|
| ||
|
|
||
Cholinergic Function (cholinergic + function)
Selected AbstractsNeostigmine and pilocarpine attenuated tumour necrosis factor , expression and cardiac hypertrophy in the heart with pressure overloadEXPERIMENTAL PHYSIOLOGY, Issue 1 2008Jessica Freeling The inflammatory cytokine tumour necrosis factor , (TNF,) is known to be a major factor contributing to cardiac remodelling and dysfunction. Parasympathetic nervous system cholinergic function can inhibit TNF, expression during systemic infection. In the present study, we tested the effects of a cholinesterase inhibitor, neostigmine, and a muscarinic cholinergic agonist, pilocarpine, on cardiac hypertrophy and TNF, levels during pressure overload. Rats with transverse aortic constriction exhibited elevated TNF, protein levels in the heart, increased heart weight to body weight ratios (an index of cardiac hypertrophy) and decreased left ventricular diastolic function. Two weeks of infusion with neostigmine (6 ,g kg,1 day,1) or pilocarpine (0.3 mg kg,1 day,1) significantly reduced cardiac hypertrophy, reduced TNF, levels and elevated interleukin-10 levels in heart tissues, and improved ventricular function in rats with transverse aortic constriction. Neither of these treatments significantly changed ventricular pressure load. Furthermore, in primary cultured neonatal cardiac cells, treatment with pilocarpine attenuated adrenergic agonist phenylephrine-induced increased TNF, expression and [3H]leucine (a marker of protein synthesis) incorporation in the cells. Collectively, both cholinergic agents decreased TNF, levels and attenuated cardiac hypertrophy. Since both agents potentially enhanced cholinergic function, the anti-inflammatory action may be involved in the cardioprotective effect of the treatments with these agents. [source] Improving clinical descriptions to understand the effects of dementia treatment: consensus recommendationsINTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, Issue 11 2002Kenneth Rockwood Abstract Objectives To recommend how the description of clinically detectable treatment effects might be improved for antidementia drug trials. Method Consensus conference, with review of available evidence. Results We suggest widespread, systematic, qualitative studies, based on prospective observations such as the clinicians' narrative descriptions of patient's changes used in the Clinician's Interview-Based Impressions of Change (CIBIC-Plus), plus caregiver input. The identification of patient and caregiver expectations, and an understanding of how these expectations are met, are proposed as priorities for future study. Conclusion Better descriptions of treatment effects can enhance our understanding of both clinical meaningfulness and cholinergic function in the brain. Copyright © 2002 John Wiley & Sons, Ltd. [source] The galanin receptor 2/3 agonist Gal2-11 protects the SN56 cells against ,-amyloid25,35 toxicityJOURNAL OF NEUROSCIENCE RESEARCH, Issue 5 2010S. Pirondi Abstract The neuropeptide galanin is a modulator of cholinergic function and may play a role in A, peptide-induced degeneration of cholinergic forebrain neurons. We have studied the effect of galanin and its galanin receptor subtype 2/3 agonist Gal2-11on toxicity induced by freshly-prepared ,-amyloid25,35 in the cholinergic cell line SN56. Both nuclear fragmentation and caspase-3 expression were analysed. ,-amyloid25,35 -exposure induced a significant increase in caspase-3 mRNA expression after 30, 60, 90 or 150 min of ,-amyloid25,35 exposure. These effects were abolished in the presence of Gal2-11 (10 nM). Similarly, ,-amyloid25,35 -induced nuclear fragmentation was prevented by the galanin agonist at all time points studied. These findings indicate that the galanin 2/3 agonist Gal2-11 protects SN56 cholinergic cells from ,-amyloid25,35 -induced cell death and that this action is mediated by an early reduction of caspase-3 expression. © 2009 Wiley-Liss, Inc. [source] Stimulation of choline acetyltransferase by C3d, a neural cell adhesion molecule ligandJOURNAL OF NEUROSCIENCE RESEARCH, Issue 3 2009Alison Burgess Abstract Septal cholinergic neurons project to the hippocampus and release acetylcholine, a neurotransmitter involved in learning and memory. The enzyme choline acetyltransferase (ChAT) is responsible for synthesizing acetylcholine. Promoting ChAT activity and acetylcholine release can lead to new treatments for neurodegenerative diseases with cholinergic deficits, such as Alzheimer's disease. We present evidence that the synthetic molecule C3d, which is a peptide mimetic of the neural cell adhesion molecule (NCAM), promotes ChAT activity in cultures of rat embryonic septal neurons. Our data demonstrate that ChAT activity triggered by C3d is dependent on