The action potential: an effect of fuel cell reactions in the synapse

The neuron and its vascular-interstitial communications form, in vivo, an electrophoretic closed circuit. It is charged by ionic pumps in the nerve cell membrane at rest. Electrophoretic products of reaction collect at biologic electrodes, represented by redox proteins. These are located in the pre- and postsynaptic membranes and also in associated capillary membranes in the vascular part of the closed circuit. Efferent brain impulses start a series of events preceding muscle contraction. They open ionic channels in the membrane of the nerve cell body. A short-circuiting is thereby created, and cations flow into the cell. The membrane pumps cannot withstand this ionic inflow and maintain the transmembranous potential difference. The circuit is no longer driven but starts selfdriving reactions by previously formed products of reaction at the biological electrodes. Fuel cell reactions start at these and create in the axon the peak of the action potential. In vivo, the action potentials preceding the contracting of a muscle are transmitted through the circuit. In the vascular pathway of the closed circuit, the action potentials appear, by summation, as the previously described slow potential waves. The function of nerve cell matrices, as well as the nodes of Ranvier, are discussed. The proposed theory is in accordance with the vascular-interstitial-neuromuscular closed circuit. It provides new possibilities to explain the development of the action potential, transport and disappearance of various synaptic structures and the neurotransmitter. Technical analogues are presented to illustrate a new possible background mechanism for understanding structure and function in neuromuscular transmission.     

The freezing threshold of the peripheral motor nerve: an electrophysiological and light-microscopical study on the sciatic nerve of the rabbit.

Fifty sciatic nerves of 39 rabbits are treated at different temperatures (+5, +1, 0, ?3, ?5, ?10, ?15 and ?20 °C), for different freezing times (10, 20, 30, 60 and 120 sec), and for different numbers of freeze-thaw cycles (1, 2 and 4). After electric supramaximal stimulation (3.8 V) action potentials of the sciatic nerve are measured before, immediately after, and 1, 3, 5, 10, 20, 30, 60, 90 min, 2, 5 and 10 days after freezing. Two or ten days after freezing, the nerves are examined in a light microscope. The cold threshold of the sciatic nerve was determined, i.e., the temperature at which after supramaximal stimulation it is still possible to measure an action potential within 1.5 hr after freezing. On application of one freeze-thaw cycle, the cold threshold is ?15 °C after a freezing time of 10 sec, ?10 °C after 20 sec and 30 sec, and ?5 °C after 60 and 120 sec. After application of two and four freeze-thaw cycles, the cold threshold is elevated, and after a super-cooling time of 10 sec it is ?10 °C, after 30 sec ?5 °C. The longer the freezing time and the more freeze-thaw cycles, the higher is the cold threshold. At ?20 °C (superthreshold temperature) an action potential can no longer be measured and all myelinated nerve fibres have decayed, except some small-caliber ones.Electrophysiologically, it is evident that some of the myelinated nerve fibres become functionally damaged for 1.5 hr, while other parts of the nerve fibres will degenerate and later regenerate. The amplitudes of the measured action potentials correlate with the decay of myelin sheaths and axons of large- and medium-caliber nerve fibres. Action potentials between 0 and 40% show a gradual paresis, above 40% a physiological motor function. The pathophysiological mechanism of this reversible functional loss after super-cooling and freezing may be a consequence of a disturbed membrane permeability.It is of clinical importance that, if the cold threshold of a peripheral motor nerve is known, the nerve can be frozen concomitantly for a short time at application of low temperatures without suffering any functional loss. This is achieved by controlling during freezing the motor function of the corresponding nerve situated on the periphery of cryolesion, and, if there is a loss of motor function, the freezing process has to be interrupted immediately.     

Sites and mechanisms of action of neuropeptides on canine gastric motility differ in vivo and in vitro

