Effects of γ-acetylenic GABA and γ-vinyl GABA on electrically-induced spinal cord convulsions and on spinal cord GABA concentration

The effects of γ-acetylenic GABA and γ-vinyl GABA on electrically-induced spinal cord convulsions were compared to the effects of these same drugs on spinal cord GABA concentration. The data show that the effects of these two compounds on seizure activity do not correlate either positively or negatively with changes in GABA concentration. Although both drugs produced marked increases in the amount of GABA in the spinal cord, their effects on spinal cord convulsions were qualitatively different and failed to correlate temporally with alterations in GABA concentration.     

Abnormal myelination in the spinal cord of PTPα-knockout mice

PTPα interacts with F3/contactin to form a membrane-spanning co-receptor complex to transduce extracellular signals to Fyn tyrosine kinase. As both F3 and Fyn regulate myelination, we investigated a role for PTPα in this process. Here, we report that both oligodendrocytes and neurons express PTPα that evenly distributes along myelinated axons of the spinal cord. The ablation of PTPα in vivo leads to early formation of transverse bands that are mainly constituted by F3 and Caspr along the axoglial interface. Notably, PTPα deficiency facilitates abnormal myelination and pronouncedly increases the number of non-landed oligodendrocyte loops at shortened paranodes in the spinal cord. Small axons, which are normally less myelinated, have thick myelin sheaths in the spinal cord of PTPα-null animals. Thus, PTPα may be involved in the formation of axoglial junctions and ensheathment in small axons during myelination of the spinal cord.     

“Axonal spheroids” in the spinal cord of normal rabbits

Summary Within the gray matter and the white matter of the spinal cord of apparently healthy rabbits, myelinated and unmyelinated axonal swellings, so called axonal spheroids, occur. Most of the spheroids contain mitochondria, dense bodies, vesicles and fragments of the tubular or smooth endoplasmic reticulum. In myelinated spheroids the process of swelling is effected by slippage of the myelin leaflets. At the periphery of the unmyelinated parts of the spheroids, synapses are regularly found. The presynaptic terminal bouton is formed by the spheroid. A few myelinated and unmyelinated spheroids are packed with fine granular material while mitochondria are lacking. The axonal spheroids may represent a physiological, perhaps age dependent phenomenon.Dedicated to Prof. Dr. Berta Scharrer on the occasion of her 70^th birthdayThe author wishes to thank Mrs. Helga Zuther-Witzsch, Mrs. Elisabeth Schöngarth and Miss Hildegard Schöning for excellent technical assistance. Supported by the Deutsche Forschungsgemeinschaft, Projekt Le 69/7-13     

Olfactory ensheathing cells - another miracle cure for spinal cord injury?

Several recent publications describe remarkably promising effects of transplanting olfactory ensheathing cells as a potential future method to repair human spinal cord injuries. But why were cells from the nose transplanted into the spinal cord? What are olfactory ensheathing cells, and how might they produce these beneficial effects? And more generally, what do we mean by spinal cord injury? To what extent can we compare repair in an animal to repair in a human?     

Up-regulation of Μ-opioid receptors in the spinal cord of morphine-tolerant rats

Though morphine remains the most powerful drug for treating pain, its effectiveness is limited by the development of tolerance and dependence. The mechanism underlying development of tolerance to morphine is still poorly understood. One of the factors could be an alteration in the number of Μ-receptors within specific parts of the nervous system. However, reports on changes in the Μ-opioid receptor density in the spinal cord after chronic morphine administration are conflicting. Most of the studies have used subcutaneously implanted morphine pellets to produce tolerance. However, it does not simulate clinical conditions, where it is more common to administer morphine at intervals, either by injections or orally. In the present study, rats were made tolerant to morphine by injecting increasing doses of morphine (10-50 mg/kg, subcutaneously) for five days.In vitro tissue autoradiography for localization of Μ-receptor in the spinal cord was done using [³H]-DAMGO. As compared to the spinal cord of control rats, the spinal cord of tolerant rats showed an 18.8% increase or up-regulation in the density of Μ-receptors in the superficial layers of the dorsal horn. This up-regulation of Μ-receptors after morphine tolerance suggests that a fraction of the receptors have been rendered desensitized, which in turn could lead to tolerance     

Treatments for spinal cord injury: is there hope in neurosteroids?

