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PubMed2026

Microglial modulation in general anesthesia: molecular.

General anesthetics profoundly alter brain function and consciousness, yet the mechanisms underlying these effects remain incompletely understood. Although traditional studies have primarily focused on neuronal targets, accumulating evidence suggests that microglia dynamically respond to anesthetic exposure and may participate in anesthesia-associated neurophysiological changes. Beyond their established immune functions, microglia are increasingly implicated in synaptic remodeling, metabolic regulation, neuronal activity surveillance, and neuron-glia communication. Recent studies indicate that different classes of anesthetic agents modulate microglial activity through diverse and context-dependent mechanisms involving inflammatory signaling, purinergic pathways, calcium dynamics, mitochondrial metabolism, and neural circuit interactions. These responses are associated with postoperative neurocognitive disorders, altered synaptic plasticity, and anesthesia-related changes in brain states. In this review, we summarize current evidence regarding the effects of volatile anesthetics, intravenous anesthetics, and analgesics on microglial function and discuss the molecular, functional, and circuit-level mechanisms underlying anesthesia-associated neuron-microglia interactions. We further highlight the dynamic and heterogeneous nature of microglial responses during anesthesia and discuss current limitations in the field, including the lack of temporally resolved and cell-specific approaches. Understanding these processes may provide insights into anesthesia-associated neurocognitive dysfunction and support the development of neuroimmune-targeted strategies in anesthesiology.

General anesthesia↗

PubMed2003

Neuroprotection and neuronal dysfunction upon repetitive inhibition of oxidative phosphorylation.

Repetitive inhibition of oxidative phosphorylation is an established model of neurodegeneration. In contrast, a single mild treatment can be neuroprotective-chemical preconditioning. Repetitive chemical inhibition of oxidative phosphorylation may thus be a tool to study deterioration and improvement of cellular hypoxic tolerance and subsequent differential regulation of cellular responses in the same model. We investigated murine hippocampal function upon repetitive intraperitoneal injections of 3-nitropropionate (3-NP; 20 mg/kg body weight), an inhibitor of mitochondrial complex II. With a 2-day interval of repetitive in vivo treatment with 3-NP, posthypoxic recovery of population spike amplitude was below control. In contrast, even after nine in vivo treatments with 3-NP at 4-day intervals, an almost complete recovery of population spike amplitude was observed. Nerve growth factor (NGF) as assessed by ELISA and expression of beta-amyloid precursor protein (APP) mRNA increased upon nine treatments at 2-day intervals, but remained at control levels with 4-day intervals. In contrast, brain-derived neurotrophic factor (BDNF) as assessed by ELISA increased with the latter treatment. Expression of mRNA for adenosine-A1 and -A3 receptors and endothelial and neuronal nitric oxide synthase remained at control level for both treatment intervals. We conclude that the time interval between mild, subclinical repetitive inhibition of oxidative phosphorylation determines hippocampal neuronal impairment and integrity and modulates NGF and BDNF differently. Decreased hypoxic tolerance and increased APP expression upon repetitive inhibition of oxidative phosphorylation at short time intervals may thus trigger a vicious cycle and be a cofactor for neuronal dysfunction in cerebral hypoxia and neurodegenerative diseases.

Action Potentials↗

PubMedDate not supplied

Methylmercury increases glutamate extracellular levels in frontal cortex of awake rats.

A current hypothesis about methylmercury (MeHg) neurotoxicity proposes that neuronal damage is due to excitotoxicity following glutamate uptake alterations in the astrocyte. By sampling from a microdialysis probe implanted in the frontal cortex of adult Wistar rats, we measured the effects of acute exposure to either 10 or 100 microM MeHg through the microdialysis probe, on glutamate extracellular levels in 15 awake animals. After baseline measurements, the perfusion of MeHg during 90 min induced immediate and significant elevations in extracellular glutamate at 10 microM (9.8-fold, P<.001) and at 100 microM (2.4-fold, P=.001). This in vivo demonstration of increments of extracellular glutamate supports the hypothesis that dysfunction of glutamate neurotransmission plays a key role in MeHg-induced neural damage.

