Tyrosine hydroxylase activity in sympathetic nervous system of rats with streptozocin-induced diabetes.

The activity of tyrosine hydroxylase (TOH), the rate-limiting enzyme in norepinephrine biosynthesis, was measured in selected sympathetic ganglia to develop a quantitative measure of sympathetic autonomic neuropathy in streptozocin-induced diabetic rats. Surprisingly, TOH activity was elevated twofold in diabetic prevertebral ganglia innervating the alimentary tract (i.e., superior mesenteric, celiac, and inferior mesenteric), which has terminal processes that develop neuroaxonal dystrophy in this model system. TOH activity of paravertebral ganglia (i.e., superior cervical and stellate) with nonalimentary targets was not increased in the same animals. Increased TOH activity in the prevertebral ganglia 1) developed within the 1st wk of diabetes and persisted for 10 mo, 2) did not represent a change in TOH affinity for d-1,6-methyl-5,6,7,8- tetrahydropterine cofactor, 3) was prevented by both nicotinamide pretreatment and early institution of insulin therapy, and 4) did not develop as a result of classical transsynaptic induction. Pair-feeding experiments confirmed that the most likely cause of increased TOH activity in this system was the marked hypertrophy and hyperplasia of the diabetic bowel resulting from compensatory hyperphagia. We conclude that TOH activity does not represent a suitable marker for sympathetic autonomic neuropathy in this experimental system. Rather, the increase appears to be an example of a selective increase in the synthesis of neurotransmitter enzymes, possibly in response to increased trophic support provided by the expanded target, i.e., the hypertrophic gut. The additional synthetic stress imposed on prevertebral neurons by the expansion of the innervation of the alimentary target coupled with the complex diabetic metabolic milieu may contribute to the development and selective distribution of dystrophic axonopathy to the innervation of the alimentary tract.

A model for slow axonal transport and its application to neurofilamentous neuropathies.

A model for slow axonal transport is developed in which the essential features are reversible binding of cytoskeletal elements and of soluble cytosolic proteins to each other and to motile elements such as actin microfilaments. Computer simulation of the equations of the model demonstrate that the model can account for many of the features of the SCa and SCb waves observed in pulse experiments. The model also provides a unified explanation for the increase and decrease of neurofilament transport rates observed in various toxicant-induced neuropathies.

Precocial neural function in the growth-retarded fetal lamb.

Clinical studies suggest that growth-retarded prematurely delivered infants are neurologically precocious. We investigated this paradoxical observation in the fetal lamb. Somatosensory and brainstem auditory-evoked potentials were studied in chronically instrumented fetal lambs in late gestation with varying degrees of growth retardation induced by preconception uterine carunclectomy. The components of the brainstem auditory-evoked response appeared earlier (p less than 0.05) in fetuses at least 2 SD less than the mean weight for gestational age (n = 5) compared to normal controls (n = 8) or carunclectomized fetuses of normal size (n = 7). Several waveforms of both the somatosensory (N20, P/N 30, and P200) and the brainstem auditory-evoked response (I, III, IV, and V) demonstrated shorter (p less than 0.05) latencies in growth-retarded fetuses relative to normal-sized fetuses. The ability to follow increasing stimulus rates for both stimuli also demonstrated precocial maturation (p less than 0.05) in growth-retarded as compared to normal-sized fetuses. Growth retardation is thus associated with precocial neurologic maturation in utero.

Effects of plasma angiotensin II and hypernatremia on subfornical organ neurons.