In this review, we describe the current therapeutic strategies to find a cure for paralysis. We use the example of DHEA, a neurosteroid normally produced in the developing neural tube, to raise the hypothesis that such a class of molecules, capable of modulating proliferation of committed neural precursors, could serve as an environmental cue in the adult injured spinal cord to promote re-population of CNS lesion with endogenous dormant precursor cells. Such mechanism may be a part of the natural response to heal the injured CNS and promote recovery of function, suggesting that neurosteroid-treatment could be a promising and novel therapeutic avenue for SCI. We will review pertinent biological activities of DHEA supporting this hypothesis, demonstrate that such activities, dependent on an intact sonic-hedgehog pathway, are responsible for the motor and bladder functional recovery observed after DHEA-treatment in the adult injured spinal cord. We will also raise the current limitations to further development of DHEA- or other neurosteroid-treatments as drug candidates, including the urgent need to further document DHEA long-term safety in CNS indications.     

The uptake of γ-aminobutyrate by organotypic cultures of chick spinal cord

1. Explants of spinal cord from 10-day chick embryos maintained for up to 16 days in culture rapidly accumulated gamma-amino[(3)H]butyrate when incubated at 25 degrees C or 36 degrees C in a medium containing 50nm-gamma-aminobutyrate. The mechanism of the uptake process has many of the properties of an active-transport system: it is Na(+)-dependent, temperature-sensitive, inhibited by ouabain, and displays saturation kinetics. The apparent K(m) for gamma-aminobutyrate is 1.7x10(-5)m, and V(max.) is 33pmol/min per g. 2. The rate of accumulation of gamma-amino[(3)H]butyrate in cultures between the ages of 3 and 16 days was remarkably constant and was not related to the morphological maturity of the spinal-cord explants. 3. The present demonstration in spinal-cord explants of an active transport system for gamma-aminobutyrate, already established for non-cultured nervous tissue, means that nervous-tissue culture can provide a convenient model for studying uptake processes in the central nervous system.     

Can regenerating axons recapitulate developmental guidance during recovery from spinal cord injury?

The precise wiring of the adult mammalian CNS originates during a period of stunning growth, guidance and plasticity that occurs during and shortly after development. When injured in adults, this intricate system fails to regenerate. Even when the obstacles to regeneration are cleared, growing adult CNS fibres usually remain misdirected and fail to reform functional connections. Here, we attempt to fill an important niche related to the topics of nervous system development and regeneration. We specifically contrast the difficulties faced by growing fibres within the adult context to the precise circuit-forming capabilities of developing fibres. In addition to focusing on methods to stimulate growth in the adult, we also expand on approaches to recapitulate development itself.     

Cystathionine β-synthase in structural elements of the human brain and spinal cord

By means of the immunohistochemical method, the presence and distribution of cystathionine β-synthase (CBS) was studied in nerve cells of the spinal cord and brainstem nuclei in eight men aged 18–44 years who had died as a result of causes not connected with damage to the central nervous system. CBS-positive neurons are revealed in all studied brain parts, in which their content varied in different nuclei from 0.9 to 17%. Large cells of motor nuclei more often had high and very high density of the reaction product deposition. In sensory nuclei the high portion was of small neurons with low intensity of the enzymatic reaction.     

In vivo utilization ofd(−)-3-hydroxybutyrate by chick brain and spinal cord

The in vivo utilization ofd-3-hydroxy[3-¹⁴C]butyrate for oxidation in the whole animal and for lipid and amino acid synthesis in brain and spinal cord of overnight-fasted 15-day-old chicks has been measured. Appreciable amounts of injected 3-hydroxy[3-¹⁴C]butyrate were expired as¹⁴CO₂ one hour after injection, the total amount of which increased with increasing dosages. Lipid synthesis was high in both brain and spinal cord. Free, cholesterol and phospholipids were the main lipids labeled in both, tissues, increasing with time after injection up to 120 min. The incorporation of radioactivity into triglycerides, esterified cholesterol and free fatty acids was not time-dependent. Increased concentrations of 3-hydroxybutyrate gave rise to higher synthetic rates both in brain and spinal cord The rate of amino acid synthesis was slightly higher in brain than in spinal cord. Glutamate was always the major amino acid formed.     

Propagation of activity along the “stepping strip” of the cat spinal cord

Three points located approximately 8 mm apart were identified in a dorsolateral funiculus of the lower thoracic spinal cord in mesencephalic cats, each producing stepping movements on the ipsilateral hindlimb when stimulated. An area 5–17 mm caudal to the caudal stepping point (SP) was scanned for neurons responding synaptically to stimulating the rostral or caudal SP prior and subsequent to electrolytic coagulation of the medial SP. Relative incidence of neurons excited by stimulating the caudal SP did not change following this type of lesioning, although stimulation of the rostral SP at the rate of 4 Hz induced response 5 times less frequently than before. Even stimulation of the rostral SP at the rate of 40–60 Hz, which had considerably increased firing index prior to coagulation, could only produce excitation in tiny numbers of neurons. This indicates that synaptic excitation of neurons becomes considerably more difficult once the stepping strip between stimulation and recording sites has been damaged.Institute for Research into Information Transmission, Academy of Sciences of the USSR, Moscow. Translated from Neirofiziologiya, Vol. 20, No. 6, pp. 763–769, November–December, 1988.     

