1,721,199 research outputs found
Ralfinamide (Newron Pharmaceuticals)
No full textRalfinamide, a sodium channel blocker, is under development by Newton Pharmaceuticals SpA for the potential treatment of neuropathic pain
BEHAVIORAL TERATOLOGY - AN INAPPROPRIATE TERM FOR SOME UNINTERPRETABLE EFFECTS
No full textSince the thalidomide tragedy, the testing of new drugs on pregnant experimental animals has become a requirement in all countries. Many countries have recently introduced tests for subtle behavioral changes (in the absence of morphological damage). However Flaminio Cattabeni and Maria Pia Abbracchio argue that we do not yet know enough about the significance of these changes to make valid interpretations, or to extrapolate from animals to humans. They also propose that the term 'behavioral teratology' with its negative implications should be replaced by the more appropriate term 'chemical imprinting' to account also for chemicals inducing behavioral effects in animals which do not necessarily cause true neurological damage
SELECTIVE ACTIVITY OF BAMIFYLLINE ON ADENOSINE-A1-RECEPTORS IN RAT-BRAIN
No full textThe activity of the xanthine derivative bamifylline on central adenosine A1 and A2 receptors has been evaluated with radio-receptor binding in rat brain in comparison with other structure-related compounds. Bamifylline displaced3H-Cyclo-hexyl-adenosine and3H-Diethyl-8-phenyl-xanthine with a potency similar to that of 8-phenyl-theophylline, suggesting a high activity on A1-receptor subtype. In contrast, when3H-N-Ethyl-car{ballot box}amido adenosine was used to label A2 adenosine receptors in rat striatum, bamifylline displayed a lower activity comparable to that of enprofylline, an alkylxanthine considered a very weak antagonist of adenosine receptors. By calculating for each xanthine derivative its relative potency at A1 and A2 receptors (A2/A1 ratio), bamifylline turned out being the most selective A1 adenosine receptor antagonist so far tested
Transplacentally induced brain lesions: An animal model to study molecular correlates of cognitive deficits
No full textNo abstract availabl
Developmental models of brain dysfunctions induced by targeted cellular ablations with methylazoxymethanol
No full textAbnormal brain development represents one of the major causes of neurological disorders in humans, and determining the factors responsible for generating specific brain malformations represents a formidable task for developmental neurobiology. The knowledge of the precise neurogenetic time table and the use of toxins, like methylazoxymethanol, able to interfere with neuroepithelial cells entering their last mitotic cycle, have allowed for targeted neuronal ablations in specific brain areas of the central nervous system (CNS) when administered at different gestational or postnatal days in various animal species. Of particular relevance are the studies in which ablations of neuronal populations of cortex, hippocampus, and cerebellum have been made. The results obtained show that these early ablations induce a number of neuroanatomic, neurochemical, and electrophysiological changes that give us the possibility to unravel the biochemical strategies utilized by surviving neurons to adapt to the perturbated environment. Most striking are the findings that target deprivation does not affect the survival of afferent neurons in the CNS (except for neurons of the lateral geniculate nucleus), in sharp contrast to the notion of target dependence for peripheral nervous system neurons. Animals showing selective ablations in the Ammon's horn of the hippocampus allow us to understand the complex biochemical pathways leading to changes in activity-dependent synaptic plasticity, and the data underscore the fundamental role of diverse Ca2+-dependent protein kinases, and their substrates, in modulating pre- and postsynaptic events during induction and maintenance of long-term potentiation (LTP). Because LTP represents a useful model to study molecular substrates of learning and memory, this animal model might be of relevance in understanding cognitive brain dysfunctions
Brain adenosine receptors as targets for therapeutic intervention in neurodegenerative diseases
No full textAdenosine acts as a neurotransmitter in the brain through the activation of four specific G-protein-coupled receptors (the A1, A2A, A2B, and A3 receptors). The A1 receptor has long been known to mediate neuroprotection, mostly by blockade of Ca2+ influx, which results in inhibition of glutamate release and reduction of its excitatory effects at a postsynaptic level. However, the development of selective A1 receptor agonists as antiischemic agents has been hampered by their major cardiovascular side effects. More recently, apparently deleterious effects have been reported following the activation of other adenosine receptor subtypes, namely, the A2A and the A3 receptors. In particular, selective A2A receptor antagonists have been demonstrated