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PubMed1984

Behavioural plasticity and the cholinergic system.

Evidence for the involvement of the cholinergic system in behavioural plasticity is reviewed by considering three forms of behavioural plasticity: habituation, learning and memory, and tolerance development. Although the cholinergic system may modulate the response tendencies of an animal, it does not appear to be involved in the process of habituation. A number of studies have indicated that the cholinergic system may be involved in learning and memory processes in infrahuman animals. In general, cholinergic antagonists tend to disrupt memory while agonists may, under the appropriate conditions, facilitate memory. Recent studies have pointed to a relation between dysfunctions of the cholinergic system and dysfunctions of memory in aged animals. Studies of tolerance development suggest that the cholinergic system may undergo plastic changes which may underlie the development of tolerance to some drugs, with receptor alterations being the most reproducible finding. However, more work is necessary to establish the degree of plasticity. The cholinergic system also appears to be involved in learning and memory processes in humans. However, attempts to correct the memory deficits in aged humans by manipulating the cholinergic system have met with limited success. The reasons for this lack of success are briefly considered.

Acetylcholine↗

PubMed1985

GABA dysfunction in the pathophysiology of tardive dyskinesia.

Pharmacologic treatments which diminish central dopaminergic transmission improve symptoms of tardive dyskinesia (TD). These clinical data, supported by results from animal model studies, have provided a basis for the dopamine (DA) receptor hypersensitivity hypothesis of TD. Since its initial formulation, however, knowledge of the multiple effects of prolonged neuroleptic administration in mammalian CNS has greatly expanded. Clinical and animal model studies carried out independently now both suggest that GABA-mediated neuronal tracts of the basal ganglia are important, perhaps pivotal, in TD. Thus, we would extend the DA hypothesis of TD to include the idea that neuroleptic-induced DA receptor hypersensitivity in striatum results in GABA system hypofunction in striatal projection areas in those individuals who develop TD.

Brain↗

PubMed1998

Are jaw and facial reflexes modulated during clinical or experimental orofacial pain?

A variety of jaw and facial reflexes can be evoked by orofacial mechanical or electrical stimuli. Because of its possible diagnostic utility in the management of pain and dysfunction of the masticatory system, the exteroceptive suppression that can be evoked in the masseter and temporalis muscles has been particularly investigated. A review of the different studies emphasizes the crucial importance of the area stimulated and the type of stimulation used to evoke the reflex. More recent studies have applied the necessary standardization of stimulus intensity, clenching levels, recording procedures, and unbiased interpretation of the reflex components in muscle electromyographic (EMG) activity. Controversial results have been reported regarding the differences in these inhibitory (and excitatory) reflex responses between temporomandibular disorder or headache patients and controls. Even if the absence of a second inhibitory phase in the masseteric EMG activity of the patients is a frequent finding, its sensitivity and specificity as a diagnostic tool for myogenous pain or bruxism remain to be tested. Controlled studies on the duration of the second exteroceptive suppression period in tension-type headache patients could not confirm the initially reported difference between patients and asymptomatic subjects. Studies that involve experimentally induced muscle pain could provide better insight into the characteristics of the afferent fibers and synaptic circuitry that are involved in the jaw and facial reflexes.

Arthralgia↗

PubMed1980

Cerebellar control of ocular gaze stability.

The ability to hold an eccentric position of gaze has been attributed to a brainstem network termed the ocular motor neural integrator. For this integrator to function properly, an intact cerebellum is necessary. This report describes a patient with cerebellar dysfunction who showed an unusual form of nystagmus: each slow phase had a waveform of increasing velocity. This contrasts with gaze paretic nystagmus, the more typical manifestation of cerebellar disorder, in which each slow phase has a waveform of decreasing velocity. Based on these observations and results from basic research, we propose that (1) the cerebellum controls neural integration in the brainstem by a positive feedback loop, and (2) pathological alterations in the strength of transmission (or gain) through the feedback loop cause the eyes to drift off target, with either an exponentially increasing (gain too high) or decreasing (gain too low) velocity.

Brain Stem↗

PubMed2003

Neurobiological correlates of the disposition and maintenance of alcoholism.