Animals↗

PubMed2002

Central serotonergic activity is related to the aggressive behaviors of Alzheimer's disease.

The clinical correlates of reduced serotonin (5-HT) in Alzheimer's disease (AD) remain unknown. The hypothesis of this study was that altered central serotonergic activity is related to aggression in AD. Twenty-two institutionalized, nondepressed elderly (12 M/10 F, mean age +/- SD: 82.2 +/- 6.4) with probable AD, severe cognitive impairment (MMSE = 4.1 +/- 4.7) and significant behavioral disturbance (Neuropsychiatric Inventory (NPI) score > or = 8) were studied. The prolactin (PRL) response to d,l-fenfluramine (60 mg p.o.) was used as an index of central serotonergic function. The NPI aggression score, NPI irritability score, and Behavioral Pathology in AD aggression score were positively correlated to prolactin concentrations following fenfluramine challenge (r(S) =.61, p =.003; r(S) =.53, p =.012; and r(S) =.47, p =.029 respectively). In addition, aggressive patients showed a greater mean PRL increase (% baseline) (215 +/- 60, n = 11) than nonaggressive subjects (123 +/- 54, n = 11) (p =.01, 2-tailed t-test). The change in PRL concentration depended on level of cognitive impairment (p =.0004) and the gender x aggression interaction (p =.015) with the overall regression model accounting for 74% of the variance (r = 0.86, F = 11.9, p =.0001). Female aggressive subjects with less cognitive impairment had the largest response to fenfluramine challenge. These results suggest a complex link between aggression in AD and central serotonergic dysfunction having interactions with gender and cognitive impairment.

Aged↗

PubMed2001

The emerging role of glutamate in the pathophysiology and treatment of schizophrenia.

OBJECTIVE: Research has implicated dysfunction of glutamatergic neurotransmission in the pathophysiology of schizophrenia. This review evaluates evidence from preclinical and clinical studies that brain glutamatergic neurotransmission is altered in schizophrenia, may affect symptom expression, and is modulated by antipsychotic drugs. METHOD: A comprehensive review of scientific articles published over the last decade that address the role of glutamate in the pathophysiology of schizophrenia was carried out. RESULTS: Glutamatergic neurons are the major excitatory pathways linking the cortex, limbic system, and thalamus, regions that have been implicated in schizophrenia. Postmortem studies have revealed alterations in pre- and postsynaptic markers for glutamatergic neurons in several brain regions in schizophrenia. The N-methyl-D-aspartic acid (NMDA) subtype of glutamate receptor may be particularly important as blockade of this receptor by the dissociative anesthetics reproduces in normal subjects the symptomatic manifestations of schizophrenia, including negative symptoms and cognitive impairments, and increases dopamine release in the mesolimbic system. Agents that indirectly enhance NMDA receptor function via the glycine modulatory site reduce negative symptoms and variably improve cognitive functioning in schizophrenic subjects receiving typical antipsychotics. CONCLUSIONS: Dysfunction of glutamatergic neurotransmission may play an important role in the pathophysiology of schizophrenia, especially of the negative symptoms and cognitive impairments associated with the disorder, and is a promising target for drug development.

Animals↗

PubMedDate not supplied

Hypothalamic digoxin and neural regulation of blood pressure and vascular thrombosis.