Upregulation of casein kinase 1ε in dorsal root ganglia and spinal cord after mouse spinal nerve injury contributes to neuropathic pain

Glycine receptors (GlyRs) play important roles in regulating hippocampal neural network activity and spinal nociception. Here we show that, in cultured rat hippocampal (HIP) and spinal dorsal horn (SDH) neurons, 17-β-estradiol (E₂) rapidly and reversibly reduced the peak amplitude of whole-cell glycine-activated currents (I _Gly). In outside-out membrane patches from HIP neurons devoid of nuclei, E₂ similarly inhibited I _Gly, suggesting a non-genomic characteristic. Moreover, the E₂ effect on I _Gly persisted in the presence of the calcium chelator BAPTA, the protein kinase inhibitor staurosporine, the classical ER (i.e. ERα and ERβ) antagonist tamoxifen, or the G-protein modulators, favoring a direct action of E₂ on GlyRs. In HEK293 cells expressing various combinations of GlyR subunits, E₂ only affected the I _Gly in cells expressing α2, α2β or α3β subunits, suggesting that either α2-containing or α3β-GlyRs mediate the E₂ effect observed in neurons. Furthermore, E₂ inhibited the GlyR-mediated tonic current in pyramidal neurons of HIP CA1 region, where abundant GlyR α2 subunit is expressed. We suggest that the neuronal GlyR is a novel molecular target of E₂ which directly inhibits the function of GlyRs in the HIP and SDH regions. This finding may shed new light on premenstrual dysphoric disorder and the gender differences in pain sensation at the CNS level.     

Construction of rat spinal cord injury model based on Allen’s animal model

The aim of this study is to explore the construction of rat spinal cord injury model guided by Allen's model. Methods: Male rats aged 4–5 weeks and weighing about 250 g are selected as subjects in the Animal Laboratory Center of XX Hospital. Rats are divided into two groups, which are experimental group 1 and experimental group 2, respectively, so as to construct spinal cord injury model in rats. The first group is given 300 g.cm hitting force of T10 spinal cord, and the second group is given 500 g.cm hitting force of T10 spinal cord. Within 25 days after spinal cord injury in Allen's rats, the survival, neurological function, diet, motor ability, tactile ability and auditory ability of the two groups are monitored and evaluated daily. Results: In terms of survival, the survival rate of rats in group 1 is 85%, while that of rats in group 2 is 21%, and there is a concentrated death phenomenon in group 2. In terms of neurological function recovery, experimental group 1 is stable and gets 7 points and experimental group 2 is stable and gets 3 points. In terms of diet, the experimental group 1 is stable and gets 5 points and the experimental group 2 is stable and gets 2 points. In terms of motor ability, the experimental group 1 is stable and gets 5 points and the experimental group 2 is stable and gets 2 points. In tactile sense, experimental group 1 is stable and gets 17 points and experimental group 2 is stable and gets 12 points. It can be seen that the post-operative recovery ability of the experimental group 1 is better than that of the experimental group 2. Conclusion: Under the guidance of Allen's model, compared with the group 2, the experimental group 1 of the rat spinal cord injury model has better recovery in each index. It can be seen that the smaller impact strength is more beneficial to the recovery of rats after spinal cord injury surgery.     

Primary afferent depolarization distribution of the γ-aminobutyric acid system in frog spinal cord

In the frog spinal cord primary afferent depolarization (PAD) constitutes a powerful inhibitory control mechanism. It has been suggested that -aminobutyric acid (GABA) is the transmitter substance involved in the genesis of PAD. In these studies we show that maximal glutamic acid decarboxylase activity is localized roughly 400–600 m from the dorsal surface, and that correlates well with the intraspinal distribution of field potentials associated with PAD. Measurement of GABA in serial spinal cord sections cut in a dorsal-ventral direction shows that high levels of GABA are seen at 400–600 m, with a peak at 800 m from the dorsal surface. Stimulation at frequencies shown to produce PAD augments the release of endogenous GABA from a superfused frog hemicord preparation.