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PubMedDate not supplied

Biochemical characteristics of gamma-glutamyl transpeptidase in capillaries from entorhinohippocampal complex of quinolinate-lesioned rat brain.

Quinolinic acid (QUIN) is an endogenous excitotoxic agonist of the N-methyl-D-aspartate (NMDA) type of glutamate receptor, which causes slowly progressing degeneration of vulnerable neurons in some brain regions. Using changes in the activity of membrane-bound gamma-glutamyl transpeptidase (GGT) as a marker of cell damage, we found a significant decrease of this enzyme activity, which was preferentially located in the ipsilateral hippocampal formation and entorhinal cortex, 4 d after the unilateral intracerebroventricular (icv) injection of 0.5 mumol QUIN. The dose of QUIN divided into two half-doses injected bilaterally led to a symmetrical decline of GGT activity in hippocampal areas. The lesion was characterized by a suppression of GGT activity in hippocampal and entorhinal capillaries, corresponding to 60 and 81% of their initial value, respectively, but no significant changes were ascertained in synaptosomal membranes. The changes in the activity of capillary GGT were associated with the decrease of apparent maximal velocity Vmaxapp, whereas apparent Michaelis constant K(m)app (0.69-0.79 mM) remained unaffected. In the nonlesioned brain, concanavalin A (Con A) affinity chromatography revealed five glycoforms of synaptosomal GGT in contrast to only one found in hippocampal and entorhinal capillaries. The results document that neither the saccharide moiety of GGT nor the value of enzyme K(m)app is significantly affected by the QUIN-induced lesion of the rat brain. However, the suppression of GGT activity, which is accompanied by a decrease in the value of Vmaxapp in brain microvessels, may suggest dysfunction of the blood-brain barrier (BBB) in the QUIN-injured rat brain.

Animals↗

PubMed1982

Auditory brainstem responses in the aged cat.

Auditory brainstem responses (ABRs) were compared in young adult and aged cats. Mean thresholds for click-evoked ABRs were greater in the aged cats. Clicks normalized to 15 and 30 dB above individual thresholds at rates of 10, 20, 50 and 100/sec evoked ABRs with similar latencies and central conduction times in both groups. Background noise at equal intensity for all cats completely suppressed ABRs evoked by clicks 30 dB above threshold in 2/3 of the young but none of the old cats. As rise time of a 25 msec noise burst at equal intensity for all cats increased 1, 2, 5, and 10 msec, latency of wave 4 increased more for the old cats than for the young. Summed monaural ABRs from both ears were greater than binaural ABRs for waves 4 and 5 in both groups. These data indicate peripheral auditory dysfunction in aged cats but little abnormality in auditory brainstem transmission with click intensity normalized for ABR threshold.

Aging↗

PubMed2000

Neuroprotective signaling and the aging brain: take away my food and let me run.

It is remarkable that neurons are able to survive and function for a century or more in many persons that age successfully. A better understanding of the molecular signaling mechanisms that permit such cell survival and synaptic plasticity may therefore lead to the development of new preventative and therapeutic strategies for age-related neurodegenerative disorders. We all know that overeating and lack of exercise are risk factors for many different age-related diseases including cardiovascular disease, diabetes and cancers. Our recent studies have shown that dietary restriction (reduced calorie intake) can increase the resistance of neurons in the brain to dysfunction and death in experimental models of Alzheimer's disease, Parkinson's disease, Huntington's disease and stroke. The mechanism underlying the beneficial effects of dietary restriction involves stimulation of the expression of 'stress proteins' and neurotrophic factors. The neurotrophic factors induced by dietary restriction may protect neurons by inducing the production of proteins that suppress oxyradical production, stabilize cellular calcium homeostasis and inhibit apoptotic biochemical cascades. Interestingly, dietary restriction also increases numbers of newly-generated neural cells in the adult brain suggesting that this dietary manipulation can increase the brain's capacity for plasticity and self-repair. Work in other laboratories suggests that physical and intellectual activity can similarly increase neurotrophic factor production and neurogenesis. Collectively, the available data suggest the that dietary restriction, and physical and mental activity, may reduce both the incidence and severity of neurodegenerative disorders in humans. A better understanding of the cellular and molecular mechanisms underlying these effects of diet and behavior on the brain is also leading to novel therapeutic agents that mimick the beneficial effects of dietary restriction and exercise.

