Contents
Amine Oxidase Inhibitors and Development of
Neuroprotective Drugs Pp. 153-168
Bernard N. Sowa, Kathryn G. Todd, Véronique A.M.I Tanay,
Andrew Holt and Glen B. Baker
Animal Models for Obsessive-Compulsive Disorder Pp.
169-181
J. Man, A. L. Hudson, D. Ashton and D. J. Nutt
Brain Oxidative Markers in Stress: Possible New Drug
Targets Against Neuroinflammation Pp. 183-189
Jose L.M. Madrigal, Javier Caso, Olivia Hurtado, Ignacio
Lizasoain, Maria A. Moro, Pedro Lorenzo and Juan C. Leza
[35S]GTPgS Autoradiography: A
Powerful Functional Approach with Expanding Potential for Neuropharmacological
Studies on Receptors Coupled to Gi Family of G Proteins Pp.
191-206
Jarmo T. Laitinen
P2Y Receptor Activation Affects the Proliferation and
Differentiation of Glial and Neuronal Cells: A Focus on Rat C6 Glioma Cells
Pp. 207-220
Patrik Claes and Herman Slegers
Neuromodulation of the Perinatal Respiratory Network
Pp. 221-243
Klaus Ballanyi
Oestradiol Signalling in the Hippocampus Pp. 245-259
I. Azcoitia, L.M. Garcia-Segura and L.L. DonCarlos
Abstracts
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Amine Oxidase Inhibitors and Development of Neuroprotective Drugs
Bernard N. Sowa, Kathryn G. Todd, Véronique A.M.I Tanay, Andrew Holt and Glen B. Baker
Monoamine oxidase (MAO) inhibitors continue to be used for treatment of a number of psychiatric and neurologic disorders. In recent years, inhibitors of MAO and other amine oxidases have received considerable attention because of their neuroprotective and neurorescue effects in such models as oxygen-glucose deprivation in vitro, thiamine deficiency, NMDA-instigated excitotoxicity, free radical-mediated oxidative stress, cerebral ischemia, and experimental models of Alzheimer’s and Parkinson’s Diseases. This review focuses on the MAO inhibitors l-deprenyl, tranylcypromine and phenelzine and the possible mechanisms underlying their neuroprotective actions. In addition, there is a discussion of analogs of phenelzine and l-deprenyl as inhibitors of other amine oxidases, including semicarbazide-sensitive amine oxidase (SSAO), and their possible involvement in neuroprotection.
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Animal Models for Obsessive-Compulsive Disorder
J. Man, A. L. Hudson, D. Ashton and D. J. Nutt
Naturally occurring animal models of OCD such as acral-lick dermatitis in dogs represent possibly the best models in terms of symptomology, predictive validity and similarity of inducing conditions. Unfortunately, these advantages are offset by the associated high cost of obtaining a sample population. The alternative is to turn to laboratory-based models and these can be classified into behavioural (e.g. food restriction-induced wheel running leading to body weight loss), pharmacological (e.g. 5-HT agonist-induced loss of spontaneous alternation; chronic quinpirole-induced compulsive checking) and genetic (e.g. HoxB8 knock-out mice) subtypes.
Each of the different models presents unique advantages and disadvantages. Of the 4 lab-based models examined, the first 3 have been interesting as OCD models because predictive validity has been demonstrated in each. However food restriction–induced wheel running does not correlate well on the similarity of symptoms with OCD, as body weight loss is more associated with anorexia nervosa. The 5-HT agonist model and chronic quinpirole model may be questioned on their inducing conditions; are 5-HT / dopamine dysfunction central in the pathology of OCD? Conversely, the knockout mouse model is exciting because the compulsive grooming phenotype elicited is similar to that observed in OCD. This behaviour appears to be due specifically to the knockdown of a gene that has so far not been implicated in the OCD story. However, no predictive validity has been demonstrated in this model at present. Finally, the review addresses future directions in OCD research and what possible new targets might exist.