Experiments were done in urethan-anesthetized rats to investigate the effect of plasma angiotensin II (ANG II) and hypernatremia on the excitability of subfornical organ (SFO) neurons projecting directly to paraventricular nucleus of the hypothalamus (PVH), supraoptic nucleus (SON), and nucleus medianus (NM). Extracellular recordings were made from 106 antidromically identified neurons in the SFO. The firing frequency of 53 (50%) was increased by the intracarotid infusion of ANG II and/or 0.5 M hypertonic NaCl. The intracarotid infusion of isotonic saline or the intravenous infusion of phenylephrine did not alter the discharge rate of these SFO neurons. Of 38 PVH projecting neurons, 21 (55%) responded to ANG II and/or hypertonic NaCl: 9 to ANG II only, 8 to hypertonic NaCl only, and 4 to both. Similarly, of 42 SON projecting neurons, 30 (71%) responded to ANG II and/or hypertonic NaCl: 10 to ANG II only, 15 to hypertonic NaCl only, and 5 to both. Finally, of 26 NM projecting neurons, one increased its firing frequency to ANG II and one other to 0.5 M NaCl. An additional eight SFO neurons were found to send collateral axons to both the PVH and SON (n = 6) and PVH and NM (n = 2): four responded in various combinations to intracarotid infusion of ANG II and 0.5 M NaCl. These data suggest that blood-borne ANG II and plasma hypernatremia can influence arterial pressure and the release of vasopressin from the neurohypophysis by altering the discharge rate of SFO neurons projecting to forebrain structures that contain magnocellular neurosecretory vasopressin neurons and neurons that are components of sympathoexcitatory pathways.

Spreading depression is not associated with neuronal injury in the normal brain.

This study was performed in order to evaluate whether waves of spreading depression (SD) induces irreversible neuronal injury. SD was elicited by topical application of 3 M KCl to the exposed cortex for 4-5 h and the resulting change of the cortical electrical potential showing the occurrence of SD, was recorded by glass microelectrodes. Histological examination of cerebral cortex revealed no signs of neuronal injury outside the area of KCl application as examine after 4 days recovery. The results indicate that recurrent waves of SD do not induce irreversible neuronal injury in the otherwise normal rat brain.

[Electrophysiological studies in the assessment of polyneuropathies]. / Apport des examens électrophysiologiques dans l'étude des polyneuropathies.

In many cases, one encounters great difficulties in finding causes of polyneuropathies among some 100 etiologies. However, in current practice, the diagnostic span is not so large. At this point, it is usual to get some aid from electrophysiologic tests in order to determine the nature of the peripheral nerve disorder. Examination with needle electrodes is mainly useful to detect fibrillation potentials or positive sharp waves which are indicative of an acute or subacute axonal neuropathy in which the process of degeneration is more important than the capacities of regeneration. Studies of sensory and motor nerve conduction velocities is of a more important utility to separate the different types of peripheral neuropathies: axonopathies in which nerve conduction velocities are normal or slightly decreased but in which muscular evoked potentials and sensory potentials are reduced, myelin disorders in which nerve conduction velocities are markedly decreased and in which finding of conduction blocks allows to individualize two forms, motor and sensory neuronopathies, where the pure lesion of the motor or sensory cell bodies correlate with the normality of sensory and motor pathways respectively.

Pharmacology of the glutamate receptor.

Glutamate is a potent candidate of the excitatory transmitter at the invertebrate NMJ and the synapse of the vertebrate CNS. But pharmacological studies have not been enough to prove that glutamate functions as an excitatory neurotransmitter. During the past 10 years, we have been studying the effects of various compounds which demonstrate the glutamate blocking action, but the glutamate responses are more effectively blocked by the drugs than the nerve-evoked synaptic response. A marked difference was revealed by TI-233, the minimum concentration of TI-233 on EJP being about a hundred times greater than the minimum threshold concentration on the glutamate-induced responses. The subsequent studies demonstrated that the action of TI-233 was able to be explained by the open channel block of the glutamate-activated ion-channel. The difference does not confute the hypothesis that glutamate is the natural transmitter substance at the crayfish NMJ, notwithstanding the fact that the action of the transmitter candidate on the postsynaptic membrane must be identical in every respect with that of the transmitter. Once something potentially useful has been found it is necessary to know not only what a substance does but how well it does it, so that comparisons can be made and better drugs discovered. Our first task therefore was to find a powerful glutamate blocker. Recently, as a result of synthesizing a series of compounds on the base of the structure-activity relationship in drug design, a series of compounds was found to reduce markedly glutamate responses at the crayfish NMJ and the mammalian central neurones at extremely low concentrations. In addition, a novel potent excitatory amino acid, acromelic acid, was found. This compound markedly excites the crayfish opener muscle and the mammalian central neurones. Agonists and antagonists have provided a very useful tool for neuroscience research, and findings of these new pharmacological tools will lead to progress in pharmacological studies to elucidate the function of glutamate in the body, in addition to other established compounds. The recent advances in our limited understanding of pharmacology of the glutamate receptor are discussed here.

