1,721,073 research outputs found
An in situ hybridization protocol to detect rare mRNA expressed in neural tissue using biotin-labelled oligonucleotide probes
No full textThe use of the non-radioactive in situ hybridization protocols has allowed in general to obtain a better resolution of different transcripts at histological and cytological levels with a shortening of the developmental time. The common protocols using digoxigenin and biotin-labelled probes share a considerable limitation depending on the amount of the transcripts present in the tissues. This problem becomes more evident when oligonucleotide probes are used, because of their small size and lower ability to give sufficient signal amplification. The protocol reported here allows to localize rare mRNA expressed in a tissue, using a combination of two biotin-labelled oligonucleotide probes followed by streptavidin-peroxidase and biotinyl tyramide amplification system
Muscarinic acetylcholine receptors: new potential therapeutic targets in antinociception and in cancer therapy
No full textThe presence and function of muscarinic receptor subtypes both in neuronal and non-neuronal cells have been demonstrated using extensive pharmacological data emerging from studies on transgenic mice. Acetylcholine, in fact is synthesized not only in the nervous system but also in other tissues where its local action contributes to the modulation of various cell functions (e.g. survival, proliferation). The possible involvement of acetylcholine and muscarinic receptors in different pathologies has been proposed in recent years and is becoming an important area of study. Although the lack of selective muscarinic receptor ligands has for a long time limited the definition of therapeutic treatment based on muscarinic receptors as targets, some muscarinic ligands such as cevimeline (patents US4855290; US5571918) or xanomeline (patent, US5980933) have been developed and used in pre-clinical or in clinical studies for the treatment of nervous system diseases (Alzheimer and Sjogren's diseases). This review will focus on the potential implications of muscarinic receptors in tumour progression and in nociception and the future use of muscarinic ligands in therapeutic protocols in cancer therapy will be discussed, considering that some muscarinic antagonists currently used in the treatment of genitourinary disease (e.g. darifenacin,; patent, US5096890; US6106864 ) have also been demonstrated to arrest tumour progression in nude mice. Moreover muscarinic agonists such as vedaclidine, CMI- 936 and CMI-1145 have been demonstrated to have analgesic effects, in animal models comparable or more pronounced to those produced by morphine or opiates
Muscarinic receptors and cancer: possible implication in tumor of the nervous system.
No full textMuscarinic receptors are expressed in several primary and metastatic tumours. In some of these, acetylcholine synthesized by the tumour cells through autocrine mechanism often mediated by muscarinic receptors, can contribute to tumour progression, modulating cell proliferation, survival, migration and angiogenesis. Acetylcholine also appears to be involved in brain tumours. In fact, patients with these pathologies show altered levels of ACh in their cerebrospinal fluid. Astrocytomas, glioblastomas and neuroblastomas express both nicotinic and muscarinic receptors, and their activation enhances different signal transduction pathways involving AKT, PIK3, MAPK and ERK. The present review is focused on recent studies demonstrating the muscarinic receptor involvement in the modulation of proliferation, survival and migration in tumours of the central and peripheral nervous system. These data together with observations reported for other pathologies, open up new interesting therapeutic perspectives for ACh and its receptors
Modulation of cholinergic system activity in neuronal and non-neuronal tissues: Therapeutic implications
No full text[No abstract available
Muscarinic acetylcholine receptors as novel therapeutic targets
No full textThe presence and function of muscarinic receptor subtypes both in neuronal and non-neuronal cells have been demonstrated using extensive pharmacological data emerging from studies on transgenic mice. Acetylcholine, in fact is synthesized not only in the nervous system but also in other tissues where its local action contributes to the modulation of various cell functions (e.g. survival, proliferation). The possible involvement of acetylcholine and muscarinic receptors in different pathologies has been proposed in recent years and is becoming an important area of study. Although the lack of selective muscarinic receptor ligands has for a long time limited the definition of therapeutic treatment based on muscarinic receptors as targets, some muscarinic ligands such as cevimeline (patents US4855290; US5571918) or xanomeline (patent , US5980933) have been developed and used in pre-clinical or in clinical studies for the treatment of nervous system diseases (Alzheimer and Sjogren’s diseases).
This review will be focused on the potential implications of muscarinic receptors in the pain therapy and in different pathologies including tumors. Moreover the future use of muscarinic ligands in therapeutic protocols in cancer therapy will be discussed, considering that some muscarinic antagonists currently used in the treatment of genitourinary disease (e.g. darifenacin,; patent, US5096890; US6106864) have also been demonstrated to arrest tumor progression in nude mice.