Motilin, pentagastrin and substance P (SP), injected intra-arterially into the canine gastric corpus in vivo increased the amplitude of contractions by an action dependent on activation of cholinergic nerves; i.e. atropine or tetrodotoxin (TTX) completely blocked the responses to motilin and pentagastrin and increased the ED50 of SP. TTX and atropine were not equally effective in increasing the ED50 for SP in vivo and the effect of combining them depended on the order of their addition. Both were much more effective than the SP analog D-Pro2, D-Trp7,9 SP (DSP) which appeared to be a weak antagonist of actions dependent on neural activity. In strips from the same region in vitro no receptors dependent on cholinergic nerve activation could be demonstrated for any peptide; i.e., all were atropine- and TTX-insensitive. Motilin, as expected in the absence of such receptors caused no contractile response in vitro. SP, also as predicted, caused contractions suggesting that a smooth muscle receptor, independent of nerve activation was present. However contrary to expectation pentagastrin induced an atropine and TTX-insensitive increase in the amplitude and frequency of contractions. These results show that 1) the most sensitive sites of action of a number of excitatory peptides depend on cholinergic nerve function in vivo; 2) such sites or the nerve activity on which they depend cannot be demonstrated in vitro; 3) SP has an additional site of action on smooth muscle demonstrable in vivo and in vitro, but motilin does not; 4) pentagastrin has only an action dependent on nerve function in vivo, but manifests an action independent of nerve function in vitro. We conclude that sites and mechanisms of action of peptides cannot be assumed to be identical in vivo and in vitro. Actions dependent on nerves are often lost in vitro and not all smooth muscle actions can be demonstrated in vivo.     

Effect of armin on the ultrastructure of the neuromuscular synapse]

Alterations induced by the cholinesterase inhibitor armin (5.10(-7) g/ml) in the ultrastructure of motor nerve endings of the rat phrenic diaphragmal preparations at rest or electric stimulation of the nerve were studied. It was shown that armin at rest induced ultrastructural lesions in the endings similar to those in the control preparations during nerve stimulation. Electric stimulation did not produce additional changes in the ultrastructure of the neuromuscular junction under armin action. It is suggested that the disorder of the nerve ending function may be of importance in the mechanism of the blocking action of armin on the neuromuscular transmission.     

Recent studies of the actions of cholinomimetic drugs on adrenergic nerves and their implications for the cholinergic link hypothesis

This review analyzes the results of recent studies of the actions of cholinomimetic drugs on adrenergic nerve terminals and their implications for the cholinergic link hypothesis. Thus far, evidence suggests that the only possible action of endogenous acetylcholine (ACh) present near noradrenaline (NA) stores is an inhibition of the release of NA from the adrenergic nerve terminals and that NA is released only when the action of acetylcholinesterase is inhibited. Nicotinic agents have been shown to act on adrenergic nerve terminal membranes, a finding that casts doubt on the proposed intraneuronal cholinergic sites for the action of endogenous ACh. Evidence also indicates that the mode of adrenergic neurone blocking action of bretylium and guanethidine is independent of the proposed cholinergic process in NA release. Current findings do not support the proposal that nicotinic agents in higher concentrations interfere with adrenergic neurotransmission. It is therefore concluded that nicotinic agents, in causing the release of NA from adrenergic nerve terminals, are merely exhibiting a pharmacological action and not mimicking the physiological function of ACh, as proposed by the cholinergic link hypothesis.     

Neuroprotective Effect of Natural Products on Peripheral Nerve Degeneration: A Systematic Review

Peripheral nerve injury (PNI) is a serious public health problem that is linked with motor, sensory and autonomic deficits. Given the fact that this type of disorder leads to a decreased quality of life in most patients and adherence of available drugs is limited and have adverse effects, we investigated the efficacy of natural products in a PNI model. The search terms plants, medicinal, nerve regeneration, nerve crush, sciatic nerve as well as MeSH terms or free-text words were used to retrieve English language articles in PubMed, Scopus, Web of Science and LILACS published until July 2015. After sciatic nerve crush, natural products have improved significantly motor performance, sensory function and electrical conductance measured over weeks. Among the pharmacological targets suggested by the action of natural products, there were citations on the activation of the antiapoptotic signaling pathway, modulation in the expression of pro-inflammatory cytokines and neurotrophic factors. The systematic review provides scientific evidence that natural products are pharmacologically effective in the treatment of PNI such as sciatic nerve crush.     