Aging↗

PubMed2003

Electromyographic detection of purinergic activity in Guinea pig detrusor smooth muscle.

PURPOSE: We recorded nerve mediated extracellular electrical activity from guinea pig detrusor smooth muscle strips using suction electrodes and determined the electrophysiological origins of this signal and its relationship to contractile activity. MATERIALS AND METHODS: Mucosa-free detrusor strips were prepared from male guinea pigs sacrificed under Home Office license, physiologically superfused, attached to a pressure transducer and electrically stimulated (0.1 millisecond pulses). Electrical signals recorded using a bipolar reversible suction electrode were processed and recorded simultaneously with changes in strip tension. The effect of superfusion with alpha, beta-methylene adenosine triphosphate (ATP), atropine, extracellular [CaCl(2)] depletion and pharmacological Ca2+ channel blockade on the electrical and mechanical signals was determined. RESULTS: A biphasic electrical signal was consistently recorded from 37 detrusor strips. The signal was sensitive to graded reduction in [CaCl(2)] of the superfusate and abolished by tetrodotoxin in 7 preparations. The signal was also abolished in 12 preparations by alpha, beta-methylene ATP in association with an attenuated contraction but not significantly reduced in amplitude (p = 0.77) despite a significant reduction in tension with atropine (mean plus or minus SD 74% +/- 14% of control, p <0.001). The signal was attenuated to a mean maximum of 9% +/- 3% of control by pharmacological Ca2+ channel blockade and the remaining signal was abolished by alpha, beta-methylene ATP. CONCLUSIONS: The extracellular electrical signal recorded from guinea pig detrusor strips using suction electrodes originates from a purinergic mechanism. Although an atropine sensitive component may be present, the signal does not depend on cholinergic neuromuscular transmission and would not be expected to be generated by normal human detrusor. Provided that the electrophysiological basis of purinergic neurotransmission in guinea pig and human bladders is similar suction electrodes may be a valuable tool with which to evaluate in vitro and clinically by electromyography the pathological purinergic neuromuscular transmission that can be expressed in addition to normal cholinergic mechanisms in detrusor from dysfunctional human bladders.

Adenosine Triphosphate↗

PubMed2000

Spatial pattern of cerebral glucose metabolism (PET) correlates with localization of intracerebral EEG-generators in Alzheimer's disease.

BACKGROUND: Since the measurement of human cerebral glucose metabolism (GluM) by positron emission tomography (PET) and that of human cerebral electrical activity by EEG reflect synaptic activity, both methods should be related in their cerebral spatial distribution. Healthy subjects do indeed demonstrate similar metabolic and neuroelectric spatial patterns. OBJECTIVE: The aim of the study was to show that this similarity of GluM and EEG spatial patterns holds true in a population with a high variability of glucose metabolism. METHODS: We investigated healthy control subjects and patients with varying degrees of cognitive dysfunction and varying GluM patterns by applying [18F]FDG PET and EEG. RESULTS: We demonstrated that the localization of intracerebral generators of EEG correlates with spatial indices of GluM. CONCLUSION: These results indicates that EEG provides similar spatial information about brain function as GluM-PET. Since EEG is a non-invasive technique, which is more widely available and can be repeated more often than PET, this may have important implications both for neuropsychiatric research and for clinical diagnosis. However, further studies are required to determine whether equivalent EEG dipole generators can yield a diagnostic specificity and sensitivity similar to that of GluM-PET.

Aged↗

PubMed2004

NMDA receptor hypofunction produces concomitant firing rate potentiation and burst activity reduction in the prefrontal cortex.

