Oligochaeta fajok idegrendszerének immunhisztológiai vizsgálata

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Idegi regeneráció és befolyásolási lehetőségei alacsonyabbrendű és emlős idegrendszerben = Neuroregeneration and its modulation in invertebrate and mammalian nervous systems

Az "Idegi regeneráció és befolyásolási lehetőségei alacsonyabbrendű és emlős idegrendszerben" ifjúsági OTKA tervezete szerint két nagy téma köré csoportosítottam az elvégzendő feladatokat. Az első részben az idegi regeneráció és a hipofízis adenilát cikláz aktiváló polipeptid (PACAP) előfordulását vizsgáltam alacsonyabbrendű idegrendszerben. Kimutattuk a PACAP és receptorainak eloszlását Eisenia idegrendszerében. Embrionális szövetekben, kokonfolyadékban, és a szaporodási időszakban a clitellaris területen is magas a PACAP szint. A dúclánc átvágása után a PACAP upregulálódik, és a trofikus faktorokat szállító coelomasejtek is magas PACAP koncentrációt tartalmaznak. Helixben, egy másik gerinctelen fajban kimutattuk, hogy a PACAP antiapoptotikus hatással rendelkezik. Ezek alapján a PACAP funkcionálisan is valószínűleg konzervált peptid, és gerinctelenekben is széles körben előfordul. A pályázat második részében az idegi lézió regenerációs lehetőségeit vizsgáltam patkányban. Kimutattuk, hogy a PACAP számos idegrendszeri lézióban védő hatást nyújt, pl. in vivo Parkinson kórban, excitotoxicus lézióban és retinális degenerációban. In vitro a PACAP az apoptózissal szemben más szöveteket, sejteket is véd, mint pl. endothelsejteket és szívizomsejteket. Ezen sejtekben és a retinában kimutattuk, hogy a PACAP az antiapoptotikus útvonalakat stimulálja, míg a proapoptotikus útvonalakat gátolja. Ezen támogatás segítségével és feltüntetésével összesen 23 közlemény született (IF:42,9). | The investigation planned in the OTKA ?Neuroregeneration and its modulation in invertebrate and mammalian nervous system? was subdivided in two major categories. First, regeneration and the occurrence of pituitary adenylate cyclase activating polypeptide (PACAP) was investigated in the invertebrate nervous system. We have shown that PACAP and its receptors occur in the nervous system of Eisenia. Levels of PACAP are very high during embryonic development, in the embryo, in the cocoon fluid, and in the clitellar region in the reproductive age. After transection of the ventral cord, PACAP is strongly upregulated, and its concentration is very high in the celomic cells which transport trophic factors. In another invertebrate species, in Helix, we showed that the peptide has antiapoptotic effects. Based on these data, PACAP seems to be a functionally conserved peptide. In the second part, I investigated the possible modulation of nerve regeneration by PACAP in rats. We have shown that PACAP has protective effects in various nerve injuries, like in vivo models of Parkinson`s disease, excitotoxic lesion and retinal degeneration. PACAP protects not only neuronal cells, but other tissues as well against apoptosis, like endothelial cells and cardiomyocytes. We have shown that PACAP stimulates antiapoptotic signaling molecules and inhibits proapoptotic signaling pathways in these cells and in the retina in vivo. With the help of this grant, we have published 23 manuscripts (IF:42.9)

PACAP neuroprotektív hatása Parkinson-kór és újszülöttkori neuronális károsodás patkány modellekben = The neuroprotective effects of PACAP in rat models of Parkinson's disease and neonatal neuronal damage

A pályázat szerves folytatása volt a korábbi T034491 projektnek. A jelen pályázatban PACAP neuroprotektív hatásainak vizsgálatát folytattuk, az eredeti terv szerint két fő téma köré csoportosítva: a PACAP hatása bazális ganglionok károsodásában és újszülöttkori agykárosodásban. Kimutattuk, hogy a PACAP csökkenti a dopaminerg sejtpusztulást a substantia nigrában és jelentősen javítja a neurológiai tüneteket patkány Parkinson kór modellben. Leírtuk az unilaterális substantia nigra roncsolás modell és ebben a PACAP protektív hatásainak kor és nemfüggését. Igazoltuk a PACAP védő hatását Huntington chorea, neurotrauma modellekben, valamint toxicus és ischemiás retinadegenerációban. Igazoltuk, hogy a PACAP nemcsak neuroprotektív, hanem általános citoprotektív tulajdonságú: védő hatást fejt ki szívizom-és endothelsejtekben, vese és bélischemiában. A hatásmechanizmust tekintve igazoltuk, hogy ezen rendszerekben a PACAP antiapoptotikus tulajdonságú, in vitro és in vivo gátolja a proapoptotikus és aktiválja az antiapoptotikus jelátviteli útvonalakat. Eddig nem ismert jelátviteli útvonalak igazolásán kívül leírtuk, hogy a PACAP hatása jelentős különbségeket mutat a kor, nem, napi ritmus és sejttípustól függően. Újszülöttkori léziókban (toxicus, hypoxiás) leírtuk a kora postnatalis neuronális fejlődést, és kimutattuk a PACAP védő hatását bizonyos reflexfejlődési mintázatra. A támogatás segítségével született közlemények összesített impakt faktora 139,807 (absztraktok nélkül). | We continued the investigation on the neuroprotective effects of PACAP. The focus of our research was to examine the neuroprotective effects in models of basal ganglia diseases and neonatal brain injuries. We showed that PACAP treatment ameliorates the substantia nigra dopaminergic cell loss and improves the neurological deficits in a model of Parkinson`s disease. We examined how this unilateral substantia nigra degeneration model and the effects of PACAP depend on age and gender. We have provided evidence that PACAP is also protective in models of Huntington chorea, brain trauma, toxic and ischemic retinal degeneration. We have also shown that PACAP is not only neuroprotective, but is a general cytoprotective peptide: it has protective effects in cardiomyocytes, endothelial cells, kidney and intestinal ischemia. Considering the neuroprotective mechanism, we showed that PACAP has antiapoptotic effects in these models, it activates the antiapoptotic and inhibits the proapoptotic signaling pathways both in vitro and in vivo. In addition to providing evidence for new neuroprotective signaling mechanisms, we also showed that the protective effects of PACAP depend on age, gender, diurnal cycle and cell type.We described the early postnatal neurobehavioral development in toxic and hypoxic injuries and the protective effects of PACAP on some neurological reflexes. The impact factor of the publications with the help of this grant is 139.807 (without abstracts)

Mesenchymal Stromal Cell derived Extracellular Vesicles reduce Hypoxia-Ischaemia Induced Perinatal Brain Injury

Background: Neonatal hypoxic ischemic (HI) insult is a leading cause of disability and death in newborns, with therapeutic hypothermia being the only currently available clinical intervention. Thus there is a great need for adjunct and novel treatments for enhanced or alternative post-HI neuroprotection. Extracellular vesicles (EVs) derived from mesenchymal stromal/stem cells (MSCs) have recently been shown to exhibit regenerative effects in various injury models. Here we present findings showing neuroprotective effects of MSC-derived EVs in the Rice-Vannucci model of severe HI-induced neonatal brain insult. Method: MSC-derived EVs were applied intranasally immediately post HI-insult and behavioural outcomes were observed 48 h following MSC-EV treatment, as assessed by negative geotaxis. Brains were thereafter excised and assessed for changes in glial responses, cell death and neuronal loss as markers of damage at 48 h post HI-insult. Results: Brains of the MSC-EV treated group showed a significant decrease in microglial activation, cell death and percentage tissue volume loss in multiple brain regions, compared to the control-treated groups. Furthermore, negative geotaxis test showed improved behavioural outcomes at 48 h following MSC-EV treatment. Conclusion: Our findings highlight the clinical potential of using MSC-derived EVs following neonatal hypoxia-ischaemia

A felnőttkori káros szerhasználat összefüggése a felnőttkori negatív életeseményekkel, a traumatizált gyermekkorral és a pszichológiai immunrendszerrel

INST: L_135Kutatásunk célja feltérképezni a gyermekkori traumák, a felnőttkori negatív életesemények és a pszichológiai immunrendszer kapcsolatát a felnőttkori káros szerhasználattal

Time-course of the regeneration of the earthworm cerebral ganglion with special reference to serotonergic elements.

In the present study we give a detailed description of the time-course of regeneration following the removal of the cerebral ganglion in the earthworm, Eisenia fetida . Cerebral ganglia were removed by cutting the circumpharyngeal connectives and regeneration was examined at different time intervals by serotonin immunohistochemistry. The number of serotonergic fibers gradually increased between days 3-6, rebuilding the neuronal network of the cerebral ganglion. By day 10, the scar tissue was filled with an interwoven fiber network, which clearly outlined the central neuropil of the cerebral ganglion. The first immunoreactive nerve cells appeared on the 25th day following the removal of the cerebral ganglion. According to our observations, the cerebral ganglion regains its original structure 70 days after removal. It can be suggested based on our results that the cerebral ganglion mainly regenerates from the subesophageal ganglion through the circumpharyngeal connective

Memory, cAMP, and PACAP-a phylogenetically conserved function? Studies in Lymnea stagnalis

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a highly conserved polypeptide, which, along with its receptors (PAC1-R, VPAC1, and VPAC2), is expressed in both vertebrate and invertebrate nervous systems. In the first part of the present study, we showed the presence of PACAP in Lymnea stagnalis by mass spectrometry and investigated whether PACAP elevates cAMP in cerebral ganglia. VIP, PACAP, and maxadilan increased cAMP levels by ~47, 79, and 82% of control levels, respectively, and this effect could be blocked by the co-application of the antagonist PACAP6-38 and maxadilan antagonist

Protective effects of pituitary adenylate cyclase activating polypeptide against neurotoxic agents

Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide highly expressed in the central and peripheral nervous system, where it exerts several neuromodulatory functions and is an important trophic and protective factor. PACAP has been shown to activate several protective pathways, mainly through its specific PAC1 receptor and protein kinase A, C and MAP kinases downstream. It has been shown to have very potent neuroprotective actions against different neurotoxic agents both in vitro and in vivo. The aim of the present review is to provide an overview on the neurotoxic injuries against which PACAP exerts protection, and to give an insight into its protective mechanism. We give a summary of the neuroprotective effects against the most commonly used neurotoxic agents, such as 6-OHDA, MPTP, glutamate and some less well-known neurotoxic compounds. Also endogenous PACAP has neuroprotective effects, known from studies in PACAP knockout mice or from blocking endogenous effects by antagonists. Altogether, the vast amount of data for the neuroprotective effects of PACAP give a firm background for its endogenous role as part of the neuroprotective machinery and its possible future therapeutic use as a neuroprotective factor