The last decade witnessed a rapid increase in the knowledge of the etiopathology and treatment of alcoholism. The current disease concept includes psychosocial and neurobiological foundations and consequences of alcoholism. Neurobiological research points to dispositional factors such as a low level of response to alcohol, which is partly heritable and seems to be associated with monoaminergic dysfunction and reduced GABAergic alcohol effects. Chronic alcohol intake stimulates counteradaptive neuroadaptation in central GABAergic and glutamatergic neurotransmission, which increases alcohol tolerance. Neuroadaptation to chronic alcohol effects is not immediately reversed during detoxification and can cause clinical withdrawal once alcohol intake is terminated. Sensitization of the dopaminergic and opioidergic reward system may contribute to alcohol craving and reduced control of alcohol intake. New treatment options include pharmacological approaches and indicate that behavior or motivational therapy and the attendance of patient groups may equally reduce the relapse risk.

Acute Disease↗

PubMed2006

Interstitial cells of Cajal at the clinical and scientific interface.

Considerable work over the past two decades has determined that interstitial cells of Cajal (ICC) serve as pacemaker cells, conduits for active transmission of electrical slow waves, sites of innervation by peripheral motor neurons, and mechanotransducers. While most of the physiology of ICC has been learned from studies of the cells within the gastrointestinal tract, ICC are found in a variety of smooth muscle tissues and may have analogous or novel physiological functions in those organs. Clinical investigations of muscles from patients with a variety of gastrointestinal motility disorders have raised the exciting possibility that loss of ICC may be responsible for the development of motor dysfunction. This review discusses the development of ICC, the kinds of human disorders in which ICC loss may be important, what factors regulate the ICC phenotype, and what therapeutic approaches might be utilized to restore or regenerate ICC. This field is primed for translational discoveries. ICC are responsible for critical physiological functions in smooth muscle tissues, they are lost in pathophysiological conditions, and it will be important now to decipher the conditions that are responsible for ICC loss and develop new therapies to relieve patients of this problem. Success in this endeavour might improve the quality of life for millions of patients.

Animals↗

PubMed1996

Human Usher 1B/mouse shaker-1: the retinal phenotype discrepancy explained by the presence/absence of myosin VIIA in the photoreceptor cells.

Usher syndrome type 1 (USH1) associates severe congenital deafness, vestibular dysfunction and progressive retinitis pigmentosa leading to blindness. The gene encoding myosin VIIA is responsible for USH1B. Mutations in the murine orthologous gene lead to the shaker-1 phenotype, which manifests cochlear and vestibular dysfunction, without any retinal defect. To address this phenotypic discrepancy, the expression of myosin VIIA in retinal cells was analyzed in human and mouse during embryonic development and adult life. In the human embryo, myosin VIIA was present first in the pigment epithelium cells, and later in these cells as well as in the photoreceptor cells. In the adult human retina, myosin VIIA was present in both cell types. In contrast, in mouse, only pigment epithelium cells expressed the protein throughout development and adult life. Myosin VIIA was also found to be absent in the photoreceptor cells of other rodents (rat and guinea-pig), whereas these cells expressed the protein in amphibians, avians and primates. These observations suggest that retinitis pigmentosa of USH1B results from a primary rod and cone defect. The USH1B/shaker-1 paradigm illustrates a species-specific cell pattern of gene expression as a possible cause for the discrepancy between phenotypes involving defective orthologous genes in man and mouse. Interestingly, in the photoreceptor cells, myosin VIIA is mainly localized in the inner and base of outer segments as well as in the synaptic ending region where it is co-localized with the synaptic vesicles. Therefore, we suggest that myosin VIIA might play a role in the trafficking of ribbon-synaptic vesicle complexes and the renewal processes of the outer photoreceptor disks.

Adult↗

PubMed2003

Degeneration of beta-amyloid-associated cholinergic structures in transgenic APP SW mice.

Cholinergic dysfunction is a consistent feature of Alzheimer's disease, and the interrelationship between beta-amyloid deposits, inflammation and early cholinergic cell loss is still not fully understood. To characterize the mechanisms by which beta-amyloid and pro-inflammatory cytokines may exert specific degenerating actions on cholinergic cells ultrastructural investigations by electron microscopy were performed in brain sections from transgenic Tg2576 mice that express the Swedish double mutation of the human amyloid precursor protein and progressively develop beta-amyloid plaques during aging. Both light and electron microscopical investigations of the cerebral cortex of 19-month-old transgenic mice revealed a number of pathological tissue responses in close proximity of beta-amyloid plaques, such as activated microglia, astroglial proliferation, increased number of fibrous astrocytes, brain edema, degeneration of nerve cells, dendrites and axon terminals. Ultrastructural detection of choline acetyl transferase (ChAT)-immunostaining in cerebral cortical sections of transgenic mice clearly demonstrated degeneration of ChAT-immunoreactive fibres in the environment of beta-amyloid plaques and activated glial cells suggesting a role of beta-amyloid and/or inflammation in specific degeneration of cholinergic synaptic structures.