to markedly reduce cell death associated with brain ischemia in the rat, suggesting that the cerebral A2A receptor may indeed contribute to the development of ischemic damage. The beneficial effects evoked by A2A antagonists may be due to blockade of presynaptic A2A receptors (which are stimulatory on glutamate release) and/or to inhibition of A2A receptor-mediated activation of microglial cells. Even more puzzling data have been reported for the A3 receptor subtype, which can indeed mediate both cell protection and cell death, simply depending upon the degree of receptor activation and/or specific pathophysiological conditions. In particular, a mild subthreshold activation of this receptor has been associated with a reinforcement of the cytoskeleton and reduction of spontaneous apoptosis, which may play a role in "ischemic preconditioning" of the brain, according to which a short ischemic period may protect the brain from a subsequent, sustained ischemic insult that would be lethal. In contrast, a robust and prolonged activation of the A3 receptor has been shown to trigger cell death by either necrosis or apoptosis. Such apparently opposing actions may be reconciled by hypothesizing that adenosine-mediated cell killing during ischemia may be aimed at isolating the most damaged areas to favor those parts of the brain that still retain a chance for functional recovery. In fact, both A3 receptor-mediated cell death and A2A receptor-mediated actions may be viewed as an attempt to selectively kill irreversibly damaged cells in the "core" ischemic area, in order to save space and energy for the surrounding live cells in the "pneumbra" area. Hence, the pharmacological modulation of the A2A and A3 receptors via selective ligands may represent a novel strategy in the therapeutic approach to pathologies characterized by acute or chronic neurodegenerative events
Pathophysiological implications of the structural organization of the excitatory synapse
No full textThe glutamatergic synapse is the key structure in the development of activity-dependent synaptic plasticity in the central nervous system. The analysis of the complex biochemical mechanisms at the basis of the long-term changes in synaptic efficacy have received a tremendous impulse by the observation that the post-synaptic constituents of the synapse can be separated and purified through a simple procedure involving detergent treatment of synaptosomes and differential centrifugation. In this fraction, called post-synaptic density (PSD), the functional interactions of its constituents are preserved. The various subunits of ionotropic glutamate receptors are held in register with the presynaptic active zone through their interaction with linker proteins. N-methyl-D-aspartate (NMDA) subunits NR2A and NR2B, bind to the PSD protein called PSD-95, which in turn binds neuroligins, providing a handle for interacting with neurexin, located in the plasma membrane at the presynaptic active zone. Additional clustering of NMDA receptors is provided through the binding of NR1 subunits to the cytoskeletal protein α-actinin-2. AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and kainate receptors are other important constituents of PSDs and bind to different anchoring proteins. Phosphorylation processes have long been known to modulate NMDA receptor functional activity: the finding that several protein kinases, particularly Ca2+/Calmodulin-dependent protein kinase II and protein tyrosine kinases of the src family, are major constituents of PSDs has allowed to demonstrate that these enzymes are localized in a strategic position of the glutamatergic synapse, so that their activation provides a means for NMDA receptor function regulation upon its activation. The relevance of these mechanisms has been demonstrated in experimental models of pathologies involving deficits in synaptic plasticity, such as in streptozotocin-induced diabetes and in an animal model of prenatal induced ablation of hippocampal neurons. Both animal models display disturbances in long-term potentiation and cognitive deficits, thus providing in vivo models to study pathology related changes in both the structure and the function of the excitatory synaps
A simple and highly sensitive mass fragmentographic procedure for γ aminobutyric acid determinations
No full textA simple and rapid method for the determination of brain γ aminobutyric acid is described. The tissue is homogenized in 0.1 M formic acid and the internal standard 5 amino valeric acid is added. After centrifugation, an aliquot of the supernatant is evaporated and reacted at room temperature with a mixture of hexamethyldisilazane, trimethylchlorosilane, and BSTFA in dry pyridine. After a short reaction time, a few microliters of the reaction mixture is directly analyzed by mass fragmentography. The sensitivity of the method allows measurement of GABA in micrograms of brain tissue
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