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Rola sygnalizacji purynergicznej i cytokin w indukcji procesów zapalnych w udarze niedokrwiennym mózgu

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Cieślak M.

Aktualności Neurologiczne

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2012

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vol. 12

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issue 4

205-214

EN

Inflammation plays an important role in the aetiology of various diseases of the central nervous system including the stroke. Accumulating evidence indicates that inflammation in the central nervous system is controlled by purinergic signalling. The mediators of purinergic signalling are extracellular nucleotides (e.g. ATP, ADP, UTP and UDP) and adenosine that act via activation of P2 and P1 purinergic receptors, respectively. The activation of P2 and P1 receptors is regulated by the enzymes ectonucleotidases that hydrolyse either extracellular nucleotides or adenosine. This review focuses on the role of purinergic signalling in the ischaemic stroke. We and others have demonstrated the presence of nucleotides and adenosine in the cerebrospinal fluid. We have also shown that the concentration of ATP and other nucleotides is increased in cerebrospinal fluid of patients with ischaemic stroke. Evidence suggests that the activation of P2 and P1 recep-tors have an opposite role in the ischaemic stroke, i.e. while the nucleoside adenosine exert neuroprotective effects, nucleotides generally promote the proinflammatory and apoptotic responses. P2X7, P2Y2, P2Y6, P2Y11 and P2Y12 are proposed to be involved in the central nervous system inflammation as they are expressed in the brain and their activation is known to control the key inflammatory processes such as release of inflammatory mediators (e.g. cytokines, NO), migration of leukocytes, phagocytosis, apoptosis and thrombosis. The activation of P2 receptors can also increase the release of excitatory neurotransmitters that further exacerbate the inflammatory response. Three cytokines whose release is controlled by P2 receptors have a major role in the ischaemic stroke, namely tumour necrosis factor alpha (TNF-α), interleukin 1 (IL-1) and interleukin 6 (IL-6). By promoting inflammation and thrombosis, these proinflammatory cytokines contribute to the increase in lesion size and thus functional impairment of the affected tissue. Cytokines as well as extracellular nucleotides are involved in leukocyte migration to lesions. By their adherence to endothelium, leukocytes impair cerebral blood circulation and thus exacerbate damage to the brain. The hydrolysis of nucleotides to adenosine by the ectonucleotidases leads to deactivation of proinflammatory responses. Similar effect can also be obtained with P2X7 and IL-1 receptor antagonists that are presently under clinical development and investigation.

PL

Wyniki badań opublikowanych w ostatnich latach wskazują, że indukcja stanów zapalnych w ośrodkowym układzie nerwowym może stanowić podstawę patofizjologiczną wielu chorób, w tym udaru niedokrwiennego mózgu. Istotną rolę w tych procesach przypisuje się sygnalizacji purynergicznej i cytokinom. Receptory purynergiczne P1 i P2 oraz enzymy uczestniczące w degradacji nukleotydów są szeroko rozpowszechnione na komórkach ośrodkowego układu nerwowego. Puryny i pirymidyny wykazują dwojakie działanie w udarze niedokrwiennym mózgu: pozytywne (neuroprotekcyjne) nukleozydów oraz negatywne (prozapalne i proapoptotyczne) nukleotydów. W przebiegu udaru niedokrwiennego mózgu udowodniono udział w indukcji procesów zapalnych trzech cytokin: czynnika martwicy nowotworów α (TNF-α), interleukiny 1 (IL-1) i interleukiny 6 (IL-6). Cytokiny prozapalne wywołują procesy zapalne i prozakrzepowe, przez co zwiększają obszar zawału, a w konsekwencji stopień deficytu neurologicznego. Cytokiny i ATP sprzyjają migracji leukocytów do miejsca niedokrwienia mózgu, natomiast adenozyna działa przeciwstawnie. Leukocyty, przylegając do śródbłonka, upośledzają przepływ mózgowy krwi, w wyniku czego nasilają uszkodzenie tkanki nerwowej. Na uwalnianie cytokin prozapalnych, głównie interleukiny 1β, wpływa aktywacja receptora P2X7. Przypuszcza się, że w procesach zapalnych ośrodkowego układu nerwowego mogą uczestniczyć także receptory: P2Y2, P2Y6, P2Y11, P2Y12. Wydaje się, że degradacja nukleotydów z powstaniem adenozyny może być skutecznym sposobem obniżenia stężenia w przestrzeni pozakomórkowej nukleotydów, jak również cytokin prozapalnych i wygaszania procesów zapalnych. Inną metodą osłabienia intensywności procesów zapalnych jest zastosowanie antagonistów receptora P2X7 oraz inhibitora receptora IL-1 (IL-1Ra). Obecnie prowadzone są badania zarówno nad potencjalnymi antagonistami receptora P2X7, jak i inhibitorem receptora IL-1 (IL-1Ra).

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Czy pochodne nukleozydów i nukleotydów mogą w przyszłości stać się skutecznymi lekami przeciwpadaczkowymi?

63%

Cieślak M., Komoszyński M.

Aktualności Neurologiczne

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2010

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vol. 10

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issue 4

206-212

EN

Many examples of experimental epilepsy show that epileptic seizures occur due to release of stimulatory neurotransmitters into intracellular spaces. In CNS adenosine suppresses exocytosis of glutamate and asparginate but guanosine increases the reverse uptake of glutamate by astrocytes and thus lowers it concentration outside the cell. In this process both nucleosides participate in suppressing the epileptic seizures. By decreasing concentration of ectoadenosine and ectoguanosine outside the cell, that compounds can protect neurons from cellular degeneration. It was shown in many animal models for experimental epilepsy that adenosine A1 and A2A receptors were involved in the process of stopping the seizures. Moreover, some of the conventional anti-epileptic drugs reveal enhance their therapeutic abilities by interactions with the adenosine receptors, being either agonists or antagonists. These interactions modulate the activity of receptors and consequently regulate the neuroprotection processes. Some agonists of adenosine receptors increase the epileptic episodes reaction to those compounds. Anti-episode action of adenosine and guanosine as well as agonists and antagonists of nucleoside receptors indicate the possibility of applying the knowledge about these processes towards production of new anti-epileptic medication. Successful anti-epileptic medication may be based on compounds that have the ability to increase the concentration of ectoadenosine i.e; adenosine deaminase inhibitors, adenosine kinase inhibitors or compounds with ability to suppress reverse uptake of nucleosides. Another method to increase the concentration of extracellular adenosine is to increase the activity of 5’-nucleotidase. That in effect will increase the amount of ectoadenosine by degradation of ectoAMP. There are very promising results revealed that oral administration of guanosine and GMP as well as guanosine by itself given intraperitoneally and intraventricularly what halted epileptic seizures caused by quinolinic acid which is a glutamate agonist.

PL

Napady drgawkowe są wynikiem uwalniania neurotransmiterów pobudzających do przestrzeni pozakomórkowej. W ośrodkowym układzie nerwowym ektoadenozyna hamuje egzocytozę glutaminianu i asparaginianu, natomiast ektoguanozyna, zwiększając wychwyt zwrotny glutaminianu przez astrocyty, obniża jego stężenie poza komórką. W ten sposób oba nukleozydy uczestniczą w hamowaniu napadu drgawkowego. Nukleozydy te, obniżając stężenie powyższych neurotransmiterów poza komórką, chronią neurony przed śmiercią, pełnią więc funkcję neuroprotekcyjną. W różnych modelach zwierzęcych padaczek eksperymentalnych wykazano, że w przerwaniu napadu drgawkowego uczestniczą receptory adenozynowe A1 i A2A. Ma miejsce współdziałanie leków przeciwpadaczkowych i receptorów adenozynowych, bowiem niektóre z nich, takie jak karbamazepina, działają za pośrednictwem receptorów adenozynowych A1, a niektórzy agoniści receptorów A1 potęgują działanie przeciwdrgawkowe tych leków. Przeciwdrgawkowe działanie adenozyny i guanozyny oraz agonistów i antagonistów receptorów nukleozydowych wskazuje na możliwość wykorzystania wiedzy o tych procesach w projektowaniu nowych leków przeciwpadaczkowych. Skutecznymi lekami przeciwdrgawkowymi mogą okazać się związki zwiększające stężenie ektoadenozyny, takie jak: inhibitory deaminazy adenozyny, kinazy adenozynowej oraz związki hamujące wychwyt zwrotny nukleozydów. Innym sposobem zwiększenia stężenia pozakomórkowej adenozyny jest wzrost aktywności 5’-nukleotydazy powiększającej pulę ektoadenozyny przez degradację ektoAMP. Obiecujące są również rezultaty doustnego podania guanozyny i GMP, a także samej guanozyny podanej dokomorowo i dootrzewnowo, które powodowało przerywanie drgawek wywoływanych przez agonistę glutaminianu – kwas chinolinowy.