Alzheimer Disease↗

PubMed2004

Nitric oxide induces apoptosis of the hair cells of cochlea.

OBJECTIVE: Nitric oxide (NO) has a toxic effect on neuronal cells related to glutamate receptors. NO released from post-synaptic cells with glutamate receptors can induce nearby cell death. In this experiment, we examined the effect of NO on cochlear hair cells. METHODS: Two concentrations, 0.5 and 0.1 molar concentration (MC) of 1-hydroxy-2-oxo-3-(3-aminopropyl)-3-isopropyl-1-triazene (NOC-5), which is a NO donor, were placed on the round window of the guinea pig cochlea and its morphological changes were investigated at 12, 28, 72 h after the treatment. RESULTS: By the trypan blue dye extrusion method, the cell death was recognized in the outer hair cells at the percentage 0, 36.0+/-6.6, 4.9+/-1.2% at 12, 28, 72 h after treatment respectively in the group 0.5 MC NOC-5, but no inner hair cell death was recognized. In the group of 0.1 MC NOC-5 and control any cell death was not detected. Transmission electron microscopy revealed this cell death was characteristic of apoptosis. CONCLUSION: The findings that apoptosis was induced in the outer hair cells of the organ of Corti by NO suggests the possibility that the cochlea is affected when extra NO release occurs there, leading to cochlear dysfunction.

Animals↗

PubMed1987

Ultrastructural findings on human Scarpa's ganglion.

The morphology of human Scarpa's ganglion from two surgically removed specimens as well as from four autopsy preparations from patients without clinical evidence of vestibular dysfunction was investigated. Ganglion cell circumference varied between 45 and 160 microns. More than half of the nerve cells ranged between 90 and 110 microns. The arrangement of ganglion cells, nerve fibres and endoneural connective tissue appeared better preserved in autopsy preparation than in biopsy specimens. Electron microscopy revealed that in half of the investigated specimens, neuroglial tissue was present as far distal as the vestibular ganglion. Almost all ganglion cells were surrounded by one or several layers of satellite cells, and did not reveal myelination. From the present study we cannot predict if neuronal function in human beings differs from that in other animals, although morphological differences do exist.

Adult↗

PubMed2002

[Glutamate hypothesis of schizophrenia and targets for new antipsychotic drugs].

N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) and ketamine have been known to cause schizophrenia-like psychosis (positive symptoms, negative symptoms, cognitive dysfunction) in humans. A dysfunction of glutamatergic neurotransmission may play an important role in the pathophysiology of schizophrenia. In this review, the glutamate hypothesis of schizophrenia, especially the mechanism of neurotoxicity of NMDA receptor antagonist in the posterior cingulate cortex and retrosplenial cortex of the brain, is summarized. Furthermore, the roles of the posterior cingulate cortex and the retrosplenial cortex in the pathophysiology of schizophrenia and Alzheimer's disease are also discussed. Moreover, the glycine site of the NMDA receptor, metabotropic glutamate receptor, AMPA receptor, and antioxidant glutathione as novel potential targets for the treatment of schizophrenia are discussed.

Animals↗

PubMed2006

Mitochondrial alterations in Alzheimer's disease.

Morphological alterations of mitochondria may be related to metabolic and energy deficiency in neurons in Alzheimer's disease and other neurodegenerative disorders. Mitochondrial dysfunction is also a hallmark of beta peptide induced neuronal toxicity in Alzheimer's disease. A general change in glucose utilization, increased oxidative stress, and Ca;{2+} deregulation are additional metabolic defects in the AD brain that may also be associated with defective mitochondrial function the result is a cycle of increased mitochondrial dysfunction causing increased oxidative damage until the cellular energy supply falls below the threshold for cellular survival. In a series of studies on the morphological and morphometric estimation of mitochondria in Alzheimer's disease, by electron microscopy we noticed substantial morphological and morphometric changes in the neurons of the hippocampus, the acoustic cortex, the frontal cortex, the cerebellar cortex, the climbing fibers, the thalamus, the globus pallidus, the red nucleus and the locus coeruleus. The morphological alterations consisted of considerable changes of the mitochondrial cristae, accumulation of osmiophilic material, and decrease of their size, in comparison with the normal controls. Mitochondrial alterations were particularly prominent in neurons, which showed loss of dendritic spines and abbreviation of the dendritic arborization. The ultrastructural study of large number of neurons in the thalamus and the red nucleus revealed that the mitochondrial alterations did not coexist with cytoskeletal pathology and accumulation of amyloid deposits, though they were prominent in neurons, which demonstrated fragmentation of the cisternae of the Golgi apparatus. Morphometric analysis showed that mitochondria are significantly reduced in Alzheimer's disease. The relationship between the site and extent of mitochondrial abnormalities and the synaptic alterations suggests an intimate and early association between these features in Alzheimer's disease.