The isoprenoid pathway produces three key metabolites--digoxin (membrane sodium-potassium ATPase inhibitor and regulator of neurotransmitter/aminoacid transport), dolichol (regulates N-glycosylation of proteins) and ubiquinone (free radical scavenger). This was assessed in patients with essential hypertension, familial hypotension, acute coronary artery disease and acute thrombotic strokes. The pathway was also assessed in patients with right hemispheric, left hemispheric and bihemispheric dominance for comparison. In patients with acute coronary artery disease, acute thrombotic stroke, essential hypertension and right hemispheric dominance, there was elevated digoxin synthesis, increased dolichol and glycoconjugate levels and low ubiquinone and high free radical levels. There was also an increase in tryptophan catabolites, reduction in tyrosine catabolites, increase in cholesterol-phospholipid ratio and a reduction in glycoconjugate level of RBC membrane in this group of patients as well as in those with right hemispheric dominance. In patients with familial hypotension and left hemispheric dominance, the patterns were reversed. The role of a dysfunctional isoprenoid pathway and endogenous digoxin in the pathogenesis of essential hypertension and familial hypotension and in thrombotic vascular disease in relation to hemispheric dominance is discussed.

Aged↗

PubMed2006

Diffuse beta-amyloid plaques and hyperphosphorylated tau are unrelated processes in aged dogs with behavioral deficits.

Single and double-labeling immunocytochemistry has been used to learn about the localization, distribution, and possible relationship between beta-amyloid protein (Abeta) deposition and tau hyperphosphorylation in the canine cerebral cortex with age. Behavioral impairment, as reported by the owners and tested in all dogs, correlated with increased Abeta burden in old dogs. Abeta plaques were diffuse and they were not accompanied by modifications in synaptic protein expression. Plaques were not associated with increased active mitogen activated protein kinase (MAPK/ERK-P) and p38 kinase (p38-P) expression, and tau hyperphosphorylation in neighboring cell processes. Yet tau hyperphosphorylation, as revealed with phospho-specific antibodies to tauThr181 and tauSer396, increased with age in individual neurons. Moreover, the subcellular pattern shifted from perinuclear localization to granular cytoplasmic and nuclear distribution with age. Our results in dog suggest that Abeta diffuse plaque formation and tau hyperphosphorylation are independent events, both occurring during the process of aging. Although increased cognitive dysfunction is associated with increased tau hyperphosphorylation, further investigation is needed to understand whether tau hyperphosphorylation is causative of cognitive impairment or an independent process related to aging.

Aging↗

PubMed2001

GABA signalling: therapeutic targets for epilepsy, Parkinson's disease and Huntington's disease.

Temporal lobe epilepsy (TLE), Parkinson's disease (PD) and Huntington's disease (HD) are neurodegenerative disorders that involve disruptions in gamma-amino butyric acid (GABA) signalling. GABA is the major inhibitory neurotransmitter in the central nervous system (CNS). TLE seizures reflect excess excitation, which may result from local inhibitory circuit dysfunction. PD devastates the input to striatal GABAergic neurones and HD destroys striatal GABAergic neurones. Controlling GABA delivery to specific brain areas should benefit each of these diseases. The molecules responsible for GABA release and signalling are ideal targets for new therapies. In this paper, we discuss the role of GABA in the circuitry affected by each of these diseases and suggest potential sites for intervention. GABA is unique among neurotransmitters because it can be synthesised by either of two related enzymes. Intracellular GABA is found throughout the cytosol and in synaptic vesicles. GABA can be released either through exocytosis, or via the plasma membrane transporter. The synthesising enzyme probably determines the intracellular location and hence the mechanism for GABA release. Directing GABA synthesis, degradation, transport or receptors can control GABA signalling. We propose that new drugs and devices aimed at GABA synthesis, release and binding will offer novel and highly effective treatments for neurodegenerative diseases.

Journal Article↗

PubMed2006

Competition between feedback loops underlies normal and pathological dynamics in the basal ganglia.

