significantly reduce — to a greater or less extent — the high affinity uptake of glutamate in rat hippocampus. A concentration of 10 M -PTX caused a reduction of 74%, while the other component, -PTX, at the same concentration, caused a reduction of 18%. Hence the effect of -PTX on high affinity glutamate uptake in the hippocampus is comparable with its effect on high affinity glutamate uptake in insect neuromuscular junctions. Contrary to our previous findings that -PTX has no effect on high affinity glutamate uptake in insect glutamatergic terminal axons, however, -PTX significantly reduces high affinity glutamate uptake in the hippocampus, albeit less effectively than -PTX.     

Effect of acute administration of Δ1-tetrahydrocannabinol on β-endorphin levels in plasma and brain tissue of the rat

Summary Acute treatment with ¹-tetrahydrocannabinol (¹-THC) elevated the concentration of -endorphin-like immunoreactivity (-ELIR) in plasma and in the hypothalamus, but not in the hippocampus of rats habituated to the injection procedure. These effects were not obtained with the psychotropically inert analog of (¹-THC), cannabidiol. In animals that had not been habituated to the injection procedure, placebo treatment induced a decrease in hippocampal -ELIR.The authors acknowledge the skillful technical assistance of Mrs Willeke Logtenberg.     

4-Aminopyridine and barium chloride attenuate the anti-epileptic effect of carbamazepine in hippocampal slices

Summary The exact mode of action of the anti-epileptic agent carbamazepine is unknown. In hippocampal slices in which epileptiform discharges were induced by addition of penicillin to the perfusion medium, the depressant effect of carbamazepine was attenuated by the potassium-channel blockers barium chloride (0.1 mM) and 4-aminopyridine (200 M), which suggested that potassium fluxes might be involved in the mechanism of action of carbamazepine.     

榆叶粗提液治疗幼鼠癫痫作用初探

近年来临床上越来越多采用中西医结合的方法控制癫痫疾病的发作;通过以灌胃给药的方式给予PTZ癫痫幼鼠不同浓度的榆叶粗提液,观察榆叶对PTZ幼鼠癫痫模型的癫痫行为和海马神经元的影响;结果发现:与PTZ癫痫模型组相比,高浓度榆叶粗提液干预将癫痫发生率降低了20%;榆叶粗提液中、高浓度组海马神经元数目明显增加;表明中、高浓度的榆叶粗提液对PTZ癫痫模型有一定的改善作用,一定程度上可以降低癫痫行为的发生率和抑制癫痫对海马神经元的损伤。     

Autotaxin (NPP-2) in the brain: cell type-specific expression and regulation during development and after neurotrauma

Autotaxin is a secreted cell motility-stimulating exo-phosphodiesterase with lysophospholipase D activity that generates bioactive lysophosphatidic acid. Lysophosphatidic acid has been implicated in various neural cell functions such as neurite remodeling, demyelination, survival and inhibition of axon growth. Here, we report on the in vivo expression of autotaxin in the brain during development and following neurotrauma. We found that autotaxin is expressed in the proliferating subventricular and choroid plexus epithelium during embryonic development. After birth, autotaxin is mainly found in white matter areas in the central nervous system. In the adult brain, autotaxin is solely expressed in leptomeningeal cells and oligodendrocyte precursor cells. Following neurotrauma, autotaxin is strongly up-regulated in reactive astrocytes adjacent to the lesion. The present study revealed the cellular distribution of autotaxin in the developing and lesioned brain and implies a function of autotaxin in oligodendrocyte precursor cells and brain injuries. Received 18 September 2006; received after revision 30 October 2006; accepted 4 December 2006