Cognitive deficits associated with frontal lobe dysfunction are a determinant of long-term disability in schizophrenia and are not effectively treated with available medications. Clinical studies show that many aspects of these deficits are transiently induced in healthy individuals treated with N-methyl-D-aspartate (NMDA) antagonists. These findings and recent genetic linkage studies strongly implicate NMDA receptor deficiency in schizophrenia and suggest that reversing this deficiency is pertinent to treating the cognitive symptoms of schizophrenia. Despite the wealth of behavioral data on the effects of NMDA antagonist treatment in humans and laboratory animals, there is a fundamental lack of understanding about the mechanisms by which a general state of NMDA deficiency influences the function of cortical neurons. Using ensemble recording in freely moving rats, we found that NMDA antagonist treatment, at doses that impaired working memory, potentiated the firing rate of most prefrontal cortex neurons. This potentiation, which correlated with expression of behavioral stereotypy, resulted from an increased number of irregularly discharged single spikes. Concurrent with the increase in spike activity, there was a significant reduction in organized bursting activity. These results identify two distinct mechanisms by which NMDA receptor deficiency may disrupt frontal lobe function: an increase in disorganized spike activity, which may enhance cortical noise and transmission of disinformation; and a decrease in burst activity, which reduces transmission efficacy of cortical neurons. These findings provide a physiological basis for the NMDA receptor deficiency model of schizophrenia and may clarify the nature of cortical dysfunction in this disease.

Action Potentials↗

PubMed1987

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.

Action Potentials↗

PubMed1984

Development of central neurotransmitter-specified neuronal systems: implications for pediatric neuro-psychiatric disorders.

An increasing focus on the mechanism of synaptic neurochemistry in pediatric neurology, may lead to a better understanding of the pathophysiology of many disorders and result in a more rational approach to their pharmacotherapy. With the burgeoning list of putative neurotransmitters in brain, and the growing evidence of co-localization of many of these neurotransmitters, chemical neurotransmission likely involves a higher degree of complexity than appreciated heretofore. The potential role of neurotransmitter dysfunction in the pathophysiology of neurologic and behavior disorders of children, should not be considered as restricted to those disorders that involve selective neuronal loss, but may encompass a much wider spectrum of syndromes due to metabolic abnormalities, as well as disturbances of the finer features of chemical neurotransmission.

Afferent Pathways↗

PubMed1985

Vascular headaches and cerebral circulation: an overview.

A complex network of neurotransmission systems underlies the control of the cerebral circulation. Classical neurotransmitters, vasoactive peptides and receptors have been found in cerebral arteries. Central and peripheral structures are also probably involved in the neurogenic control of the cerebral circulation. Vascular and neurotransmission changes reported in vascular headaches suggest that an alteration of the neurogenic control of the brain circulation may be implicated in vascular headaches. In particular, locus coeruleus, which may control the intracerebral adrenergic pathway, can induce vascular changes similar to those of migraine. Moreover, the trigeminal ganglion, which may induce the release of substance P, can change the extracranial and intracranial vasodilator activity. The vascular theory of migraine, proposed by Wolff, is re-evaluated on the grounds of a possible mediation of the vascular responses by neurotransmitters. It is hypothesized that a deficient modulation by enkephalins may cause alterations of locus coeruleus and/or trigeminal ganglion. The problem of pain in vascular headaches is also considered: whether it is of vascular origin or whether it is due to a dysfunction of the central nociceptive pathway. Knowledge of the neurogenic control of the cerebral circulation may be useful in understanding some pathogenetic mechanisms of vascular headaches.

Acetylcholine↗

PubMed2003

Sleep function.