Alzheimer Disease↗

PubMed2004

Recent advances in research on Parkinson disease: synuclein and parkin.

BACKGROUND: Until recently, most research effort on Parkinson disease (PD) was focused on possible environmental causes. With the discovery of mutations in two genes, synuclein and parkin, which are responsible for rare familial forms of the disease, there has been a major change in emphasis. REVIEW SUMMARY: The first genetic cause of PD to be identified was in the gene for synuclein, resulting in an alanine to threonine substitution at position 53. The likely pathogenetic significance of this mutation was supported by the discovery of a second mutation, and the presence of synuclein in Lewy bodies in sporadic PD cases. The synuclein protein has a tendency to self aggregate, and this tendency is increased in the mutants, and by oxidative injury to the protein. While there is growing evidence in animal models that overexpression of wildtype or mutant synuclein may lead to intracytoplasmic inclusions, and dysfunction of dopamine neurons, no animal models in rodents have yet replicated all important features of the disease. Deletions or point mutations in the gene for parkin cause an autosomal recessive, early onset form of parkinsonism. The parkin protein functions as an E3 ubiquitin-protein ligase, and it is involved in the degradation of cellular proteins by the proteasomal pathway. It is hypothesized that the loss of this function results in the toxic accumulation of its target proteins. CONCLUSIONS: Research on these inherited forms of PD is pointing towards a common theme, that disturbances of cellular protein handling can lead to the death of dopamine neurons in PD.

Animals↗

PubMed1998

Transgenic mice with cerebral expression of human immunodeficiency virus type-1 coat protein gp120 show divergent changes in short- and long-term potentiation in CA1 hippocampus.

The human immunodeficiency virus type-1 envelope glycoprotein gp120 is shed from the virus and from infected cells and thus can diffuse and interact with a variety of central nervous system cells. Transgenic mice constitutively expressing glial fibrillary acidic protein-driven gp120 from brain astrocytes display neuronal and glial changes resembling abnormalities in human immunodeficiency virus type-1-infected human brains. To assess the neurophysiology of these transgenic mice and determine whether gp120 expression impairs synaptic plasticity, we examined CA1 population excitatory postsynaptic potentials in hippocampal slices from transgenic mice and from non-transgenic controls, using a double-blind protocol. Compared with slices from non-transgenic littermate controls, slices from gp120 transgenic mice showed four significant alterations: (i) increased mean slopes of normalized population excitatory postsynaptic potentials; (ii) larger paired-pulse facilitation after induction of long-term potentiation at 50 ms interpulse intervals; (iii) markedly elevated short-term potentiation after 10 and 20 shocks at 100 Hz; and (iv) a significant reduction in the magnitude of CA1 long-term potentiation. In slices from transgenic mice expressing Escherichia coli beta-galactosidase from the same promoter, paired-pulse facilitation and long-term potentiation were normal. These results indicate that brain slice preparations from gp120 transgenic mice can be used to assess pathophysiological effects of gp120 on neuronal networks. Because short-term potentiation involves presynaptic mechanisms, our results suggest that gp120 expression in these mice enhances either presynaptic glutamate release or postsynaptic glutamate receptor function, or both. These changes could lead to increased Ca2+ influx, thereby contributing to neuronal dysfunction and injury. As long-term potentiation is a cellular model of learning and memory, our results may be relevant to memory (cognitive) impairments seen in patients with AIDS.

Animals↗

PubMed1999

Clinical benefits of a new piperidine-class AChE inhibitor.