Relationship between single-unit activity and the electroencephalogram in a neocortical, cobalt-induced epileptogenic focus.

Although the importance of neuronal synchrony in epilepsy has not been disputed, few attempts have been made to examine quantitatively the relationship between this parameter and seizure occurrence. The specific objective of the present investigation was to determine how the amount and type of synchrony between EEG and single-unit activity in an experimental model of focal epilepsy are related to the occurrence of seizures. This was accomplished by examining EEG/single unit relationships in two types of cobalt-induced epileptogenic focus: (1) foci that initiated seizures, and (2) foci that exhibited only interictal spike activity. These relationships were examined during slow-wave sleep, a time when synchronous neuronal activity is thought to be augmented. In control rats and rats that had seizures, the majority of units exhibited a non-random relationship between unit discharge and the EEG. In cobalt-treated rats that were not observed to have seizures, however, the percentage of units exhibiting EEG/single unit relationships was significantly less than that in either controls or rats that had seizures. This observation, paired with observations of the details of the EEG/single unit relationships, led to the hypothesis that cobalt treatment produces a shift from an inhibition dominated synchrony (observed in controls) to an excitation dominated synchrony (observed in rats that had seizures). Intermediate between these two types of synchrony is a less synchronized state (observed in seizure-free, cobalt-treated rats), which probably results from a loss of inhibition dominated synchrony without a concomitant increase in excitation dominated synchrony.

Taurine improves the recovery of neuronal function following cerebral hypoxia: an in vitro study.

Rat hippocampal slices were used in the present study to assess the effect of a pretreatment with the amino acid taurine on their ability to recover synaptic function following a standardized hypoxic insult. After 10 min hypoxia, 47% of all control (untreated) slices exhibited recovery of synaptic function (orthodromically evoked CA1 population spike). Of slices pretreated with 0.5, 1.0 or 2.0 mM taurine, 63, 88 and 97% recovered from the same hypoxic insult. This dose-dependent protective effect was biphasic, as 5.0 mM taurine produced no protection. When hypoxia was extended to 15 min, only 20% of the untreated slices recovered, while 88% of slices treated with 1.0 mM taurine recovered their population spike. The same pretreatment attenuated the fall in the population spike amplitude upon Ca2+ depletion. We hypothesize that taurine plays an important role in an endogenous antihypoxic mechanism through the attenuation of Ca2+ movement across the neuronal membrane.

Technical limitations to the efficacy of radiofrequency neurotomy for spinal pain.

Prompted by clinical failures of percutaneous radiofrequency neurotomy in the treatment of back pain and neck pain, we performed a study to determine the shape and size of lesions made by radiofrequency electrodes. Experimental lesions were made in egg white and fresh meat at temperatures recommended in clinical practice. The cardinal finding was that lesions do not extend distal to the tip of the electrode. They only extend radially around the electrode tip in the shape of an oblate spheroid, with a maximal effective radius of only 2 mm. Consequently, if electrodes are directed perpendicularly onto a nerve, the nerve may not be encompassed by the lesion generated. Some of the clinical failures of percutaneous medial branch neurotomy ("facet rhizotomy") may be due to this phenomenon. We suggest modified techniques for medial branch neurotomy in which the electrodes are introduced parallel to the target nerve whereupon it is more readily encompassed by the radial spread of the lesion.

Reversibility of alcohol-related brain damage: clinical and experimental observations.

Chronic alcoholics who maintain abstinence often demonstrate remarkable improvement of neurological and mental dysfunction. This paper presents an overview of the clinical and laboratory work of our group. Reversible clinical manifestations include psychometric scores, ataxia, tremor, Parkinsonism, dyskinesia, cerebral atrophy, EEG parameters, and a CSF acidosis. Electrophysiological investigations showed that in the in vitro hippocampus of rats fed ethanol for several months there was evidence for diminished long-term potentiation, impaired neuronal inhibitory mechanisms (diminished inhibitory post-synaptic potentials and post-spike after hyperpolarisations), decreased neuronal specific membrane capacitance and increased specific membrane resistance. Golgi stains showed attenuation of hippocampal CA1 neuronal dendrites in rats fed ethanol for five months, which reverted to control size in rats permitted two months of alcohol withdrawal.