A theory of sleep function and brain organization positing that sleep serves a neuronal connectivity function and is a fundamental property of highly interconnected groups of neurons (neuronal groups) is presented. Cellular electrical activity within neuronal groups leads to the production of sleep-promoting substances which are also cytokine growth factors. The somnogenic cytokine growth factors (SCGF) in turn, induce molecules necessary for synaptic connectivity. The SCGFs change the synaptic activation patterns within neuronal groups. SCGFs thus induce changes in the input-output relationships of neuronal groups and thereby, cause a neuronal group state shift. Altered input-output relations result in increased efficacy of some synapses. Sleep is thus, targeted to active neuronal groups and serves to incorporate novel stimulus patterns into a synaptic contextual network and also to preserve that network. Coordination of neuronal group state is brought about by sleep regulatory networks. Organism sleep is an emergent property of a population of neuronal groups in the sleep state. After the neuronal group state shift, environmental input is divorced from output. Sleep is thus, useful to keep the animal stationary at a time when its brain is most dysfunctional. Thus, not only is unconsciousness needed because output activity would be out of phase with environmental events, but it is the consequence of the process itself.

Animals↗

PubMed2006

Small animal imaging using a conventional gamma camera exemplified in studies on the striatal dopaminergic system.

BACKGROUND: Small animal imaging has recently been the subject of increasing interest and specific imaging devices in particular for positron emission tomography (PET) have been developed. To bypass limitations arising from high acquisition costs and dependence on an in-house cyclotron unit inevitably associated with PET, a conventional gamma camera has been equipped with a pinhole collimator and used to visualize striatal pre- and post-synaptic dopaminergic function in rats measured by the dopamine transporter ligand [123I]beta-CIT and the dopamine D2/dopamine D3 receptor ligand [123I]IBZM. In order to precisely estimate brain regions of low radioligand uptake, single photon emission computed tomography (SPECT) images were coregistered onto an MRI template. MATERIAL AND METHODS: Our pinhole SPECT/MRI approach has been employed in animal models of pre- and postsynaptic dopaminergic dysfunction. The physical characteristics of the scanner, the tracer kinetics and modelling as well as image postprocessing have been addressed and associated intrinsic problems and constraints discussed. CONCLUSIONS: An outlook has been provided on the application of pinhole SPECT and MRI coregistration towards non-invasive investigations of drug-receptor interactions and binding characteristics of newly developed radiopharmaceuticals.

Animals↗

PubMed1987

Peripheral and autonomic nerve function in long-term insulin-dependent diabetes.

In a cross sectional study, motor nerve conduction velocity (MNCV) and sensory nerve conduction velocity (SNCV), beat-to-beat variation (BBV) at rest and speed of pupillary dilatation (SPD) have been investigated in 127 nonketonuric long-term insulin-dependent diabetics aged 19-72 yr and in age-matched control subjects. 84% of the patients had electrophysiologic abnormalities, 58% had symptomatic peripheral neuropathy, 35% had abnormal cardiac parasympathetic tests and 26% had abnormal pupillary tests. The most frequent pathologic feature was a decreased sural SNCV (66%). Among the patients without symptomatic peripheral neuropathy, 71% showed electrophysiologic abnormalities. MNCV and SNCV in median, peroneal and sural nerves correlated with BBV (p less than 0.005), but only peroneal MNCV was related to SPD (p less than 0.005). There was also a relationship between BBV and SPD (p less than 0.05). Glycosylated hemoglobin (HbA1) levels correlated inversely with median MNCV (p less than 0.001), and SNCV (p less than 0.03), peroneal MNCV (p less than 0.05) and sural SNCV (p less than 0.05). Patients with abnormal peripheral or autonomic nerve function tests or symptomatic peripheral neuropathy had significantly higher HbA1 levels than those with normal tests (p less than 0.04) or asymptomatic patients (p less than 0.01). Median MNCV and SNCV, sural SNCV and BBV deteriorated with age (p less than 0.05) and median SNCV and peroneal MNCV deteriorated with the duration of diabetes (p less than 0.001). Our findings show an association between peripheral and autonomic nerve dysfunction in long-term insulin-dependent diabetics.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

[Thalamocortical relations in the brain of white rats in the postischemic period (a morphometric study of the cyto- and synaptoarchitectonics)].