the fibroblast growth factor receptor (FGFR) and the mitogen-activated protein kinase (MAPK) pathway. C3d did not affect the number of cholinergic neurons in culture, indicating that NCAM homophilic binding enhances ChAT activity, without affecting cholinergic cell survival. In conclusion, the NCAM mimetic peptide C3d promotes ChAT activity in septal neurons through FGFR and MAPK. These findings are relevant to the design of new strategies aimed at stimulating cholinergic function and improving cognition in disorders such as Alzheimer's disease. © 2008 Wiley-Liss, Inc. [source] Muscarinic receptor subtypes in neuronal and non-neuronal cholinergic functionAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 3 2006R. M. Eglen Summary 1 Muscarinic M1,M5 receptors mediate the metabotropic actions of acetylcholine in the nervous system. A growing body of data indicate they also mediate autocrine functions of the molecule. The availability of novel and selective muscarinic agonists and antagonists, as well as in vivo gene disruption techniques, has clarified the roles of muscarinic receptors in mediating both functions of acetylcholine. 2 Selective M1 agonists or mixed M1 agonists/M2 antagonists may provide an approach to the treatment of cognitive disorders, while M3 antagonism, or mixed M2/M3 antagonists, are approved for the treatment of contractility disorders including overactive bladder and chronic obstructive pulmonary disease. Preclinical data suggest that selective agonism of the M4 receptor will provide novel anti-nociceptive agents, while therapeutics-based upon agonism or antagonism of the muscarinic M5 receptor have yet to be reported. 3 The autocrine functions of muscarinic receptors broadly fall into two areas , control of cell growth or proliferation and mediation of the release of chemical mediators from epithelial cells, ultimately causing muscle relaxation. The former particularly are involved in embryological development, oncogenesis, keratinocyte function and immune responsiveness. The latter regulate contractility of smooth muscle in the vasculature, airways and urinary bladder. 4 Most attention has focused on muscarinic M1 or M3 receptors which mediate lymphocyte immunoresponsiveness, cell migration and release of smooth muscle relaxant factors. Muscarinic M4 receptors are implicated in the regulation of keratinocyte adhesion and M2 receptors in stem cell proliferation and development. Little data are available concerning the M5 receptor, partly due to the difficulties in defining the subtype pharmacologically. 5 The autocrine functions of acetylcholine, like those in the nervous system, involve activation of several muscarinic receptor subtypes. Consequently, the role of these subtypes in autocrine, as well neuronal cholinergic systems, significantly expands their importance in physiology and pathophysiology. [source] GABAB receptor function in the ileum and urinary bladder of wildtype and GABAB1 subunit null miceAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 3 2002G. J. Sanger Summary1 GABAB1 receptor subunit knockout mice were generated and the effects of the GABAB receptor agonist, baclofen, were evaluated within the peripheral nervous system (PNS) of wildtype (+/+), heterozygote (+/,) and knockout (,/,) animals. For this purpose, neuronally-mediated responses were evoked in both the isolated ileum and urinary bladder, using selective electrical field stimulation (EFS). 2 In ileum resected from 4,8-week-old-mice, low frequencies of EFS (0.5 Hz) evoked irregular muscle contractions which were prevented by atropine 1 ,M and reduced by baclofen (33.4 ± 5.6%, 100 ,m). The latter effect was antagonized by the GABAB receptor antagonist CGP54626 0.2 ,m. Baclofen 100 ,m did not affect contractions of similar amplitude induced by carbachol, indicating that the ability of baclofen to inhibit cholinergic function in mouse ileum may be due to an action at prejunctional GABAB receptors. 3 To avoid the development of grand mal seizure by GABAB1 (,/,) mice, a behaviour observed when the mice were greater than 3 weeks old, it was necessary to study the effects of this knockout in 1,3-week-old-animals. However, at this age, EFS at 0.5 Hz did not evoke robust muscle contractions. Consequently we used EFS at 5 Hz, which did evoke cholinergically mediated contractions, found to be of similar amplitude in (+/+) and (+/,) mice, of both 1,3 weeks and 4,8 weeks of age. At this frequency of EFS, baclofen reduced the amplitude of the evoked contractions [n=6 (+/+) and n=5 (+/,), IC50 19.2 ± 4.8 ,m) and this effect was greatly reduced in the presence of CGP54626 0.2 ,m. 4 In urinary bladder from 1,3-week-old-mice, using higher frequencies of EFS to evoke clear, nerve-mediated contractions (10 Hz), baclofen 10,300 ,m concentration-dependently inhibited contractions in (+/+) mice (IC50 9.6 ± 3.8 ,m). This effect was inhibited by CGP54626 (0.2 ,m, 46.2 ± 13.6% inhibition, 300 ,m baclofen n=7) a concentration which, by itself, had no effect on the EFS-evoked contractions. 