Alzheimer's disease, Parkinson's disease, and motoneurone disease: abiotrophic interaction between ageing and environment?

The hypothesis is that Alzheimer's disease, Parkinson's disease (PD), and motoneurone disease are due to environmental damage to specific regions of the central nervous system and that the damage remains subclinical for several decades but makes those affected especially prone to the consequences of age-related neuronal attrition. This proposal is based on the association between environmental factors and certain neurodegenerative diseases (eg, methylphenyltetra-hydropyridine and parkinsonism, poliovirus infection and post-poliomyelitis syndrome, chickling pea ingestion and lathyrism, an unidentified environmental factor and amyotrophic lateral sclerosis-PD complex of Guam, and trauma and pugilist's encephalopathy) and on the long latent period between exposure to environmental factor and the appearance of symptoms in some of these disorders. The practical implications of this hypothesis are that epidemiological attention should be focussed on the environment in early rather than late life, prevention may be a realistic goal if the cause of subclinical damage can be identified, a search should be undertaken for causal mechanisms linking subclinical neuronal damage due to an environmental factor and the normal ageing process, and (4) better understanding of the regional selective vulnerability of the nervous system to the ageing process might allow a rational approach to treatment.

Differential depressive action of two mu and delta opioid ligands on neuronal responses to noxious stimuli in the thalamic ventrobasal complex of rat.

In the present investigation the effects of selective agonists for mu (Tyr-D-Ala-Me-Phe-Gly-ol (DAGO)) and delta (Tyr-D-Thr-Gly-Phe-Leu-Thr (DTLET)) opioid receptors on neuronal activities induced by noxious cutaneous stimuli in the rat ventrobasal (VB) thalamus were analyzed. The two agonists produced a clear depressive action on thermal as well as mechanical noxious stimuli. The depressive action of DTLET (3 mg/kg i.v.) was lower and of shorter duration than that of DAGO (2 mg/kg i.v.). However, this effect is unambiguously related to the selective stimulation of opioid receptors since a consistent effect was also observed for a dose as low as 1.5 mg/kg i.v. of DTLET. Moreover, DTLET effect needs a high concentration of naloxone (0.5 mg/kg i.v.) to be reversed, while DAGO effect is totally reversed with 0.1 mg/kg i.v.

The organization of spinal pathways to ventrobasal thalamus in an experimental model of pain (the arthritic rat). An electrophysiological study.

The spinal ascending pathways responsible for neuronal ventrobasal (VB) thalamic responses elicited by joint stimulation of the posterior paw were determined in arthritic rats used as a model of experimental pain. Responses of a same neurone to mechanical (movement--pressure--brushing) or thermal stimulation (50 degrees C) were analysed before and after discrete lesions in the white matter of the spinal cord. For 6 neurones responding exclusively to brushing applied on a small receptive field (RF) strictly contralateral to the recording site, responses were not altered as long as the contralateral dorsal column was intact. Twenty neurones exhibited bilateral symmetrical RF located on the posterior paws including the ankles and for some units the digits. They were driven by moderate pressure and/or mild sustained joint movement and by immersion in a hot water bath at 50 degrees C. Their responses were not significantly modified when the lesions destroyed most of the dorsal and the dorsolateral parts of the spinal cord. In 16/20 cases effect of one hemisection of the cord was studied: when the hemisection was contralateral to the recording site (n = 8) VB neuronal responses elicited from the paw ipsilateral to this side were eliminated in 6/8 cases; when the 1/2 section was ipsilateral to the recording site (n = 8) the lesion induced the elimination of the responses elicited from the paw opposite to the recorded VB for one unit only. The involvement of the spino-reticular pathways which have not only a crossed but also a non-crossed component is suggested. This hypothesis is discussed by comparison to data previously obtained, showing that by contrast in healthy rats the spino-thalamic tract is essential for VB neuronal responses to noxious stimuli.