氢气影响大鼠神经兴奋传导的研究

氢气是一种具有重要生物学功能的气体分子,可以用于神经退行性疾病、抑郁、睡眠障碍和毒瘾戒断症状等的治疗和改善,普遍认为和氢气的选择性抗氧化有关,但氢气对神经功能的调控机制尚不清楚。为了探究氢气对神经功能的调控机制,通过脑片膜片钳技术分别检测了氢瞬时作用大鼠大脑切片皮层神经细胞和饮用富氢水（8周）大鼠大脑切片皮层神经细胞的动作电位变化,以判断氢的干预是否能够影响神经兴奋的传导;利用液相色谱质谱联用仪（liquid chromatograph-mass spectrometer,LCMS）检测饮用富氢水（8周）大鼠大脑切片皮层神经递质的含量变化,以进一步探究氢气影响神经兴奋传导的具体机制。结果表明,氢气处理组与对照组相比大鼠皮层神经细胞的阈值电压、动作电位间隔和输入抗阻具有显著性差异（P<0.05）,氢气处理组静息膜电位升高,神经细胞爆发动作电位阈值升高,表明氢气可能对神经细胞膜离子通道的开放和关闭有影响,氢处理能够使皮层神经细胞兴奋性明显降低。大鼠在连续饮用富氢水8周后大脑皮层同样显现出兴奋性降低趋势,经LCMS测定,发现神经递质的含量没有明显变化。研究提示,氢气可能是通过改变细胞内外电荷差异变化或者直接影响神经细胞表面钠、钾等离子通道的打开或关闭,从而实现对神经细胞兴奋性的调节。     

Muscles that act on glabellar skin: a closer look

The coronal incision forehead lift became a component of the face-lift procedure 35 years ago and increased the cosmetic benefit for the facial aesthetic surgery patient. Later, this enhanced cosmetic effect achieved from eyebrow resuspension was complemented by treatment of the glabellar skin lines by modifying corrugator supercilii and procerus muscle function through the same coronal incision. In recent years, newer procedures for treating the corrugator supercilii and procerus muscles by using endoscopy or limited incision techniques have eliminated the need for the coronal incision. With these newer techniques has come a renewed interest in the surgical anatomy of the muscle complex that acts on glabellar skin. This study was designed to examine the current understanding of the anatomy of these muscles and to resolve misconceptions and controversy concerning them. Fresh cadaver dissections and simulated muscle action studies done on the glabellar musculature of four specimens were correlated with nerve blockade studies performed in 10 subjects on the temporal and zygomatic branches of the facial nerve. The presence of the depressor supercilii muscle as a distinct entity was confirmed. The little-appreciated oblique head of the corrugator supercilii muscle was identified. The conclusions from this study suggest that the transverse head of the corrugator supercilii muscle produces the vertical component of the glabellar skin line and also contributes to the formation of the oblique component of the glabellar skin line. The oblique head of the corrugator supercilii muscle, the depressor supercilii muscle, and the medial head of the orbital portion of the orbicularis oculi muscle all appear to depress the medial head of the eyebrow and contribute to the formation of the oblique glabellar skin line. The nerve block study provided evidence that the zygomatic branch of the facial nerve supplies the three medial eyebrow depressor muscles, which opens the possibility for future nerve ablation techniques to control the action of the medial eyebrow depressor muscle group. This nerve block study also supports the concept of "physiologic" elevation of the medial eyebrow as an effective component of foreheadplasty.     

Opioids and neuropeptides: mechanisms in circulatory shock

Endogenous opioid systems are activated in stressful situations such as circulatory shock. The opiate antagonist naloxone improves cardiovascular function in several models of shock caused by endotoxemia, hypovolemia, anaphylaxis, and spinal trauma. The ergotropic neuropeptide, thyrotropin-releasing hormone, in supraphysiological doses, also improves cardiovascular function in these shock models, but this effect does not result from action at the opiate receptor. For both these agents a central nervous system (CNS) site of action has been partially characterized. A variety of neuropeptides, including the opioids, seem capable of modulating autonomic function through their CNS actions. In addition, they may play a role in peripheral integration and transmission of autonomic nervous activity by actions at the ganglia and/or at nerve endings. Some neuropeptides also have direct autacoid effects on cells, including those of the microvasculature. This raises new questions concerning possible peripheral functions of neuropeptides during circulatory shock, and the nature of their interactions with other potential shock mediators such as monokines and arachidonic acid derivatives.     

Bioenergetics and Transmitter Release in the Isolated Nerve Terminal

The isolated nerve terminal (or synaptosome) is the simplest preparation that allows mitochondrial bioenergetics to be studied in a physiological milieu, as well as facilitating investigation of the protein chemistry and regulation of synaptic vesicle exocytosis and recovery and providing a target for the study of the mechanism of action of numerous neurotoxins. This brief review discusses studies from our laboratory that may have provided some insight into these aspects of nerve terminal function.     