The involvement of muscarinic receptors in nociception has also been reported. In fact muscarinic agonists such as vedaclidine, CMI-936 and CMI-1145 have been demonstrated to have analgesic effects, in animal models comparable or more pronounced to those produced by morphine or opiates
New pharmacological approaches to the cholinergic system: An overview on muscarinic receptor ligands and cholinesterase inhibitors
No full textThe cholinergic system is expressed in neuronal and in non-neuronal tissues. Acetylcholine (ACh), synthesized in and out of the nervous system can locally contribute to modulation of various cell functions (e.g. survival, proliferation). Considering that the cholinergic system and its functions are impaired in a number of disorders, the identification of new pharmacological approaches to regulate cholinergic system components appears of great relevance. The present review focuses on recent pharmacological drugs able to modulate the activity of cholinergic receptors and thereby, cholinergic function, with an emphasis on the muscarinic receptor subtype, and additionally covers the cholinesterases, the main enzymes involved in ACh hydrolysis. The presence and function of muscarinic receptor subtypes both in neuronal and non-neuronal cells has been demonstrated using extensive pharmacological data emerging from studies on transgenic mice. The possible involvement of ACh in different pathologies has been proposed in recent years and is becoming an important area of study. Although the lack of selective muscarinic receptor ligands has for a long time limited the definition of therapeutic treatment based on muscarinic receptors as targets, some muscarinic ligands such as cevimeline (patents US4855290; US5571918) or xanomeline (patent, US5980933) have been developed and used in pre-clinical or in clinical studies for the treatment of nervous system diseases (Alzheimer' and Sjogren's diseases). The present review focuses on the potential implications of muscarinic receptors in different pathologies, including tumors. Moreover, the future use of muscarinic ligands in therapeutic protocols in cancer therapy will be discussed, considering that some muscarinic antagonists currently used in the treatment of genitourinary disease (e.g. darifenacin, patent, US5096890; US6106864) have also been demonstrated to arrest tumor progression in nude mice. The involvement of muscarinic receptors in nociception also is over-viewed. In fact, muscarinic agonists such as vedaclidine, CMI-936 and CMI-1145 have been demonstrated to have analgesic effects in animal models comparable or more pronounced to those produced by morphine or opiates. Likewise, the crucial role of cholinesterases (acetylcholinesterase and butirylcholinesterase) in neural transmission is discussed, as large number of drugs inhibiting cholinesterase activity have become of increasing relevance particularly for the treatment of neurodegenerative disorders. Herein we summarize the current knowledge of the cholinesterase inhibitors with particular attention to recent patents for Alzheimer's disease drugs. © 2013 Bentham Science Publishers
Acetylcholine and regulation of gene expression in developing systems.
No full textOne of the major questions related to nervous system development is the identification of signals directing neuronal populations to specific phenotypes (e.g., cholinergic, adrenergic, or peptidergic neurons) and involved in cell-to-cell interactions. Although neurotrophins have long been known for their function in development, the neurotransmitter role as modulator of gene expression and differentiation has been recognized only recently. Evidence for the ability of various neurotransmitter molecules to influence various cellular events during neuron differentiation has been reported in several systems (Lauder and Schambra, 1999). We have focused our interest on acetylcholine (ACh) and its possible role in the regulation of neuron-specific gene expression, using different experimental systems: (1) neuroblastoma cell lines, as a model of cholinergic neuron differentiation; (2) dorsal root ganglia (DRG) sensory neurons, which activate the expression of a cholinergic system early in development, in spite of their peptidergic or aminoacidergic neurotransmission; and (3) primary cultures of Schwann cells. Data obtained on each system will be described briefly
Promising Therapies for Alzheimer's Disease.
No full textBACKGROUND:
Alzheimer's disease (AD) is the most frequent progressive neurodegenerative disease. Cholinergic dysfunction is one of the major pathological alteration, although depletion of cholinergic neurons is caused by the well-established toxicity of the beta-amyloid plaques and neurofibrillary tangles. Cholinergic dysfunctions are consequences of the decrease in acetylcholine synthesis and release, and altered function of muscarinic and nicotinic cholinergic receptors. In addition, a direct correlation between cholinergic alteration, amyloidbeta production and tau phosphorylation, two main AD-pathology hallmarks, has been identified.
METHODS:
In the present review we focused our discussion on the identification of new allosteric or bitopic ligands able to modulate the cholinergic receptor activity. Moreover drug delivery methodology (nanoparticeles, liposomes, etc.) that might contribute to drive the drug in the brain, reducing their toxicity and potential side effects have been also discussed.
RESULTS:
Many drugs are currently in use for AD (e.g. donepezil, rivastigmine etc.) and several of those in development such as muscarininc and nicotinic agonists, target specifically the cholinergic system; the main mechanism aims to rescue the cholinergic dysfunction, to reduce neurotoxic protein accumulation and improve the cholinergic impairments responsible of the cognitive deficits. Promising approaches aim to either improve drug delivery into the brain or develope new compounds targeting known or new molecular pathways. Nanoparticles and liposomes are also described as new nanotechnology tools that overcome traditional routes of administration, with a particular focus on their employment for compounddelivery that targets the cholinergic system. Ultimately, a new fields of research is emerging as the use of induced pluripotent stem cells, a technology that allows to obtain cells directly from the patients that can be propagated indefinetely and differentiated into the susceptible neuronal subtypes. This may significantly contribute to improve the understanding of AD pathological processes and enhance current AD pharmacology beyond the cholinergic dysfunction.
CONCLUSION:
From the topics discussed in the present review, emerges that the combination between pharmacological studies and nanotechnological approaches for drug delivery and the identification of new specific models may largely enhance and improve the therapeutic strategies for different neurological disease including AD
Analgesic effects mediated by muscarinic receptors: mechanisms and pharmacological approaches
No full textChronic pain represents a research field on great clinical relevance and social impactful. It
is associated to a variety of pathological events causing un altered excitability of peripheral nerves derived
by tissue damage depending on physical, biological and chemical injury. In the last years much
attention has been paid in the identification of novel molecules involved in mediating pain sensation
useful as therapeutic tools for the development of new analgesic drugs. Muscarinic receptors are
widely distributed both in the central and peripheral nervous system. It is known that muscarinic agonists
cause analgesic effects via spinal and supraspinal mechanisms. Considering that the analgesia induced
by cholinergic agonists is comparable to that observed with morphine, the identification of receptor subtypes involved
and the identification of the muscarinic ligands capable of selectively activate these receptors, is of considerable
interest for potential therapeutic application. In the present review we describe the role of muscarinic receptors in mediating
central and peripheral pain and the mechanisms downstream these receptors responsible of the modulation of nociceptive
stimuli. Moreover the therapeutic perspectives and the identification of potential drugs binding muscarinic receptors
involved in pain modulation will also be discussed
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