1,721,040 research outputs found
The effects of Locus Coeruleus and norepinephrine in methamphetamine toxicity
No full textThe activity of locus coeruleus (LC) neurons has been extensively investigated in a variety of behavioural states. In fact this norepinephrine (NE)-containing nucleus modulates many physiological and pathological conditions including the sleep-waking cycle, movement disorders, mood alterations, convulsive seizures, and the effects of drugs such as psychostimulants and opioids. This review focuses on the modulation exerted by central NE pathways on the behavioural and neurotoxic effects produced by the psychostimulant methamphetamine, essentially the modulation of the activity of mesencephalic dopamine (DA) neurons. In fact, although NE in itself mediates some behavioural effects induced by methamphetamine, NE modulation of DA release is pivotal for methamphetamine-induced behavioural states and neurotoxicity. These interactions are discussed on the basis of the state of the art of the functional neuroanatomy of central NE- and DA systems. Emphasis is given to those brain sites possessing a remarkable overlapping of both neurotransmitters
Epilepsy and Alzheimer's Disease: Potential mechanisms for an association.
Full text linkAlzheimer's Disease (AD) and epilepsy are common neurological diseases. The prevalence of epilepsy in AD patients is higher than in healthy subjects, but identifying the reasons for this association, the characteristics of seizures in AD, and the implications for prognosis and treatment is challenging. The present review provides first of all an overview of the main clinical aspects of AD and epilepsy, of their reciprocal relationship, and of the challenges that identifying seizures in AD patients presents. Limitations of clinical studies addressing this topic are discussed, including their mostly prospective nature and possible selection biases. A comprehensive, mechanistic discussion on the factors that are most likely to underlie the increased risk for seizures in AD follows. These include, for instance, GABAergic and glutamatergic alterations, Aβ and Tau protein, the role of the noradrenergic nucleus Locus Coeruleus, and neuroinflammation. Finally, evidence concerning the role that epilepsy may have in exacerbating or initiating AD is reviewed. A mechanistic insight on the relationship between epilepsy and AD might have relevant implications for improving the treatment of AD patients, as well as in elucidating pathophysiological mechanisms
AMPA receptor desensitization as a determinant of vulnerability to focally evoked status epilepticus
No full textWithin the area tempestas (AT) in the anterior piriform cortex, unilateral
microinfusions of GABA receptor antagonists and glutamate receptor agonists
trigger brief episodic limbic seizures. In the present study, we document a
synergistic effect of coinfusing bicuculline (GABAA receptor antagonist) with
either carbachol (muscarinic receptor agonist) or cyclothiazide (inhibitor of
AMPA receptor desensitization) but not with glutamate receptor agonists (AMPA,
NMDA or kainate) in the rat AT. In particular, coadministration of bicuculline
(118 pmol) with either carbachol (328 pmol) or cyclothiazide (1.2 nmol) triggered
continuous self-sustaining seizures (status epilepticus; SE). Cyclothiazide alone
did not evoke seizures. Although blockade of NMDA receptors with AP-7 (100 or 500
pmol) prevented episodic seizures evoked by carbachol or bicuculline alone, it
was without effect on the continuous seizures evoked by combined treatments.
NMDA-insensitive self-sustaining seizures were also evoked by the combination of
AMPA and cyclothiazide. Regardless of the mechanism by which SE was evoked, it
was prevented only by an AMPA receptor antagonist, NBQX, thus reinforcing the
crucial role of AMPA receptors in the transition to SE. Further evidence for AMPA
receptor regulation of seizure severity came from the overexpression of the GluR1
AMPA receptor subunit in AT. This resulted in substantially increased severity of
bicuculline-evoked seizures that was reversed by focal application of NBQX. Thus,
desensitization of AMPA receptors appears to limit the duration and severity of
seizure activity, and a failure of this mechanism, or an overabundance of slowly
desensitizing AMPA receptors, predisposes to severe and prolonged seizures
The nature of catecholamine-containing neurons in the enteric nervous system in relationship with organogenesis, normal human anatomy and neurodegeneration.
No full textThe gastrointestinal tract is provided with extrinsic and intrinsic innervation. The extrinsic innervation includes the classic vagal parasympathetic and sympathetic components, with afferent sensitive and efferent secretomotor fibers. The intrinsic innervations is represented by the enteric nervous system (ENS), which is recognized as a complex neural network controlling a variety of cell populations, including smooth muscle cells, mucosal secretory cells, endocrine cells, microvasculature, immune and inflammatory cells. This is finalized to regulate gastrointestinal secretion, absorption and motility. In particular, this network is organized in several plexuses each one providing quite autonomous control of gastrointestinal functions (hence the definition of "second brain"). The similarity between ENS and CNS is further substantiated by the presence of local sensitive pseudo- unipolar ganglionic neurons with both peripheral and central branching which terminate in the enteric wall. A large variety of neurons and neurotransmitters takes part in the ENS. However, the nature of these neurons and their role in the regulation of gastrointestinal functions is debatable. In particular, the available literature reporting the specific nature of catecholamine- containing neurons provides conflicting evidence. This is critical both for understanding the specific role of each catecholamine in the gut and, mostly, to characterize specifically the enteric neuropathology occurring in a variety of diseases. An emphasis is posed on neurodegenerative disorders, such as Parkinson's disease, which is associated with the loss of catecholamine neurons. In this respect, the recognition of the nature of such neurons within the ENS would contribute to elucidate the pathological mechanisms which produce both CNS and ENS degeneration and to achieve more effective therapeutic approaches. Despite a great emphasis is posed on the role of noradrenaline to regulate enteric activities only a few reports are available on the anatomy and physiology of enteric dopamine neurons. Remarkably, this review limits the presence of enteric noradrenaline (and adrenaline) only within extrinsic sympathetic nerve terminals. This is based on careful morphological studies showing that the only catecholamine-containing neurons within ENS would be dopaminergic. This means that enteric pathology of catecholamine neurons should be conceived as axon pathology for noradrenaline neurons and whole cell pathology for dopamine neurons which would be the sole catecholamine cell within intrinsic circuitries affecting gut motility and secretions.The gastrointestinal tract is provided with extrinsic and intrinsic innervation. The extrinsic innervation includes the classic vagal parasympathetic and sympathetic components, with afferent sensitive and efferent secretomotor fibers. The intrinsic innervations is represented by the enteric nervous system (ENS), which is recognized as a complex neural network controlling a variety of cell populations, including smooth muscle cells, mucosal secretory cells, endocrine cells, microvasculature, immune and inflammatory cells. This is finalized to regulate gastrointestinal secretion, absorption and motility. In particular, this network is organized in several plexuses each one providing quite autonomous control of gastrointestinal functions (hence the definition of "second brain"). The similarity between ENS and CNS is further substantiated by the presence of local sensitive pseudounipolar ganglionic neurons with both peripheral and central branching which terminate in the enteric wall. A large variety of neurons and neurotransmitters takes part in the ENS. However, the nature of these neurons and their role in the regulation of gastrointestinal functions is debatable. In particular, the available literature reporting the specific nature of catecholamine-containing neurons provides conflicting evidence. This is critical both for understanding the specific role of each catecholamine in the gut and, mostly, to characterize specifically the enteric neuropathology occurring in a variety of diseases. An emphasis is posed on neurodegenerative disorders, such as including Parkinson's disease, which is associated with the loss of catecholamine neurons. In this respect, the recognition of the nature of such neurons within the ENS would contribute to elucidate the pathological mechanisms which produce both CNS and ENS degeneration and to achieve more effective therapeutic approaches. Despite a great emphasis is posed on the role of noradrenaline to regulate enteric activities only a few reports are available on the anatomy and physiology of enteric dopamine neurons. Remarkably, this review limits the presence of enteric noradrenaline (and adrenaline) only within extrinsic sympathetic nerve terminals. This is based on careful morphological studies showing that the only catecholamine-containing neurons within ENS would be dopaminergic. This means that enteric pathology of catecholamine neurons should be conceived as axon pathology for noradrenaline neurons and whole cell pathology for dopamine neurons which would be the sole catecholamine cell within intrinsic circuitries affecting gut motility and secretions
Is there a role for uridine and pyrimidine nucleosides in the treatment of vascular dementia?
No full textn the 70s, the discovery of a constant loss of acetylcholine (Ach) in the brains of people suffering from dementia led to the development, in order to improve cognitive functions, of drugs that increased Ach levels. The possibility that loss of a given neurotransmitter might be associated with the onset of a specific neurological syndrome led to suggestions that, as had already been found in Parkinson's disease, replacement therapy might drastically improve the course of the syndrome. We are now aware of the limits of this therapeutic approach. In this review, we analyse potential factors contributing to the partial failure of Ach replacement therapy, contrasting common beliefs regarding the Ach synapse with the difficulties in restoring its activity through replacement drugs. Considering the search for alternative strategies, in the second part of the review, we overview progress of research into pyrimidine compounds, now emerging as a new modulatory system acting through specific pyrimidino-receptors involved in various steps of cell signalling. Pyrimidine nucleosides might be useful in the chronic treatment of cognitive deficits resulting from vascular dementia
mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders.