[Back to top] Brain
Oxidative Markers in Stress: Possible New Drug Targets Against
Neuroinflammation
Jose L.M. Madrigal, Javier Caso, Olivia Hurtado, Ignacio
Lizasoain, Maria A. Moro, Pedro Lorenzo and Juan C. Leza
Stress is triggered by numerous unexpected environmental, social or pathological conditions occurring during life of animals and humans that determine changes in all their systems. Although acute stress is essential for surviving, chronic, long lasting stress can be detrimental. In the present review we present data supporting the hypothesis that stress-related events are characterized by modifications of oxidative/nitrosative pathways in brain in relation to the activation of inflammatory mediators. Recent findings indicate a key role for nitric oxide (NO) and the excess of pro-oxidants in various brain structures as responsible for both neuronal functional impairment and structural damage. Similarly, other known source of oxidants, cyclooxygenase-2 (COX-2) accounts for stress-induced brain damage. The stress-induced activation of both biochemical pathways depends on the activation of the NMDA subtype of glutamate receptor and on the activation of the transcription factor nuclear factor kB (NFkB). In the case of inducible NO synthase (iNOS), the release of the cytokine TNFa also accounts for its expression. Different pharmacological strategies acting at different sites in iNOS or COX-2 pathways have been shown to be neuroprotective in stress-induced brain damage: NMDA receptor blockers, inhibitors of TNFa activation and release, inhibitors of NFkB, and specific inhibitors of iNOS and COX-2 activities. This article reviews recent contributions addressing a possible new pharmacological target for stress-induced neuropsychiatric disorders.
[Back
to top] [35S]GTPgS
Autoradiography: A Powerful Functional Approach with Expanding Potential for
Neuropharmacological Studies on Receptors Coupled to Gi Family of G
Proteins
[35S]GTPgS autoradiography is a novel functional approach to detect G protein activity in brain cryostat sections in response to stimulation of G protein-coupled receptors (GPCRs). One immediate advantage of this approach is that for the first time receptor signalling can be studied in anatomically defined brain structures. A salient feature is the heterogeneously distributed signal in many regions under basal assay conditions. Endogenous adenosine, acting via A1 receptors, is so far the only identified factor contributing to this. Despite elimination of the adenosine signal, several “hot spot” loci (e.g. the hypothalamus) representing high local basal G protein activity persist, awaiting for the identification of the endogenous ligands responsible for this activity. [35S]GTPgS autoradiography predominantly detects signalling of receptors that couple to the Gi class of G proteins, and some 20 distinct receptors belonging to this category have been studied to date under various experimental settings. Although inactivation of Gi, the predominant class of brain G proteins, by N-ethylmaleimide largely eliminates responses to all studied receptors, such treatment does not facilitate detection of responses to Gs- or Gq-coupled receptors. [35S]GTPgS autoradiography is particularly well-suited for functional studies on brain lysophospholipid receptors, for which conventional radioligand binding assays are not available. [35S]GTPgS autoradiography has facilitated the discovery of novel GPCRs, such as the P2Y12 receptor, in the nervous system. Additional applications are also emerging. It is evident that the integrity of the basic signalling unit, which for an increasing number of GPCRs resides in specialized membrane microdomains, is better preserved in cryostat sections than in bulk membrane preparations, suggesting that controversial issues, such as constitutive receptor activity in native brain tissue, can be rigorously addressed using [35S]GTPgS autoradiography. Perhaps we are only beginning to appreciate the true potential of this approach for the neuropharmacological studies on the divergent family of GPCRs.
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P2Y Receptor Activation Affects the Proliferation and Differentiation of Glial
and Neuronal Cells: A Focus on Rat C6 Glioma Cells
Patrik Claes and Herman Slegers
Astrocytes and neuronal cells have been shown to release nucleotides by non-lytic, transport-mediated mechanisms. Released nucleotides elicit a broad range of physiological responses including neurotransmission, regulation of cardiovascular function, platelet aggregation, secretion of hormones, modulation of the immune response, protection in hypoxia and ischaemia, and control of cell proliferation and differentiation. Distinct effects of nucleotides like ATP and adenosine reflect differences in nucleotide receptor expression and the modulating role of nucleotide hydrolysis by ecto-nucleotidases. Current research is mainly focused on short-term effects of nucleotide receptor activation e.g. Ca2+ influx, activation of phospholipase C, regulation of adenylate cyclase, but less on the long-term trophic effects of nucleotides.
