Szteroidok hatása a központi idegrendszeri neuronok aktivitására, plaszticitására, a kéreg reorganizációjára = The effects of steroids on the neural activity, plasticity and cortical reorganization of the CNS

A pályázat első évében sikeresen bevezettük a fokális agyi ischémia egyik modelljét a hidegléziót, és segítségével a dehidroepiandroszteron szulfát (DHEAS) és a 17béta-ösztradiol hatását vizsgáltuk. Mindkét szteroid szignifikánsan csökkentette a lézió nagyságát, és a DHEAS egyszeri alkalmazása utókezelésként is védőhatású volt. In vivo elektrofiziológiai kísérleteinkben a DHEAS-kezelés hatását vizsgáltuk az agykérgi kiváltott aktivitásra hideglézióval kombinálva. A hideglézió hatására nagyfokú és kiterjedt kérgi diszinhibíciót tapasztaltunk vizsgált kérgi területeken. A DHEAS-kezelés önmagában a kiváltott válaszok amplitúdójának nagyfokú növekedését eredményezte. A DHEAS és a hideglézió kombinációjakor a kérgi diszinhibíció nagymértékben lecsökkent, ezzel párhuzamosan a válaszok amplitúdóinak szórása is lecsökkent, és felgyorsult a recovery. A hideglézió során az érintett agyi régióban sérül a véragy-gát. Új módszerként leírtuk azt, hogy az Evans kékkel történő in situ festés alkalmas a penumbrában lévő sérült neuronok megjelölésére, és azok kvantitatív elemzésére. Globális ischémia (2VO) alkalmazása során elektrofiziológiai kísérletben leírtuk a Harlan és Charles River patkányok alapvetően különböző ischémiás toleranciáját a hippocampus CA1 régiójában. Kiegészítve legelső kísérletünket 5 mg/kg DHEAS valamint 4 és 40 mg/kg progeszteron protektív hatását teszteltük hidegléziós modellünkben: egyik esetben sem tapasztaltunk védőhatást. A progeszteron és THDOC a vizsgált koncentrációkban facilitálta a motoros kérgi mezőpotenciálokat in vitro elektrofiziológiai kísérleteinkben.. | During the first year of this grand we standardized the cortical cold lesion and tested with its help the neuroprotective effects of dehydroepiandrosterone sulfate (DHEAS) and 17beta-estradiol. Both steroids were effective, even as a single posttraumatic administration. In in vivo electrophysiological experiments the effects of peripherally administered DHEAS were studied on the evoked cortical potentials in combination with cold lesion. DHEAS administration resulted in an increase in amplitudes. After focal cold lesion a high level of disinhibition in extended cortical areas were seen. In the course of combined intervention the disinhibition was decreased and the recovery period of cortical responses was significantly shorter. Cold lesion causes enhanced permeability of the blood-brain barrier. As a new method it was described that in situ administration of Evans blue is a suitable tool for detecting injured neurons in the perilesion rim. During global cerebral ischemia (2VO) we described the extremely high difference in the ischemic tolerance within Wistar rats (Harlan vs Charles River). These observations draw attention to the importance of the careful choice of the laboratory rats. In a comparative study the lower doses of DHEAS treatment (5 mg/kg) and 4 and 40 mg/kg progesterone treatment were studied: no neuroprotection was seen in the cold lesion model. Progesterone and tetrahydrodesoxycorticosterone (THDOC) facilitated the motor cortical fEPSPs in the studied concentrations in our in vitro electrophysiological experiments

Use of a recombinant pseudorabies virus to analyze motor cortical reorganization after unilateral facial denervation

A unilateral facial nerve injury (n7x) was found to influence the transcallosal spread of the attenuated strain of pseudorabies virus (PRV Bartha) from the affected (left) primary motor cortex (MI) to the contralateral MI of rats. We used Ba-DupLac, a recombinant PRV strain, for the tracing experiments since this virus was demonstrated to exhibit much more restricted transportation kinetics than that of PRV Bartha, and is therefore more suitable for studies of neuronal plasticity. Ba-Duplac injection primarily infected several neurons around the penetration channel, but hardly any transcallosally infected neurons were observed in the contraleral MI. In contrast, after right facial nerve injury, Ba-DupLac was transported from the primarily infected neurons in the left MI to the contralateral side, and resulted in the labeling of several neurons due to a transneuronal infection. These results reveal that a peripheral nerve injury induces changes in the Ba-DupLac infection pattern in the related cortical areas. These findings and the literature data suggest that this phenomenon may be related to the changes in the expression or to the redistribution of cell-adhesion molecules, which are known to facilitate the entrance and/or transmission of PRV into neurons

Idegi plaszticitás és neuroprotekció lehetőségeinek kutatása triptofán metabolitokkal és származékaikkal = Neuronal plasticity and neuronal protection - research with triptophan-metabolites and conjugates