5 The effects of baclofen in both ileum and urinary bladder were absent in the GABAB1 receptor subunit (,/,) mice; however, responses to EFS were unaffected in (,/,) when compared to the (+/+) mice. 6 Our data suggest that, as in the central nervous system (CNS), the GABAB1 receptor subunit is an essential requirement for GABAB receptor function in the enteric and PNS. As such, these data do not provide a structural explanation for the existence of putative subtypes of GABAB receptor, suggested by studies such as those in which different rank-orders of GABAB agonist affinity have been reported in different tissues. [source] The experimental Alzheimer drug phenserine: preclinical pharmacokinetics and pharmacodynamicsACTA NEUROLOGICA SCANDINAVICA, Issue 2000N. H. Greig Phenserine, a phenylcarbamate of physostigmine, is a new potent and highly selective acetylcholinesterase (AChE) inhibitor, with a >50-fold activity versus butyrylcholinesterase (BChE), in clinical trials for the treatment of Alzheimer's disease (AD). Compared to physostigmine and tacrine, it is less toxic and robustly enhances cognition in animal models. To determine the time-dependent effects of phenserine on cholinergic function, AChE activity, brain and plasma drug levels and brain extracellular acetylcholine (ACh) concentrations were measured in rats before and after phenserine administration. Additionally, its maximum tolerated dose, compared to physostigmine and tacrine, was determined. Following i.v. dosing, brain drug levels were 10-fold higher than those achieved in plasma, peaked within 5 min and rapidly declined with half-lives of 8.5 and 12.6 min, respectively. In contrast, a high (>70%) and long-lasting inhibition of AChE was achieved (half-life >8.25 h). A comparison between the time-dependent plasma AChE inhibition achieved after similar oral and i.v. doses provided an estimate of oral bioavailability of 100%. Striatal, in vivo microdialysis in conscious, freely-moving phenserine-treated rats demonstrated >3-fold rise in brain ACh levels. Phenserine thus is rapidly absorbed and cleared from the body, but produces a long-lasting stimulation of brain cholinergic function at well tolerated doses and hence has superior properties as a drug candidate for AD. It selectively inhibits AChE, minimizing potential BChE side effects. Its long duration of action, coupled with its short pharmacokinetic half-life, reduces dosing frequency, decreases body drug exposure and minimizes the dependence of drug action on the individual variations of drug metabolism commonly found in the elderly. [source] Medicinal chemistry approaches for the treatment and prevention of Alzheimer's diseaseMEDICINAL RESEARCH REVIEWS, Issue 1 2003S.O. Bachurin Abstract Alzheimer's disease (AD) is the most common form of dementia, which is characterised by progressive deterioration of memory and higher cortical functions that ultimately result in total degradation of intellectual and mental activities. Modern strategies in the search of new therapeutic approaches are based on the morphological and biochemical characteristics of AD, and focused on following directions: agents that compensate the hypofunction of cholinergic system, agents that interfere with the metabolism of beta-amyloid peptide, agents that protect nerve cells from toxic metabolites formed in neurodegenerative processes, agents that activate other neurotransmitter systems that indirectly compensate for the deficit of cholinergic functions, agents that affect the process of the formation of neurofibrillary tangles, anti-inflammatory agents that prevent the negative response of nerve cells to the pathological process. The goal of the present review is the validation and an analysis from the point of view of medicinal chemistry of the principles of the directed search of drugs for the treatment and prevention of AD and related neurodegenerative disorders. It is based on systematization of the data on biochemical and structural similarities in the interaction between physiologically active compounds and their biological targets related to the development of such pathologies. The main emphasis is on cholinomimetic, anti-amyloid and anti-metabolic agents, using the data that were published during the last 3 to 4 years, as well as the results of clinical trials presented on corresponding websites. © 2002 Wiley Periodicals, Inc. Med Res Rev, 23, No. 1, 48,88, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/med.10026 [source] | |||||||||||||