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Purinergic signaling in the pancreas and the therapeutic potential of ecto-nucleotidases in diabetes

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Cieślak M., Roszek K.

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2014

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vol. 61

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issue 4

655-662

EN

It is widely accepted that purinergic signaling is involved in the regulation of functions of all known tissues and organs. Extracellular purines activate two classes of receptors, P1-adenosine receptors and P2-nucleotide receptors, in a concentration-dependent manner. Ecto-enzymes metabolizing nucleotides outside the cell are involved in the termination of the nucleotide signaling pathway through the release of ligands from their receptors. The pancreas is a central organ in nutrient and energy homeostasis with endocrine, exocrine and immunoreactive functions. The disturbances in cellular metabolism in diabetes mellitus lead also to changes in concentrations of intra- and extracellular nucleotides. Purinergic receptors P1 and P2 are present on the pancreatic islet cells as well as on hepatocytes, adipocytes, pancreatic blood vessels and nerves. The ATP-dependent P2X receptor activation on pancreatic β-cells results in a positive autocrine signal and subsequent insulin secretion. Ecto-NTPDases play the key role in regulation of extracellular ATP concentration. These enzymes, in cooperation with 5'-nucleotidase can significantly increase ecto-adenosine concentration. It has been demonstrated that adenosine, through activation of P1 receptors present on adipocytes and pancreatic islets cells, inhibits the release of insulin. Even though we know for 50 years about the regulatory role of nucleotides in the secretion of insulin, an integrated understanding of the involvement of purinergic signaling in pancreas function is still required. This comprehensive review presents our current knowledge about purinergic signaling in physiology and pathology of the pancreas as well as its potential therapeutic relevance in diabetes.

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Role of pro-inflammatory cytokines of pancreatic islets and prospects of elaboration of new methods for the diabetes treatment

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Cieślak M., Wojtczak A., Cieślak M.

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2015

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vol. 62

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issue 1

15-21

EN

Several relations between cytokines and pathogenesis of diabetes are reviewed. In type 1 and type 2 diabetes an increased synthesis is observed and as well as the release of pro-inflammatory cytokines, which cause the damage of pancreatic islet cells and, in type 2 diabetes, the development of the insulin resistance. That process results in the disturbed balance between pro-inflammatory and protective cytokines. Pro-inflammatory cytokines such as interleukin 1β (IL-1β), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), as well as recently discovered pancreatic derived factor PANDER are involved in the apoptosis of pancreatic β-cells. Inside β-cells, cytokines activate different metabolic pathways leading to the cell death. IL-1β activates the mitogen-activated protein kinases (MAPK), affects the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activates the inducible nitric oxide synthase (iNOS). TNF-α and IFN-γ in a synergic way activate calcium channels, what leads to the mitochondrial dysfunction and activation of caspases. Neutralization of pro-inflammatory cytokines, especially interleukin 1β with the IL-1 receptor antagonist (IL-1Ra) and/or IL-1β antibodies might cause the extinction of the inflammatory process of pancreatic islets, and consequently normalize concentration of glucose in blood and decrease the insulin resistance. In type 1 diabetes interleukin-6 participates in regulation of balance between Th17 and regulatory T cells. In type 2 diabetes and obesity, the long-duration increase of IL-6 concentration in blood above 5 pg/ml leads to the chronic and permanent increase in expression of SOCS3, contributing to the increase in the insulin resistance in cells of the skeletal muscles, liver and adipose tissue.