Experiments performed in normal animals suggest that the basal ganglia (BG) are crucial in motor program selection. BG are also involved in movement disorders. In particular, BG neuronal activity in parkinsonian animals and patients is more oscillatory and more synchronous than in normal individuals. We propose a new model for the function and dysfunction of the motor part of BG. We hypothesize that the striatum, the subthalamic nucleus, the internal pallidum (GPi), the thalamus, and the cortex are involved in closed feedback loops. The direct (cortex-striatum-GPi-thalamus-cortex) and the hyperdirect loops (cortex-subthalamic nucleus-GPi-thalamus-cortex), which have different polarities, play a key role in the model. We show that the competition between these two loops provides the BG-cortex system with the ability to perform motor program selection. Under the assumption that dopamine potentiates corticostriatal synaptic transmission, we demonstrate that, in our model, moderate dopamine depletion leads to a complete loss of action selection ability. High depletion can lead to synchronous oscillations. These modifications of the network dynamical state stem from an imbalance between the feedback in the direct and hyperdirect loops when dopamine is depleted. Our model predicts that the loss of selection ability occurs before the appearance of oscillations, suggesting that Parkinson's disease motor impairments are not directly related to abnormal oscillatory activity. Another major prediction of our model is that synchronous oscillations driven by the hyperdirect loop appear in BG after inactivation of the striatum.

Action Potentials↗

PubMed2005

Evidence for glutamatergic neuronal dysfunction in the prefrontal cortex in chronic but not in first-episode patients with schizophrenia: a proton magnetic resonance spectroscopy study.

Based upon pharmacological challenge and postmortem studies, schizophrenia has been hypothesized to be caused by decreased glutamatergic neurotransmission. We investigated the glutamatergic neuronal metabolism of the dorsolateral prefrontal cortex with localized 1H magnetic resonance spectroscopy in 18 first-episode patients, 21 chronic patients with schizophrenia, and 21 age-matched controls. Chronic patients had significantly lower levels of glutamate/glutamine (Glx) and N-acetylaspartate (NAA) compared to healthy controls and first-episode patients. Reduced metabolite levels were not correlated with duration of illness or medication. Our results indicate glutamatergic dysfunction in chronic schizophrenia that could be evidence of a progressive brain disorder.

Adult↗

PubMed1990

Glutamatergic neurotransmission in Alzheimer's disease.

The studies described here provide convincing evidence of glutamatergic deafferentation in Alzheimer's disease. This deafferentation is presumed to represent the biochemical correlate of pyramidal neuron dysfunction in the disorder. In addition, there is a growing consensus of opinion that there is no widespread depletion of glutamate NMDA receptors in Alzheimer's disease. The significance of glutamatergic neurotransmission abnormalities to the pathogenesis and clinical progression of the disease remains to be established.

Alzheimer Disease↗

PubMed1999

Frontal lobe dysfunction in patients with non-frontal malignant gliomas: a monoaminergic dysregulation?

Previous investigations concerned with the neuropsychological function of patients with intracerebral supratentorial malignant gliomas has revealed the frequent occurrence of signs suggestive of an inhibitory frontal lobe dysfunction regardless of the intracerebral localization of the tumor and before the diagnosis was known to either the investigator or the patient. Upon closer analysis, the frontal lobe dysfunction has been verified by the demonstration of reduced blood flow in frontal areas in these patients. Since many of the findings can be related to a dysfunction of dopaminergic neurotransmission, we hypothesize that abnormal astrocytes interfere with the metabolism, transport and release of various neurotransmitters of which dopamine may be the one responsible for the most striking neuropsychological abnormalities in patients with malignant gliomas.

Animals↗

PubMed2003

The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes.

Through a widespread efferent projection system, the locus coeruleus-noradrenergic system supplies norepinephrine throughout the central nervous system. Initial studies provided critical insight into the basic organization and properties of this system. More recent work identifies a complicated array of behavioral and electrophysiological actions that have in common the facilitation of processing of relevant, or salient, information. This involves two basic levels of action. First, the system contributes to the initiation and maintenance of behavioral and forebrain neuronal activity states appropriate for the collection of sensory information (e.g. waking). Second, within the waking state, this system modulates the collection and processing of salient sensory information through a diversity of concentration-dependent actions within cortical and subcortical sensory, attention, and memory circuits. Norepinephrine-dependent modulation of long-term alterations in synaptic strength, gene transcription and other processes suggest a potentially critical role of this neurotransmitter system in experience-dependent alterations in neural function and behavior. The ability of a given stimulus to increase locus coeruleus discharge activity appears independent of affective valence (appetitive vs. aversive). Combined, these observations suggest that the locus coeruleus-noradrenergic system is a critical component of the neural architecture supporting interaction with, and navigation through, a complex world. These observations further suggest that dysregulation of locus coeruleus-noradrenergic neurotransmission may contribute to cognitive and/or arousal dysfunction associated with a variety of psychiatric disorders, including attention-deficit hyperactivity disorder, sleep and arousal disorders, as well as certain affective disorders, including post-traumatic stress disorder. Independent of an etiological role in these disorders, the locus coeruleus-noradrenergic system represents an appropriate target for pharmacological treatment of specific attention, memory and/or arousal dysfunction associated with a variety of behavioral/cognitive disorders.

