• MeSH
• aminy metabolismus   MeSH
• deprese farmakoterapie   MeSH
• inhibitory MAO farmakologie   MeSH
• noradrenalin fyziologie   MeSH
• Publikační typ
• sborníky MeSH

• Konspekt
• Farmacie. Farmakologie
• NLK Obory
• psychofarmakologie
• psychiatrie
• behaviorální vědy

• MeSH
• inhibitory MAO farmakokinetika   farmakologie   terapeutické užití   MeSH
• management farmakoterapie MeSH
• Parkinsonova nemoc farmakoterapie   MeSH
• Publikační typ
• sborníky MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• neurologie

Lidské monoaminooxidasy (hMAOs) jsou mitochondriální enzymy katalyzující degradaci biogenních aminů. Téměř ve všech tkáních nalézáme dvě isoformy – hMAO A a hMAO B. Inhibitory hMAO A patří mezi dlouhodobě nejpoužívanější antidepresiva. Díky strukturním studiím, které odhalily rozdíly mezi oběma isoformami, mohou být efektivně navrhovány velmi specifické reversibilní inhibitory. Možnost použití inhibitorů zacílených pouze proti jednomu z enzymů významně zlepšuje jejich terapeutický potenciál. Dnes se inhibitory hMAO B standardně používají k léčbě Parkinsonovy choroby a další možnosti aplikací jsou ve fázi klinického testování. Tento článek shrnuje základní problematiku hMAOs a jejich inhibitorů.

Human monoamine oxidases (hMAOs) are mitochondrial enzymes that catalyze degradation of biogenic amines. In almost all tissues are found two isoforms – hMAO A and hMAO B. Inhibitors of hMAO A belongs to one of the longest used antidepressants. Specific reversible inhibitors could be effectively designed due to structural studies that reveal differences between both isoforms. The possibility of application of inhibitors targeting only one of the enzymes significantly improves their therapeutic potential. hMAO B inhibitors are currently commonly used to treat Parkinson’s disease. Other applications of hMAO B inhibitorsare in the clinical trial phase. This article summarizes basic issues of hMAOs and their inhibitors.

• MeSH
• inhibitory MAO * farmakologie   škodlivé účinky   terapeutické užití   MeSH
• lidé MeSH
• monoaminoxidasa * fyziologie   metabolismus   MeSH
• neurodegenerativní nemoci farmakoterapie   MeSH
• Parkinsonova nemoc farmakoterapie   MeSH
• Check Tag
• lidé MeSH

Progress in understanding the role of monoamine neurotransmission in pathophysiology of neuropsychiatric disorders was made after the discovery of the mechanisms of action of psychoactive drugs, including monoamine oxidase (MAO) inhibitors. The increase in monoamine neurotransmitter availability, decrease in hydrogen peroxide production, and neuroprotective effects evoked by MAO inhibitors represent an important approach in the development of new drugs for the treatment of mental disorders and neurodegenerative diseases. New drugs are synthesized by acting as multitarget-directed ligands, with MAO, acetylcholinesterase, and iron chelation as targets. Basic information is summarized in this paper about the drug-induced regulation of monoaminergic systems in the brain, with a focus on MAO inhibition. Desirable effects of MAO inhibition include increased availability of monoamine neurotransmitters, decreased oxidative stress, decreased formation of neurotoxins, induction of pro-survival genes and antiapoptotic factors, and improved mitochondrial functions.

• MeSH
• duševní poruchy farmakoterapie   enzymologie   MeSH
• inhibitory MAO chemická syntéza   farmakologie   terapeutické užití   MeSH
• lidé MeSH
• monoaminoxidasa metabolismus   MeSH
• nervový přenos účinky léků   fyziologie   MeSH
• neurodegenerativní nemoci farmakoterapie   enzymologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Brain monoamines are involved in many of the same processes affected by neuropsychiatric disorders and psychotropic drugs, including cannabinoids. This study investigated in vitro effects of cannabinoids on the activity of monoamine oxidase (MAO), the enzyme responsible for metabolism of monoamine neurotransmitters and affecting brain development and function. The effects of the phytocannabinoid Delta(9)-tetrahydrocannabinol (THC), the endocannabinoid anandamide (N-arachidonoylethanolamide [AEA]), and the synthetic cannabinoid receptor agonist WIN 55,212-2 (WIN) on the activity of MAO were measured in a crude mitochondrial fraction isolated from pig brain cortex. Monoamine oxidase activity was inhibited by the cannabinoids; however, higher half maximal inhibitory concentrations (IC(50)) of cannabinoids were required compared to the known MAO inhibitor iproniazid. The IC(50) was 24.7 micromol/l for THC, 751 micromol/l for AEA, and 17.9 micromol/l for WIN when serotonin was used as substrate (MAO-A), and 22.6 micromol/l for THC, 1,668 micromol/l for AEA, and 21.2 micromol/l for WIN when phenylethylamine was used as substrate (MAO-B). The inhibition of MAOs by THC was noncompetitive. N-Arachidonoylethanolamide was a competitive inhibitor of MAO-A and a noncompetitive inhibitor of MAO-B. WIN was a noncompetitive inhibitor of MAO-A and an uncompetitive inhibitor of MAO-B. Monoamine oxidase activity is affected by cannabinoids at relatively high drug concentrations, and this effect is inhibitory. Decrease of MAO activity may play a role in some effects of cannabinoids on serotonergic, noradrenergic, and dopaminergic neurotransmission.