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Relationship between the induction of inflammatory processes and infectious diseases in patients with ischemic stroke

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Cieślak M., Wojtczak A., Cieślak M.

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2013

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vol. 60

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issue 3

345-349

EN

Pro-inflammatory cytokines participate in the induction of ischemic stroke. So far, their participation in the cerebral ischemia was proven for the tumor necrosis factor TNF-α, interleukin-1 (IL-1), and interleukin-6 (IL-6). The release of the pro-inflammatory cytokines into the extracellular space causes the enlargement of the brain damage region, and consequently increases the neurological deficit and negatively affects the survival rate prognoses. That is confirmed by the increased concentration of pro-inflammatory cytokines in blood and the cerebrospinal fluid of patients with brain stroke, as well as by the research on the induced/experimental cerebral ischemia in animals. The pro-inflammatory cytokines participate in the migration of the reactive T lymphocytes to the regions of brain ischemia where they enhance the nerve tissue damage by down-regulation of microcirculation, induce the pro-thrombotic processes and release other neurotoxic cytokines. Also, in the early stage of cerebral ischemia, cytokines activate the axis hypothalamus-pituitary gland-adrenal cortex and increase the cortisol concentration in blood, what results in the decreased resistance to infectious diseases. Administration of the inhibitor of the interleukin-1 receptor (IL-1Ra) inhibits the inflammatory processes in the region of brain ischemia, and subsequently improves the prognosis for the size of the neurological deficit and the survival rate, as well as resistance to infectious diseases.

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The roles of purinergic signaling in psychiatric disorders

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Cieślak M., Czarnecka J., Roszek K.

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2016

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vol. 63

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issue 1

1-9

EN

Ecto-purines and ecto-pyrimidines are present in the extracellular space of the central nervous system (CNS). Together with P1 and P2 receptors and nucleotides metabolizing ecto-enzymes, they make signaling system involved in neurotransmission, the modulation of sensory signals, including pain stimuli conduction, and the induction of apoptosis and necrosis of the cells. Purines and pyrimidines have a dual effect: positive (neuroprotective) of nucleosides, and negative (pro-inflammatory and pro-apoptotic) of nucleotides. Adenosine-5'-triphosphate (ATP) in the CNS triggers the pro-inflammatory reactions, predominantly by activation of the P2X7 receptor, which results in production and release of pro-inflammatory cytokines. In contrast to ATP, adenosine acts generally as an anti-inflammatory agent and plays an important role in neuroprotection. Currently, it is believed that the initiation of CNS diseases, including mental disorders, is caused by any imbalance between the concentration of ATP and adenosine in the extracellular space. Genetic tests provide also the evidence for the participation of purinergic signaling in psychiatric disorders. It is believed that any action leading to the effective increase of adenosine concentration: activation of nucleotide metabolizing ecto-enzymes (mainly NTPDases - nucleoside triphosphate diphosphohydrolases), inhibition of adenosine deaminase and/or adenosine kinase activity as well as therapies using P1 receptor agonists (adenosine or its analogues) might be beneficial in therapy of psychiatric disorders.

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Rola sygnalizacji purynergicznej i cytokin w indukcji procesów zapalnych w udarze niedokrwiennym mózgu

Czy pochodne nukleozydów i nukleotydów mogą w przyszłości stać się skutecznymi lekami przeciwpadaczkowymi?

Purinergic signaling in the pancreas and the therapeutic potential of ecto-nucleotidases in diabetes

Role of pro-inflammatory cytokines of pancreatic islets and prospects of elaboration of new methods for the diabetes treatment

Relationship between the induction of inflammatory processes and infectious diseases in patients with ischemic stroke

The roles of purinergic signaling in psychiatric disorders