Our laboratory has studied the trophic actions of nucleotides on the proliferation and differentiation of rat C6 glioma cells, often used as biochemical model system for astrocytes. These cells have oligodendrocytic and astrocytic progenitor properties and express the P2Y1, P2Y2, P2Y4, P2Y6, P2Y12 receptors and the A2B adenosine receptor. In these cells, differentiation towards an astrocyte type II is induced by elevation of the intracellular cAMP concentration. In this review, P2Y receptor-mediated short- and long-term effects on glial and neuronal cells are discussed in view of the results obtained with C6 cells. Long-term trophic effects of adenosine and uridine nucleotides are related to short-term events initiated in the cells upon P2Y receptor stimulation.
[Back to top] Neuromodulation
of the Perinatal Respiratory Network
Klaus Ballanyi
Breathing movements are initiated and controlled by a neuronal network within the lower brainstem that is influenced by peripheral and suprapontine inputs. To provide adaptation of breathing to vocalisation, exercise or hypoxia, rhythmogenic neurons of the ventral respiratory group (VRG) within the ventrolateral medulla (VLM) are controlled by numerous neuromodulators. Underlying cellular mechanisms are currently analysed in respiratory active medulla preparations from perinatal rodents. This reveals properties of the perinatal respiratory network pivotal for understanding spontaneous or drug-induced perturbation of breathing in preterm and term infants. Already at birth, ligand-gated anion channels can inhibit VLM-VRG neurons. But impairment of Cl- extrusion by hormones or growth factors may interfere with respiratory functions. During severe hypoxia, resulting in anoxia of the VLM-VRG, perinatal respiratory activity persists for more than twenty minutes, although at a greatly reduced frequency. This frequency depression, associated with a hyperpolarisation of rhythmogenic VLM-VRG neurons, is reversed by K+ channel blockers, thyrotropin-releasing hormone or substance-P, for example. This response may represent an adaptive mechanism for energy conservation during oxygen depletion. Endogenous frequency depression of the normoxic perinatal respiratory rhythm, possibly mediated by endorphins or prostaglandins, may serve to dampen excessive respiratory activity in utero. Opiates and prostaglandins, known to impair breathing in infants during clinical administration, likely act directly to depress rhythmogenic VLM-VRG neurons. Based upon such findings in perinatal rodent models on synaptic inhibition and responses to hypoxia-anoxia or clinically-applicable drugs, novel pharmacological strategies are discussed that aim to stabilise infant breathing by targeting rhythmogenic respiratory neurons.
[Back to top] Oestradiol
Signalling in the Hippocampus
I. Azcoitia, L.M. Garcia-Segura and L.L. DonCarlos
Since the pioneering experiments demonstrating that oestradiol and related hormones can alter CNS responses other than the control of sexual behaviour, the hippocampus has been utilised as a valuable experimental model for deciphering the multiple roles of sex steroids in the mammalian brain. These roles include the regulation by oestradiol of neuronal and glial proliferation and survival throughout the lifespan, neuroprotection after insults, and the synaptic modulation essential for consolidation of learning and memory. Oestradiol exerts all these functions by various routes, including its receptor-mediated control of transcription, activation of intracellular signal transduction cascades, cross-talk with signalling mechanisms activated by other molecules, such as growth factors, allosteric modulation of membrane proteins, and its antioxidant properties. This review is focussed on the manner in which oestradiol exerts its effects within the hippocampus, and summarizes data on the distribution of known oestrogen receptors as well as how oestradiol modulates nuclear transcription and cell signalling events.