• MeSH
• benzoxaziny aplikace a dávkování   farmakologie   MeSH
• inhibiční koncentrace 50 MeSH
• inhibitory MAO aplikace a dávkování   farmakologie   MeSH
• iproniazid aplikace a dávkování   farmakologie   MeSH
• kyseliny arachidonové aplikace a dávkování   farmakologie   MeSH
• monoaminoxidasa účinky léků   metabolismus   MeSH
• morfoliny aplikace a dávkování   farmakologie   MeSH
• mozek účinky léků   enzymologie   MeSH
• naftaleny aplikace a dávkování   farmakologie   MeSH
• polynenasycené alkamidy aplikace a dávkování   farmakologie   MeSH
• prasata MeSH
• tetrahydrokanabinol aplikace a dávkování   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

Administration of acetylcholinesterase (AChE) reactivators (oximes) is usually used in order to counteract the poisoning effects of nerve agents. The possibility was suggested that oximes may show some therapeutic and/or adverse effects through their action in central nervous system. There are no sufficient data about interaction of oximes with monoaminergic neurotransmitter's systems in the brain. Oxime-type AChE reactivators pralidoxime, obidoxime, trimedoxime, methoxime and HI-6 were tested for their potential to affect the activity of monoamine oxidase of type A (MAO-A) and type B (MAO-B) in crude mitochondrial fraction of pig brains. The compounds were found to inhibit fully MAO-A with half maximal inhibitory concentration (IC(50)) of 0.375 mmol/l (pralidoxime), 1.53 mmol/l (HI-6), 2.31 mmol/l (methoxime), 2.42 mmol/l (obidoxime) and 4.98 mmol/l (trimedoxime). Activity of MAO-B was fully inhibited by HI-6 and pralidoxime only with IC(50) 4.81 mmol/l and 11.01 mmol/l, respectively. Methoxime, obidoxime and trimedoxime displayed non-monotonic concentration dependent effect on MAO-B activity. Because oximes concentrations effective for MAO inhibition could not be achieved in vivo at the cerebral level, we suppose that oximes investigated do not interfere with brain MAO at therapeutically relevant concentrations.

• MeSH
• inhibitory MAO farmakologie   MeSH
• monoaminoxidasa metabolismus   MeSH
• mozek enzymologie   MeSH
• obidoxim chlorid farmakologie   MeSH
• oximy farmakologie   MeSH
• pralidoximové sloučeniny farmakologie   MeSH
• prasata MeSH
• pyridinové sloučeniny farmakologie   MeSH
• reaktivátory cholinesterázy farmakologie   MeSH
• trimedoxim farmakologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• deprese farmakoterapie   MeSH
• inhibitory MAO * farmakologie   terapeutické užití   MeSH
• komorbidita MeSH
• lidé MeSH
• monoaminoxidasa MeSH
• nádory prostaty * farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• dopisy MeSH
• práce podpořená grantem MeSH

• MeSH
• fluorescenční mikroskopie metody   MeSH
• inhibitory MAO metabolismus   MeSH
• mozek - chemie účinky záření   MeSH
• mozek cytologie   ultrastruktura   MeSH
• myši MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH

The trends of novel AD therapeutics are focused on multitarget-directed ligands (MTDLs), which combine cholinesterase inhibition with additional biological properties such as antioxidant properties to positively affect neuronal energy metabolism as well as mitochondrial function. We examined the in vitro effects of 10 novel MTDLs on the activities of mitochondrial enzymes (electron transport chain complexes and citrate synthase), mitochondrial respiration, and monoamine oxidase isoform (MAO-A and MAO-B) activity. The drug-induced effects of 7-MEOTA-adamantylamine heterodimers (K1011, K1013, K1018, K1020, and K1022) and tacrine/7-MEOTA/6-chlorotacrine-trolox heterodimers (K1046, K1053, K1056, K1060, and K1065) were measured in pig brain mitochondria. Most of the substances inhibited complex I- and complex II-linked respiration at high concentrations; K1046, K1053, K1056, and K1060 resulted in the least inhibition of mitochondrial respiration. Citrate synthase activity was not significantly inhibited by the tested substances; the least inhibition of complex I was observed for compounds K1060 and K1053, while both complex II/III and complex IV activity were markedly inhibited by K1011 and K1018. MAO-A was fully inhibited by K1018 and K1065, and MAO-B was fully inhibited by K1053 and K1065; the other tested drugs were partial inhibitors of both MAO-A and MAO-B. The tacrine/7-MEOTA/6-chlorotacrine-trolox heterodimers K1046, K1053, and K1060 seem to be the most suitable molecules for subsequent in vivo studies. These compounds had balanced inhibitory effects on mitochondrial respiration, with low complex I and complex II/III inhibition and full or partial inhibition of MAO-B activity.

• MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• buněčné dýchání účinky léků   MeSH
• energetický metabolismus * účinky léků   MeSH
• inhibitory MAO farmakologie   MeSH
• mitochondrie účinky léků   enzymologie   metabolismus   MeSH
• monoaminoxidasa metabolismus   MeSH
• prasata MeSH
• respirační komplex II metabolismus   MeSH
• takrin chemie   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• 5-hydroxytryptofan farmakologie   MeSH
• dihydroxyfenylalanin farmakologie   MeSH
• fenelzin farmakologie   MeSH
• fluorescenční mikroskopie MeSH
• inhibitory MAO farmakologie   MeSH
• isokarboxazid farmakologie   MeSH
• katecholaminy analýza   MeSH
• monoaminoxidasa metabolismus   MeSH
• mozek - chemie MeSH
• mozek enzymologie   MeSH
• myši MeSH
• nialamid farmakologie   MeSH
• pargylin farmakologie   MeSH
• serotonin analýza   MeSH
• tranylcypromin farmakologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH