Stroke is a devastating cerebrovascular pathology with high morbidity and mortality. Inflammation plays a central role in the pathophysiology of stroke. Vagus nerve stimulation (VNS) is a promising immunomodulatory method that has shown positive effects in stroke treatment, including neuroprotection, anti-apoptosis, anti-inflammation, antioxidation, reduced infarct volume, improved neurological scores, and promotion of M2 microglial polarization. In this review, we summarize the current knowledge about the vagus nerve's immunomodulatory effects through the cholinergic anti-inflammatory pathway (CAP) and provide a comprehensive assessment of the available experimental literature focusing on the use of VNS in stroke treatment.
Alzheimer's disease (AD) is characterised by the accumulation of intracytoplasmic aggregates of tau protein, which are suggested to spread in a prion-like manner between interconnected brain regions. This spreading is mediated by the secretion and uptake of tau from the extracellular space or direct cell-to-cell transmission through cellular protrusions. The prion-like tau then converts the endogenous, normal tau into pathological forms, resulting in neurodegeneration. The endoplasmic reticulum/Golgi-independent tau secretion through unconventional secretory pathways involves delivering misfolded and aggregated tau to the plasma membrane and its release into the extracellular space by non-vesicular and vesicular mechanisms. Although cytoplasmic tau was thought to be released only from degenerating cells, studies now show that cells constitutively secrete tau at low levels under physiological conditions. The mechanisms of secretion of tau under physiological and pathological conditions remain unclear. Therefore, a better understanding of these pathways is essential for developing therapeutic approaches that can target prion-like tau forms to prevent neurodegeneration progression in AD. This review focuses on unconventional secretion pathways involved in the spread of tau pathology in AD and presents these pathways as prospective areas for future AD drug discovery and development.
- MeSH
- Alzheimerova nemoc metabolismus patologie MeSH
- lidé MeSH
- mezibuněčná komunikace fyziologie MeSH
- mozek metabolismus patologie MeSH
- patologická konformace proteinů metabolismus patologie MeSH
- proteiny tau metabolismus MeSH
- tauopatie metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Regeneration capacity is reduced as CNS axons mature. Using laser-mediated axotomy, proteomics and puromycin-based tagging of newly-synthesized proteins in a human embryonic stem cell-derived neuron culture system that allows isolation of axons from cell bodies, we show here that efficient regeneration in younger axons (d45 in culture) is associated with local axonal protein synthesis (local translation). Enhanced regeneration, promoted by co-culture with human glial precursor cells, is associated with increased axonal synthesis of proteins, including those constituting the translation machinery itself. Reduced regeneration, as occurs with the maturation of these axons by d65 in culture, correlates with reduced levels of axonal proteins involved in translation and an inability to respond by increased translation of regeneration promoting axonal mRNAs released from stress granules. Together, our results provide evidence that, as in development and in the PNS, local translation contributes to CNS axon regeneration.