Properties of the derived cochlear action potential during tonal forward masking in guinea pigs]

In awake preimplanted guinea pigs, characteristics of auditory nerve and derived action potentials were investigated using a pure-tone forward masking paradigm. Auditory nerve action potentials are recorded from round window. The derived potential was obtained by subtracting the masked action potential from unmasked response. The results show that the derived potential is more sensitive to changes in auditory nerve action potential during masking than widely used indicator of masking--the decrement in auditory nerve action potential. Derived response reflects the response changes both in amplitude and waveform induced by masker. The differences between the auditory nerve and derived action potentials suggest that the amplitude and time changes in the derived potential give a more detailed information on the characteristics of the auditory nerve fibers responses.     

Measurement of fasciculations as motor nerve ending discharges in the rat: a dose related effect of neostigmine

The muscle fasciculations caused by neostigmine and similar agents are the result of a primary drug action on motor nerve endings. Asynchronous, repetitive firing of action potentials are evoked at motor nerve endings which are then transmitted to muscle. A dose-response relationship between neostigmine dose and the rate of/or total neural activity has been established in the rat. This fasciculatory response to neostigmine can serve as an index of motor nerve ending excitability and may be useful in assessing the effects of certain pathological states or drug actions at the neuromuscular junction.     

Rita Levi-Montalcini: the discovery of nerve growth factor and modern neurobiology

The remarkable accomplishments in developmental neurobiology within the past 60 years have depended on two things: (i) a succession of original histochemical and immunohistochemical methodologies for identifying pathways in the nervous system with increasing precision and sensitivity, and (ii) the discovery of growth factors for neurons. Growth factors are naturally occurring, essential biological mediators that promote cell growth, differentiation, survival and function in specific nerve cell populations. The discovery of nerve growth factor (NGF) by Rita Levi-Montalcini in the 1950s represents an important milestone in the processes that led to modern cell biology. NGF was the first growth factor identified, for its action on the morphological differentiation of neural-crest-derived nerve cells. Later, its effect on neuronal cells of the peripheral and central nervous systems, and on several non-neuronal cells was also determined. Thus, Levi-Montalcini's work on NGF represents, as acknowledged by the Nobel Prize Assembly in its press release of 13 October 1986, "a fascinating example of how a skilled observer can create a concept out of apparent chaos".     

Identification of the characteristics that underlie botulinum toxin potency: implications for designing novel drugs

Botulinum toxin is a uniquely potent substance whose natural site of action is the peripheral cholinergic nerve ending. A substantial amount of information on the cellular, subcellular and molecular aspects of toxin action has been accumulated, and as a result a sound understanding of the basis for toxin potency has been developed. The principal characteristics of the toxin molecule that account for its potency are its ability: a) to be absorbed from the gut with minimal degradation; b) to bind to receptors that maximize the prospects of a pathophysiologic outcome; c) to act by a multiplicative (viz., enzymatic) mechanism; and d) to modify a substrate that is essential for neuronal function. Interestingly, the same properties that account for potency can also be exploited to utilize the toxin as a research tool and as a therapeutic agent. Several specific examples of ways to use the toxin advantageously are presented, including: a) development of oral medications and vaccines; b) analysis of subcellular mechanisms that govern transcytosis; c) identification of cell surface markers characteristic of cholinergic nerve endings; and d) analysis of specific aspects of exocytosis, such as spontaneous quantal release and synchronous quantal release. In all likelihood, further studies on the mechanism of botulinum toxin action will reveal yet further opportunities for utilizing it as a research tool or therapeutic agent.     

Cesium: postjunctional repetitive firing in sympathetic ganglion

Bullfrog ganglion cells in Cs⁺-Ringer's solution developed postjunctional repetitive spike responses to single preganglionic stimuli but not to single antidromic or direct stimuli. This action of Cs⁺ is equivalent to that of the neostigmine-like drugs and is apparently generated by primary action on presynaptic nerve terminals. Alterations of K⁺ and Na⁺ currents in the nerve terminal membrane could be the underlying mechanism.     

Walking track analysis: a long-term assessment of peripheral nerve recovery.