A pályázati támogatás olyan neuroprotekciós eljárások, anyagok kidolgozását szolgálta, mely ischemiás állapotok, traumák után fellépő hiperexcitáció csökkentésével mérsékli az ilyenkor fellépő másodlagos sejtpusztulást. A triptofán egyik metabolitja a kinurénsav (KYNA), mely az NMDA receptorok természetes inhibitoraként viselkedik a NMDA receptorokhoz kapcsolódva. A KYNA azonban nem megy át a vér-agy gáton, viszont előanyaga a kinurenin (KYN) igen. Kidolgoztunk egy módszert, melyben a KYN-t (300 mg/kg, i.p.) probeneciddel (PROB, 200 mg/kg, i.p.) együtt adva, oly mértékig meg tudjuk emelni a KYNA szintet az agyban, hogy az hatékonyan képes gátolni az agyi sérüléseket követő hiperexcitációt. Ezzel a módszerrel hatékony neuroprotekciót értünk el focalis és globalis agyi ischemiában, pentylentetrazollal (PTZ) kiváltott görcstevékenységben, de még migrén modellben is. Kifejlesztettünk két további kinurénsav származékot, a glukozamin-kinurénsavat (KYNA-NH-GLUC) és az SZR-72-nek nevezett szert, melyek szintén hatékony neuroprotektív anyagok, ugyanakkor átjutnak a vér-agy gáton, tehát szisztémásan is adhatók. Kísérleti körülmények között tehát hatékony neuroprotektív eljárást dolgoztunk ki, és hatékony anyagokat állítottunk elő. Továbbá, kimutattuk a KYNA-ról, hogy Janus-arcú, mert gátló hatása mellett, amit ?M-os koncentrációban fejt ki, ennél jóval alacsonyabb koncentrációban (200-250 nM) serkentő hatású. Mindez felveti a KYNA lehetséges neuromodulátor szerepét. | The aim of this project was to develop neuroprotective agents and protocols, which are able to reduce the late neuronal death following ischemic brain attack or brain trauma. The kynurenine pathway converts tryptophan into various compounds, including L-kynurenine (KYN), which in turn can be converted into the excitatory amino acid receptor (namely NMDA receptor) antagonist kynurenic acid (KYNA). The use of KYNA as a neuroprotective agent is rather restricted, however, because KYNA has only a very limited ability to cross the blood-brain barrier. In contrast, KYN crosses this barrier more readily. We have developed a protocol in which KYN (300 mg/kg, i.p.) administration together with probenedid (PROB, 200 mg/kg, i.p.), an organic acid transport blocker, led to significant neuroprotection in both focal and global brain ischemia, in traumatic brain attack, in migraine, and led to the inhibition of pentylenetetrazole (PTZ)-induced seizures. In addition, we have developed two kynurenic acid derivatives; glucosamine-kynurenic acid (KYNA-NH-GLUC) and SZR-72. Both of them cross the blood-brain barrier easily, and are neuroprotective agents. In addition to these experimental results, we have shown that KYNA is a Janus-faced agent, which in ?M concentration behaves as a neuroinhibitor, while in nM concentration, it stimulates the neuronal activity. This result suggests that KYNA might be play a role of a neuromodulator in the central nervoussystem

Gender-Specific Degeneration of Dementia-Related Subcortical Structures Throughout the Lifespan

Age-related changes in brain structure are a question of interest to a broad field of research. Structural decline has been consistently, but not unambiguously, linked to functional consequences, including cognitive impairment and dementia. One of the areas considered of crucial importance throughout this process is the medial temporal lobe, and primarily the hippocampal region. Gender also has a considerable effect on volume deterioration of subcortical grey matter (GM) structures, such as the hippocampus. The influence of age×gender interaction on disproportionate GM volume changes might be mediated by hormonal effects on the brain. Hippocampal volume loss appears to become accelerated in the postmenopausal period. This decline might have significant influences on neuroplasticity in the CA1 region of the hippocampus highly vulnerable to pathological influences. Additionally, menopause has been associated with critical pathobiochemical changes involved in neurodegeneration. The micro- and macrostructural alterations and consequent functional deterioration of critical hippocampal regions might result in clinical cognitive impairment-especially if there already is a decline in the cognitive reserve capacity. Several lines of potential vulnerability factors appear to interact in the menopausal period eventually leading to cognitive decline, mild cognitive impairment, or Alzheimer's disease. This focused review aims to delineate the influence of unmodifiable risk factors of neurodegenerative processes, i.e., age and gender, on critical subcortical GM structures in the light of brain derived estrogen effects. The menopausal period appears to be of key importance for the risk of cognitive decline representing a time of special vulnerability for molecular, structural, and functional influences and offering only a narrow window for potential protective effects. © 2017 - IOS Press and the authors

Epstein-Barr virus encephalitis mimicking clinical and electroencephalographic characteristics of herpes simplex encephalitis.

A rare case of EBV encephalitis initially diagnosed as Herpes simplex infection is presented to highlight the importance of EBV specific intrathecal ELISA and liquor PCR based differential diagnosis when Herpes simplex encephalitis specific clinical symptoms, neuroimaging signs and electroencephalographic features are present. The case report also suggests that acyclovir treatment might be beneficial for the long term outcome in adult EBV encephalitis patients

Facial nerve injury induces facilitation of responses in both trigeminal and facial nuclei of rat

Astudywasmade of the effects of facial nerve transection on trigeminal stimulation- evoked field potentials in the principal trigeminal (Pr5) and facial nuclei (7) in rats. Although the transected branch of the facial nerve contains puremotoric efferents, it resulted in enhanced responses in both Pr5 and 7. These electrophysiological results suggest a functional circuitry involving thewhiskers, trigeminal nerve, Pr5 and 7 and the facial nerve as efferent. The disconnection (opening) of this loop results in enhanced responsiveness of the neurons in both Pr5 and 7

The modulatory effect of estrogen on the neuronal activity in the barrel cortex of the rat. An electrophysiological study

In acute experiments, the effects of iontophoretically applied 17 beta -estradiol hemisuccinate on the activity of the primary somatosensory cortical neurons were studied in ovariectomized rats by extracellular single-unit recording. 17 beta -Estradiol increased both the spontaneous and the vibrissa deflection-evoked responses, with an average latency of 24 min. It is suggested that this relatively long latency of the 17 beta -estradiol effect is based not so much on membrane mechanisms as on genomic mechanism