Numerical density of neurons and synapses in one mm3 was determined in layer III and IV of sensomotor cortex (SMC) and ventrobasal complex of thalamic nuclei (VBN) in the dynamics of postischemic period. It was demonstrated that during first seven days numerical density of neurons and synapses changes equally. Fourteen and especially thirty days later VBN of thalamus and synaptic population of layers III and IV of SMC, forming the SMC "entry" were most disturbed. A conclusion is made on more fast synapse restoration in dendritic zone of VBN neurons and insufficiency of this period (thirty days) for the forming of new contacts between the axons of the reserved VBN neurons and the reserved cortical neurons which can probably be a structural base of postischemic dysfunctions in the specific thalamo-cortical system.

Animals↗

PubMed1997

NCAM and schizophrenia: genetic studies.

The hypothesis of a neurodevelopmental dysfunction being involved in the etiology of schizophrenia is suggested by the observation of morphological alterations in the brains of schizophrenia patients. These alterations may be caused by defects in neural cell differentiation or migration, which could lead to disrupted neuronal circuitry and to the schizophrenia symptomatology. The neural cell adhesion molecule (NCAM) plays a major role in cell migration and axon outgrowth, and is involved in synaptic plasticity mechanisms implicated in adult cognitive functions. Altered levels of the NCAM polysialylated form, PSA-NCAM, in the brain of schizophrenia patients have been reported, and are supportive of a role for this molecule in the disorder. To investigate the possible involvement of the NCAM gene in schizophrenia, we conducted a comprehensive genetic study, which included linkage analysis and an association study employing the Haplotype Relative Risk (HRR) design in nuclear families. Our results indicate that structural alterations in the NCAM gene are unlikely to play a major role in schizophrenia, although a function for the NCAM molecule in the etiology of the disease remains an intriguing hypothesis.

Adult↗

PubMed2007

Chronic hypoxia stress-induced differential modulation of heat-shock protein 70 and presynaptic proteins.

Chronic hypoxia exposure can cause neurobehavioral dysfunction, but the underlying cellular and molecular mechanisms remain unclear. Here, we found that adult Lymnaea stagnalis snails maintained in low O(2) (approximately 5%) for 4 days developed slowed reactions to light stimuli, and reduced righting movement. Semiquantitative immunoblotting analyses showed that hypoxia exposure induced increased expression of heat-shock protein (HSP)70 in ganglion preparations, and suppressed expression of the presynaptic proteins syntaxin I, synaptic vesicle protein 2 (SV2) and synaptotagmin I. Detailed time course analyses showed that an early moderate increase developed within 6 h, preceding a substantial up-regulation of HSP70 after 4 days; an early reduction of syntaxin I in the first 24 h; a delayed reduction of synaptotagmin I after 4 days; and a biphasic change in SV2. Using a double-stranded RNA interference approach, we demonstrated that preventing the hypoxia inducible HSP70 enhanced down-regulation of syntaxin and synaptotagmin, and aggravated motor and sensory suppression. Co-immunoprecipitation analysis revealed an interaction between HSP70 and syntaxin. We have thus provided the first evidence that early induction of HSP70 by chronic hypoxia is critical for maintaining expression levels of presynaptic proteins. These findings implicate a new molecular mechanism underlying chronic hypoxia-induced neurobehavioral adaptation and impairment.

Animals↗

PubMed2003

An Alzheimer's disease hypothesis based on transcriptional dysregulation.

Alzheimer's disease (AD) is a neurodegenerative disorder of the central nervous system (CNS) characterized by progressive loss of memory and other cognitive skills. Neurons in the limbic and association cortices become progressively dysfunctional affecting almost all cognitive functions and memory. The PSI-regulated epsilon-secretase cleavage of type I transmembrane receptors controls production of transcriptionally active intracellular fragments (ICFs) suggesting that this cleavage is a key factor in surface-to-nucleus signal transduction and gene expression. Signal-induced gene expression mediates neuronal responses to environmental changes and is a key event in neuronal survival and synaptic function. Familial Alzheimer's Disease (FAD) mutations may interfere with nuclear signaling and transcription by interfering with the PS1/epsilon-secretase cleavage and production of transcriptionally active ICFs. This raises the possibility that, similar to polyglutamine induced neurodegeneration like Huntington's chorea, transcriptional abnormalities are involved in the development of FAD.