Functional recovery following sciatic, tibial, and peroneal nerve injury was assessed over a 1-year period using walking track analysis in the rat. Internal neurolysis did not affect nerve function. Crush injury induced a temporary, but complete, loss of function that recovered to control levels by 4 weeks. Nerve transection resulted in complete loss of function without any evidence of recovery. After nerve repair, functional recovery occurred, reaching near-optimal recovery by 12 weeks. The degree of functional recovery varied with the specific nerve involved. The sciatic nerve recovered 41 percent of function, whereas the tibial nerve recovered 54 percent of function. The peroneal nerve exhibited the highest degree of recovery, achieving functional levels similar to control values. Assessment of neural regeneration using walking track analysis appears to be a valuable addition to the traditional methods of histology and electrophysiology.     

链霉素对鸟听觉毒性作用的研究

目的：了解链霉素对鸟听觉毒性的作用。方法：选33只健康成年虎皮鹦鹉,不同剂量的链霉素肌肉注射15日,脑干听觉诱发电位测试外周的听觉敏度和听觉通路中神经的传导和传递能力。结果：链霉素对鸟听觉有毒性作用。结论：用链霉素处理鸟可以制作聋鸟模型。     

Click-evoked responses from the exposed intracranial portion of the eight nerve during vestibular nerve section: bipolar and monopolar recordings

We compare the click-evoked compound action potentials from the exposed intracranial portion of the eight nerve using bipolar and monopolar recording electrodes in patients undergoing vestibular nerve section. It is assumed that a bipolar recording electrode will only record propagated neural activity in the auditory nerve, whereas a monopolar recording electrode may in addition record electrical activity that is conducted passively to the recording site. The results of the present study confirm that the earliest detectable propagated neural activity in the intracranial portion of the auditory nerve occurs with a latency that is close to that of peak II of the brain-stem auditory evoked potentials, and the results also confirm that the late components in the click-evoked compound action potentials that have been demonstrated previously using the monopolar recording technique represent propagated neural activity in the auditory nerve. The results also indicate that the responses that are recorded by a bipolar recording electrode, when the small tips of which are placed on the eight nerve when it is relatively dry, represent only small populations of nerve fibers. Even when an attempt is made to align the two tips of a bipolar electrode with the course of the auditory nerve, this type of electrode may record from different populations of nerve fibers.     

Nerve,spinal cord and brain somatosensory evoked responses: a comparative study during electrical and magnetic peripheral nerve stimulation

Somatosensory evoked potentials (SEPs) and compound nerve action potentials (cNAPs) have been recorded in 15 subjects during electrical and magnetic nerve stimulation. Peripheral records were gathered at Erb's point and on nerve trunks at the elbow during median and ulnar nerve stimulation at the wrist. Erb responses to electrical stimulation were larger in amplitude and shorter in duration than the magnetic ones when ‘electrical’ and ‘magnetic’ compound muscle action potentials (cMAPs) of comparable amplitudes were elicited. SEPs were recorded respectively at Cv7 and on the somatosensory scalp areas contra- and ipsilateral to the stimulated side. SEPs showed a statistically significant difference in amplitude only for the brachial plexus response and for the ‘cortical’ N20-P25 complex; differences were not found between the magnetic and electrical central conduction times (CCTs) or for the peripheral nerve response latencies. Magnetic stimulation preferentially excited the motor and proprioceptive fibres when the nerve trunks were stimulated at motor threshold intensities.     

Mechanism of inhibitory action of peptide YY on cholecystokinin-induced contractions of isolated dog ileum

In isolated canine ileal longitudinal muscle preparations, cholecystokinin-octapeptide (CCK-8) produced a concentration-dependent contraction, which was suppressed by peptide YY (PYY) and was abolished by tetrodotoxin and atropine. PYY was approximately 2200-times as potent as CR1505, a CCK-receptor antagonist. PYY opposed the action of CCK-8 to a greater extent than that of nicotine and transmural electrical stimulation. Acetylcholine-induced contractions were not influenced by PYY. It seems likely that the CCK-8-induced ileal muscle contraction is associated with an activation of CCK receptors in cholinergic nerves, which generates nerve action potentials and releases acetylcholine, whereas CCK-8 acts on CCK receptors in gallbladder smooth muscle, producing contractions. It may be concluded that PYY inhibits the action of CCK-8 on ileal muscle strips, by inhibiting the release of acetylcholine from cholinergic nerve terminals. On the other hand, in the gallbladder, PYY does not appear to block cholinergic nerve function.