Adrenergic Uptake Inhibitors↗

PubMed1999

Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues.

Patients with panic disorders show a deficit of GABAA receptors in the hippocampus, parahippocampus and orbitofrontal cortex. Synaptic clustering of GABAA receptors in mice heterozygous for the gamma2 subunit was reduced, mainly in hippocampus and cerebral cortex. The gamma2 +/- mice showed enhanced behavioral inhibition toward natural aversive stimuli and heightened responsiveness in trace fear conditioning and ambiguous cue discrimination learning. Implicit and spatial memory as well as long-term potentiation in hippocampus were unchanged. Thus gamma2 +/- mice represent a model of anxiety characterized by harm avoidance behavior and an explicit memory bias for threat cues, resulting in heightened sensitivity to negative associations. This model implicates GABAA-receptor dysfunction in patients as a causal predisposition to anxiety disorders.

Animals↗

PubMed2006

Volume changes in neurons: hyperexcitability and neuronal death.

Hyponatremia propitiates and increases susceptibility to seizure episodes. In vitro, hyposmolarity induces hyperexcitability and epileptiform activity and increases the amplitude of excitatory postsynaptic potentials. Synaptic (increased glutamate vesicular release) and non-synaptic (swelling-induced extracellular space shrinkage and ephaptic interactions) might be responsible for the hyposmolarity effects on brain excitability. Neuronal volume constancy in hyponatremia is preserved by the isovolumetric regulation, relying importantly on organic osmolytes. Changes in cell volume are closely linked to neuronal death: swelling characterizes necrotic death as in acute ischemic episodes or brain trauma, whereas volume decrease is typical of apoptotic death. Swelling in necrotic death results from the intracellular Na(+) increase followed by Cl(-) and water influx. Na(+) accumulation is due initially to the Na(+)/K(+)ATPase dysfunction and subsequently from the Na(+) influx through the overactivated ionotropic glutamate receptors. A second wave of swelling generates by excitotoxic derived formation of reactive oxygen species, membrane lipoperoxidation and further ion overload. Excessive swelling contributes to membrane rupture and release of cell debris, propagating the damage to adjacent cells. Apoptotic death is characterized by cell volume decrease termed apoptotic volume decrease, which in neurons seems to occur by mechanisms remarkably similar to those operating in the hyposmotic swelling-activated volume regulatory decrease, i.e. channel-mediated efflux of K(+) and Cl(-). A variety of K(+) channels and the volume-regulated anion channel participate in apoptotic volume decrease. K(+) has a protagonic role as an early element in neuronal apoptosis since a delayed rectifier K(+) current IK(DR) is enhanced by apoptosis prior to the caspase activation, increased extracellular K(+) and IK(DR) blockers attenuate apoptosis and intracellular K(+) loss through ionophores induces apoptosis. Volume-regulated anion channel participates as well in the Cl(-) efflux although its role and hierarchy in the apoptotic program are not well defined. Efflux of organic osmolytes, such as taurine participate as well in apoptotic volume decrease.

Animals↗

PubMedDate not supplied

Involvement of nerve growth factor in visual cortex plasticity.