Alzheimer Disease↗

PubMed1999

Soluble HIV-1 infected macrophage secretory products mediate blockade of long-term potentiation: a mechanism for cognitive dysfunction in HIV-1-associated dementia.

It is generally accepted that viral and cellular products from immune competent mononuclear phagocytes (MP) (brain macrophages and microglia) underlie the neuropathogenesis of HIV-1-associated dementia (HAD). What remains unanswered, however, is the composition of and mechanisms for such MP-induced neurological dysfunctions. In attempts to address these issues culture fluids from HIV-1ADA-infected monocyte-derived macrophages (MDMs) (depleted or enriched with progeny virus) were placed onto the CA1 area of rat hippocampal brain slices (the site of mammalian learning and memory) and neuronal long-term potentiation (LTP) assayed. LTP was induced by high frequency stimulation (HFS). Lipopolysaccharide (LPS) served as a surrogate macrophage activator. Synaptic strength was assayed by the initial slope of evoked field excitatory postsynaptic potentials (EPSPs). Synaptic potentiation following HFS was observed in slices incubated with uninfected (control) MDM culture fluids. The magnitude of the LTP response was 150.2 +/- 21.10% compared to basal levels (n=6). Synaptic strength was enhanced in virus-infected (135.7+/-28.9%, n=8) and LPS-activated MDM (123.3+/-5.1%, n=7) but at lower levels than controls. The lowest levels of LTP were in brain slices incubated with virus-infected and LPS-activated MDM fluids at (109.5+/-9.9% n=12). Interestingly, bath application of progeny HIV-1 virions showed minimal LTP effects. Virus-infected, LPS-activated MDM fluids, with progenyvirus, reduced synaptic strength but were not statistically different than replicate culture fluids depleted of virus. In contrast, IL-1beta and quinolinic acid, significantly diminished synaptic strength. These results, taken together, suggest that soluble HIV-1-infected MDM secretory products, but not virus per se, significantly affect LTP. This electrophysiological system, which monitors neuronal function following cell exposure to HIV-1 infected materials could provide a novel testing ground for therapeutics designed to protect brain function in HAD.

AIDS Dementia Complex↗

PubMedDate not supplied

Manganese neurotoxicity: a mechanistic hypothesis.

This review provides a summary of the presentations and abstracts presented at the 15th International Neurotoxicology Conference which may contribute to an understanding of the mechanism and pathogenesis of manganese (Mn2+) neurotoxicity. We propose that an understanding of the pathogenesis of Mn2+ neurotoxicity must incorporate data on (1) the factors controlling Mn2+ uptake and distribution within the CNS, (2) account for the apparent selectivity of dopaminergic neurons, (3) analyze the role of mitochondrial dysfunction and (4) provide data to support or refute the role of oxidative injury in the genesis of toxicity. We propose a multifactor hypothesis coupling Mn2+ uptake with coincident transport of aluminum and iron. Selectivity of dopaminergic neurons is dependent upon interactions of Mn2+ with dopamine transport and the role of Mn2+ as a pro-oxidative toxicant in conjunction with changes in iron concentration. Within the synaptic milieu, Mn(2+)-mitochondrial interaction will influence mitochondrial--Ca2+ transport kinetics leading to defective mitochondrial function, decreased oxidative phosphorylation, decreased ATP and accumulation of reactive oxygen species. Under the influence of excessive depolarization, energy failure will occur leading to secondary activation of an excitotoxic state. These conceptual ideas provide for mechanistic based hypotheses and testing and are likely to lead to rational therapeutic avenues directed against Mn2+ neurotoxicity.

Animals↗