ABSTRACT
Muscarinc receptor-mediated signaling takes part in many physiological functions ranging from complex higher nervous activity to vegetative responses. Specificity of action of the natural muscarinic agonist acetylcholine is effected by action on five muscarinic receptor subtypes with particular tissue and cellular localization, and coupling preference with different G-proteins and their signaling pathways. In addition to physiological roles it is also implicated in pathologic events like promotion of carcinoma cells growth, early pathogenesis of neurodegenerative diseases in the central nervous system like Alzheimer's disease and Parkinson's disease, schizophrenia, intoxications resulting in drug addiction, or overactive bladder in the periphery. All of these disturbances demonstrate involvement of specific muscarinic receptor subtypes and point to the importance to develop selective pharmacotherapeutic interventions. Because of the high homology of the orthosteric binding site of muscarinic receptor subtypes there is virtually no subtype selective agonist that binds to this site. Activation of specific receptor subtypes may be achieved by developing allosteric modulators of acetylcholine binding, since ectopic binding domains on the receptor are less conserved compared to the orthosteric site. Potentiation of the effects of acetylcholine by allosteric modulators would be beneficial in cases where acetylcholine release is reduced due to pathological conditions. When presynaptic function is severely compromised, the utilization of ectopic agonists can be a thinkable solution.
Subject(s)
Muscarinic Agonists/therapeutic use , Muscarinic Antagonists/therapeutic use , Nervous System Diseases/drug therapy , Nervous System Diseases/metabolism , Neurons/metabolism , Receptors, Muscarinic/metabolism , Signal Transduction/drug effects , Animals , Humans , Neurons/drug effects , Receptors, Muscarinic/drug effectsABSTRACT
Photodynamic therapy (PDT) is a new method for the treatment of both cancer or non-cancer diseases. It combines three basic elements (a photosensitizer, light, oxygen), every single one with no toxicity or biological activity. The photosensitizer (PS) is activated by light and it gets excited. It transfers absorbed energy from this excited form to oxygen forming reactive oxygen species (ROS), mainly singlet oxygen. Then ROS attack surrounding biomolecules, inhibit their biological function leading in the end to a cell death. The complete destruction of the tumour is provided not only by a direct effect on the cells, but also a vasculature shutdown (leading to nourishment and oxygen depletion) and an activation of the immunity response play an important role in this process. The present paper proposes to introduce the readers to the history and basic principles of PDT from the point of view of either the physical mechanism of PS activation or biological effects on the target tissue (on molecular, subcellular, cellular, and tissue levels).
Subject(s)
Neoplasms/drug therapy , Photochemotherapy , Humans , Photochemistry , Photosensitizing Agents/chemistryABSTRACT
Since the time when hematoporphyrine derivative (trade name Photofrin) has been introduced into clinical practice in Canada in 1993, a lot of new photosensitizers (PS) have been studied. Some of them successfully passed the clinical trials and are in use in the treatment of cancerous (ALA, temoporfin) and non-cancerous (verteporfin) diseases. The others (motexafin lutecium, talaporfin, phthalocyanines and SnET2) are entering or passing the clinical trials now. The newer PS are also called the second generation PS, when the first generation is composed of Photofrin only. The second generation PS usually possesses better properties, especially concerning absorption at longer wavelengths, shorter skin photosensitivity, better accumulation ratio between tumorous and healthy tissue and pharmacokinetics.