The physiological role of nerve growth factor (NGF), the prototype member of the neurotrophin family, has been widely studied. NGF has been shown to promote survival, sprouting and differentiation of sympathetic ganglion cells and sensory neurons in the peripheral nervous system; it has also been shown to support survival and regeneration of cholinergic neurons in the central nervous system. Recent evidence indicates that NGF is also involved in the neuronal plasticity of the visual cortex. Exogenous supplies of NGF have been shown to interfere with normal processes underlying activity- and age-dependent synaptic modifications in both developing and adult visual cortex. In parallel to these physiological effects, numerous neuronal markers in the visual cortex have been found to be influenced by NGF. Several proposals have been introduced to explain the physiological role of NGF in visual cortex plasticity. Although the mechanisms underlying NGF effects in the visual cortex are still under active investigation, current evidence implies that NGF, and perhaps other neurotrophins as well, may be useful for preventing or correcting inappropriate or anomalous connections in the visual cortex, and thus for treating visual dysfunctions such as amblyopia and strabismus.

Animals↗

PubMed2001

Inhibition of acetylcholine synthesis and tyrosine nitration induced by peroxynitrite are differentially prevented by antioxidants.

Evidence of an overload of reactive oxygen species and peroxynitrite, a derivative of nitric oxide, in sporadic amyotrophic lateral sclerosis suggests that peroxynitrite could impair cholinergic functions. Because of the impossibility of obtaining synaptosomes from vertebrate neuromuscular junctions, we used cholinergic synaptosomes purified from Torpedo marmorata electroneurons to characterize the defects triggered by peroxynitrite in more detail. Addition of peroxynitrite or its donor 3-morpholinosydnonimine abolished high-affinity choline uptake and synthesis of acetylcholine from acetate. T. marmorata choline acetyltransferase (ChAT) was impaired to the same extent as bovine brain ChAT. A hallmark of peroxynitrite action is the nitration of tyrosine residues in proteins. Peroxynitrite induced a concentration-dependent appearance of nitrotyrosines in several neuronal proteins from synaptosomes and, more readily, from synaptic vesicles. Peroxynitrite also triggered tyrosine nitrations in purified ChAT. Peroxynitrite-dependent nitrations were impaired when synaptosomes were pretreated with thioreductants (glutathione, N-acetyl cysteine, dithiothreitol) or antioxidants (uric acid, melatonin, bovine serum albumin, desferrioxamine). Deleterious effects of peroxynitrite on choline transport and ChAT activity were prevented by the thioreductants but only partially by the antioxidants, suggesting a mechanism other than tyrosine nitration, which may involve cysteine oxidation. Further development of protective agents acting on choline transport and on ChAT activity may offer interesting therapeutic possibilities with respect to cholinergic dysfunction occurring in neurodegenerative diseases.

Acetates↗

PubMed2002

Macrophages, chemokines and neuronal injury in HIV-1-associated dementia.

Human immunodeficiency virus type-one (HIV- 1)-associated dementia (HAD) is manifested as a spectrum of behavioral, motor and cognitive dysfunctions. The disorder commonly occurs during late stage HIV disease and remains an important complication despite highly active antiretroviral therapies. A metabolic encephalopathy, fueled by neurotoxic secretions from brain mononuclear phagocytes (MP) (macrophages and microglia) underlies HIV- I neuropathogenesis. One pivotal question, however, is how brain MP evolve from neurotrophic to neurotoxic cells. The interplay between the virus, the macrophage and the neuron has just recently begun to be unraveled. Along with a multitude of other MP secretory products, chemokines effect neuronal function by engaging neuronal receptors then activating pathways that alter synaptic transmission, cell growth, injury and protection. Both neurons and glia secrete chemokines. Interestingly, HIV-1 and its gene products can mimic chemokine neuronal signaling by binding to neuronal chemokine receptors or by other non-specific mechanisms. The elucidation of mechanisms involved in chemokine-mediated neural compromise will likely provide unique insights into the pathogenesis and treatment, not only of HAD, but of a wide range of neurodegenerative disorders.

AIDS Dementia Complex↗