- MeSH
- axony fyziologie MeSH
- embryonální kmenové buňky fyziologie MeSH
- kokultivační techniky MeSH
- lidé MeSH
- proteosyntéza fyziologie MeSH
- regenerace nervu fyziologie MeSH
- stárnutí buněk fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Regeneration after spinal cord injury is a goal of many studies. Although the most obvious target is to recover motor function, restoration of sensation can also improve the quality of life after spinal cord injury. For many patients, recovery of sensation in the perineal and genital area is a high priority. Currently there is no experimental test in rodents for measuring changes in sensation in the perineal and genital area after spinal cord injury. The aim of our study was to develop a behavioural test for measuring the sensitivity of the perineal and genital area in rats. We have modified the tape removal test used routinely to test sensorimotor deficits after stroke and spinal cord injury to test the perineal area with several variations. A small piece of tape (approximately 1 cm2) was attached to the perineal area. Time to first contact and to the removal of the tape was measured. Each rat was trained for 5 consecutive days and then tested weekly. We compared different rat strains (Wistar, Sprague-Dawley, Long-Evans and Lewis), both genders, shaving and non-shaving and different types of tape. We found that the test was suitable for all tested strains, however, Lewis rats achieved the lowest contact times, but this difference was significant only for the first few days of learning the task. There were no significant differences between gender and different types of tape or shaving. After training the animals underwent dorsal column lesion at T10 and were tested at day 3, 8, 14 and 21. The test detected a sensory deficit, the average time across all animals to sense the stimulus increased from 1'32 up to 3'20. There was a strong relationship between lesion size and tape detection time, and only lesions that extended laterally to the dorsal root entry zone produced significant sensory deficits. Other standard behavioural tests (BBB, von Frey, ladder and Plantar test) were performed in the same animals. There was a correlation between lesion size and deficit for the ladder and BBB tests, but not for the von Frey and Plantar tests. We conclude that the tape removal test is suitable for testing perineal sensation in rats, can be used in different strains and is appropriate for monitoring changes in sensation after spinal cord injury.
- MeSH
- adaptace psychologická * MeSH
- chování zvířat MeSH
- druhová specificita MeSH
- fyzikální stimulace MeSH
- krysa rodu rattus MeSH
- kůže zranění MeSH
- perineum zranění fyziologie MeSH
- pohlavní orgány zranění MeSH
- poranění míchy psychologie MeSH
- poruchy senzitivity etiologie psychologie MeSH
- potkani inbrední LEW MeSH
- potkani Long-Evans MeSH
- potkani Sprague-Dawley MeSH
- potkani Wistar MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
We have demonstrated previously that activation of either the ETA or ETB receptor can induce acute electrographic seizures following the intrahippocampal infusion of endothelin-1 (ET-1) in immature (P12) rats. We also demonstrated that activation of the ETA receptor is associated with marked focal ischemia, while activation of the ETB receptor is not. Exploring the mechanisms underlying seizures induced by these two ET-1 receptor interactions can potentially provide insight into how focal ischemia in immature animals produces seizures and whether ischemiarelated seizures differ from seizures not associated with ischemia. To explore these seizure mechanisms we used microdialysis to determine biomarkers associated with seizures in P12 rats following the intrahippocampal infusion of two different agents: (1) ET-1, which activates both the ETA and ETB receptors and causes focal ischemia and (2) Ala-ET-1, which selectively activates only the ETB receptor and does not cause ischemia. Our results show that seizures associated with combined ETA and ETB receptor activation (and ischemia) have a different temporal distribution and microdialysis profile from seizures associated with ETB activation alone (and without ischemia). Seizures with combined activation peak within the first hour after infusion and the microdialysis profile is characterized by a significant increase in the ratio of glutamic acid to GABA. By contrast, seizures with activation of only the ETB receptor peak in the second hour after infusion and microdialysis shows a significant increase in the ratio of leukotriene B4 to prostaglandin E2. These findings suggest that ischemia-related seizures in immature animals involve an imbalance of excitation and inhibition, while non-ischemiarelated seizures involve an inflammatory process resulting from an excess of leukotrienes.