Alzheimer's disease (AD) is associated with a deficiency of acetylcholine (ACh) in the forebrain that correlates with brain pathology and cognitive dysfunction. The most promising approach to enhancing central ACh neurotransmission has been the utilization of agents that inhibit cholinesterases which block its catabolism. Initially, the success of this strategy was limited by subtherapeutic levels of acetylcholinesterase (AChE) inhibition, tolerability problems and toxicity of the first agents. Donepezil HCI represents a new chemical class of AChE inhibitors, the piperidines. In clinical trials, donepezil has been shown to improve significantly cognition and global function in patients with mild to moderately severe AD, and has demonstrated an excellent tolerability and safety profile. These benefits, as well as a simple, once-daily dosing regimen, make donepezil a viable therapeutic option for AD patients.

Aged↗

PubMed2005

Indomethacin-induced ileitis is associated with tensiometric, vascular and oxidative changes in the experimental rat model.

BACKGROUND: Indomethacin-induced enteritis is a model of inflammatory bowel disease. MATERIALS AND METHODS: To further characterize this model, rats received two injections of indomethacin (7.5 mg kg(-1)) 24 h apart and histological damage of intestinal mucosa, oxidative stress, alterations of intestinal motility and mesenteric vascular bed (MVB) reactivity were investigated after 5 days. RESULTS: The results show that indomethacin caused several histological and functional changes at the ileal level. In particular, response to carbachol as well as the nonadrenergic-noncholinergic inhibitory response to electrical field stimulation (EFS) was lower in the treated than control rats. Moreover, nitric oxide (NO)-component of the inhibitory response was higher in the treated than control rats. Mesenteric vessels preparations from the treated rats showed increased noradrenaline (NA)-induced perfusion pressure, whereas relaxant responses to acetylcholine, although not significantly reduced in the treated rats, had a higher nitrergic component. This finding suggests that vascular dysfunction may contribute to chronic inflammation. Indomethacin injection also determined acute and severe oxidative stress in ileum mucosa. CONCLUSIONS: In conclusion, our study contributes to further characterize the rat model of indomethacin-induced enteritis and suggests that it is suitable for drug screening in rats, as this model can be obtained in a very short period and is simple and reproducible.

Acetylcholine↗

PubMed2005

Temporal pattern of plasma membrane calcium ATPase 2 expression in the spinal cord correlates with the course of clinical symptoms in two rodent models of autoimmune encephalomyelitis.

Axonal/neuronal pathology is an important and early feature of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). However, the underlying molecular mechanisms remain elusive. We have previously reported that the levels of an important neuronal calcium pump, plasma membrane calcium ATPase 2 and synaptic proteins, synapsin IIa and syntaxin 1B are decreased in the rat spinal cord at onset of acute EAE. Whether the expression of these genes is restored during neurological recovery and affected in other EAE models is currently unknown. The present study was undertaken to address these issues by use of validated multiplex quantitative real-time RT-PCR with fluoro-primers, western blot and immunocytochemistry. We report that plasma membrane calcium ATPase 2 (PMCA2) transcript and protein levels return to control values during recovery from acute disease in the Lewis rat, whereas they are reduced throughout the course of chronic, non-remitting EAE in the C57Bl/6 mouse. These results indicate a close correlation between PMCA2 levels and disease course as defined by clinical scores reflecting motor deficits. Decrease in synapsin IIa expression also correlated with the onset and progression of neurological symptoms, whereas the pattern of syntaxin 1B mRNA and protein expression suggested post-transcriptional regulation. The decrease in PMCA2 transcript and protein levels and the correlation between expression and disease course in two different EAE models further highlight the importance of this calcium pump in neuronal dysfunction during inflammation.

Animals↗

PubMedDate not supplied

[New therapeutic options in Alzheimer's disease].

INTRODUCTION: At present, cholinesterase inhibitors constitute the basis for therapy of Alzheimer's disease (AD); these drugs were rationally introduced given the loss of central cholinergic neurotransmission, even though there are many other systems affected in AD, including glutamatergic pathway. DEVELOPMENT: In addition to the loss of central cholinergic neurotransmission, biochemical evidence suggests glutamatergic dysfunction in AD and thus, therapeutic strategies directed at the glutamatergic system may be useful. These drugs include milacemide, cicloserine and ampakines (positive modulation) and memantine (negative modulation). Lithium seems to be a promising agent in AD, although the mechanism of action is poorly understood. Finally anti-inflammatory agents may be another therapeutic approach to AD. CONCLUSION: In addition to drugs acting on the cholinergic system, a large number of drugs with different mechanism could be used for the treatment and prevention of AD.

Acetamides↗