Full text linkThe mammalian target of rapamycin (mTOR) is an ubiquitously expressed serine-threonine kinase, which senses and integrates several intracellular and environmental cues to orchestrate major processes such as cell growth and metabolism. Altered mTOR signalling is associated with brain malformation and neurological disorders. Emerging evidence indicates that even subtle defects in the mTOR pathway may produce severe effects, which are evident as neurological and psychiatric disorders. On the other hand, administration of mTOR inhibitors may be beneficial for a variety of neuropsychiatric alterations encompassing neurodegeneration, brain tumors, brain ischemia, epilepsy, autism, mood disorders, drugs of abuse, and schizophrenia. mTOR has been widely implicated in synaptic plasticity and autophagy activation. This review addresses the role of mTOR-dependent autophagy dysfunction in a variety of neuropsychiatric disorders, to focus mainly on psychiatric syndromes including schizophrenia and drug addiction. For instance, amphetamines-induced addiction fairly overlaps with some neuropsychiatric disorders including neurodegeneration and schizophrenia. For this reason, in the present review, a special emphasis is placed on the role of mTOR on methamphetamine-induced brain alterations
Dopamine stimulation via infusion in the lateral ventricle
No full textContinuous dopamine (DA) stimulation is a therapeutic approach that applies to the treatment of motor fluctuations due to pulsatile DA stimulation in Parkinson's disease (PD), to cure the abuse of drugs, such as cocaine or amphetamine (which produce short-lasting peaks of extracellular DA), and as a safe therapeutic approach to avoid hedonistic homeostatic dysregulation (which sometime develops as an abuse pattern in PD patients receiving a pulsatile DA replacement therapy). However, systemic continuous delivery of DA agonists leads to a variety of side effects. In search for an alterative approach, in the present study we evaluated the possibility of delivering intracerebroventricularly (i.c.v.), a DA agonist: lisuride that was already shown to be effective when administered continuously subcutaneously (s.c.). In particular, we were interested in examining whether lisuride infused within the lateral ventricle was still able to stimulate DA receptor by inducing contralateral turning behavior in hemiparkinsonian rats. We found that lisuride, when infused in the lateral ventricle was effective in reducing the threshold for stimulating DA receptors. These results offer a more reliable and safe therapeutic approach to deliver continuous DA selectively in the brain
Endogenous activation of mGLU5 metabotropic glutamate receptors contributes to the development of nigro-striatal damage induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice
No full textWe combined the use of knock-out mice and subtype-selective antagonists
[2-methyl-6-(phenylethynyl)pyridine (MPEP) and
(E)-2-methyl-6-(2-phenylethenyl)-pyridine (SIB1893)] to examine whether
endogenous activation of mGlu5 metabotropic glutamate receptors contributes to
the pathophysiology of nigro-striatal damage in the
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of parkinsonism. High
doses of MPTP (four injections of 20 mg/kg, i.p., every 2 hr) induced a high
mortality rate and a nearly total degeneration of the nigro-striatal pathway in
wild-type mice. mGlu5 knock-out mice were less sensitive to MPTP toxicity, as
shown by a higher survival and a milder nigro-striatal damage. Protection against
MPTP (80 mg/kg) toxicity was also observed after MPEP injections (four injections
of 5 mg/kg, i.p., 30 min before each MPTP injection). MPEP treatment did not
further increase neuroprotection against 80 mg/kg of MPTP in mGlu5 knock-out
mice, indicating that the drug acted by inhibiting mGlu5 receptors. In wild-type
mice, MPEP was also neuroprotective when challenged against lower doses of MPTP
(either 30 mg/kg, single injection, or four of 10 mg/kg injections). The action
of MPEP was mimicked by SIB1893 but not by the mGlu1 receptor antagonist
7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester. MPEP did not
change the kinetics of 1-methyl-4-phenylpyridinium ion formation in the striatum
of mice injected with MPTP. We conclude that mGlu5 receptors act as amplifiers of
MPTP toxicity and that mGlu5 receptor antagonists may limit the extent of
nigro-striatal damage in experimental models of parkinsonism
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