- MeSH
- endotelin-1 toxicita MeSH
- hipokampus účinky léků metabolismus MeSH
- ischemie mozku chemicky indukované metabolismus MeSH
- krysa rodu rattus MeSH
- potkani Wistar MeSH
- receptor endotelinu A metabolismus MeSH
- receptor endotelinu B metabolismus MeSH
- záchvaty chemicky indukované metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Epilepsy, the most common neurologic disorder in childhood, is associated with a subset of psychiatric dysfunctions, including cognitive deficits, and alterations in emotionality (e.g., anxiety and depression) and social functioning. In the present study, we evaluated an integrative set of behavioral responses, including cognitive/socio-cognitive and emotional dimensions, using a number of behavioral paradigms in the LiCl/pilocarpine model of status epilepticus (SE) in rats. The aims of the study were to examine whether SE affects: 1) non-associative learning (habituation of exploratory behavior); 2) investigatory response to an indifferent stimulus object; 3) sociability/social novelty preference; 4) social recognition or discrimination; and 4) short- and long-term memory in the Morris water maze (MWM). Finally, we investigated the morphology of key brain structures involved in the examined behavioral dysfunctions. SE did not affect habituation to an open-field arena in juvenile (P25), adolescent (P32), or adult (P80) rats. SE rats spent less time in the central part of the arena. SE adolescent rats (P32) displayed a higher number of rearings with a shorter duration. SE rats displayed a markedly attenuated investigatory response to an indifferent stimulus object. SE rats in all age groups demonstrated pronounced deficits in sociability and the preference for social novelty. In addition, SE rats spent a reduced amount of time investigating a juvenile rat upon first exposure. After 30 min re-exposure together with an additional, novel juvenile, the SE rats spent equal time investigating both juveniles. In the MWM task, acquisition was unimpaired but there was a deficit in delayed memory retention after 10 days. SE did not affect cognitive flexibility expressed by reversal learning. Together, these findings suggest that early-life SE leads to alterations in emotional/anxiety-related behavior and affects sociability/preference for social novelty and social discrimination. Early-life SE did not alter acquisition of spatial learning, but it impaired delayed retention. Using Fluoro Jade B staining performed 24 h after SE revealed apparent neurodegeneration in the dorsal hippocampus, mediodorsal thalamic nucleus and medial amygdala, brain areas that are critically involved in network underlying emotional behavior and cognitive functions.
- MeSH
- bludiště - učení fyziologie MeSH
- chování zvířat fyziologie MeSH
- epilepsie temporálního laloku patologie patofyziologie MeSH
- kognitivní poruchy patologie patofyziologie MeSH
- krysa rodu rattus MeSH
- mozek patologie patofyziologie MeSH
- potkani Wistar MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Ventral root avulsion (VRA) triggers a strong glial reaction which contributes to neuronal loss, as well as to synaptic detachment. To overcome the degenerative effects of VRA, treatments with neurotrophic factors and stem cells have been proposed. Thus, we investigated neuroprotection elicited by human embryonic stem cells (hESC), modified to overexpress a human fibroblast growth factor 2 (FGF-2), on motoneurons subjected to VRA. Lewis rats were submitted to VRA (L4-L6) and hESC/FGF-2 were applied to the injury site using a fibrin scaffold. The spinal cords were processed to evaluate neuronal survival, synaptic stability, and glial reactivity two weeks post lesion. Then, qRT-PCR was used to assess gene expression of β2-microglobulin (β2m), TNFα, IL1β, IL6 and IL10 in the spinal cord in vivo and FGF2 mRNA levels in hESC in vitro. The results indicate that hESC overexpressing FGF2 significantly rescued avulsed motoneurons, preserving synaptic covering and reducing astroglial reactivity. The cells were also shown to express BDNF and GDNF at the site of injury. Additionally, engraftment of hESC led to a significant reduction in mRNA levels of TNFα at the spinal cord ventral horn, indicating their immunomodulatory properties. Overall, the present data suggest that hESC overexpressing FGF2 are neuroprotective and can shift gene expression towards an anti-inflammatory environment.
- MeSH
- doxycyklin terapeutické užití MeSH
- fibrinová tkáňová adheziva toxicita MeSH
- fibroblastový růstový faktor 2 genetika metabolismus MeSH
- genetické vektory fyziologie MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- lidské embryonální kmenové buňky metabolismus transplantace MeSH
- míšní kořeny patologie MeSH
- modely nemocí na zvířatech MeSH
- motorické neurony metabolismus patologie MeSH
- neuroglie účinky léků metabolismus MeSH
- pohyb buněk MeSH
- potkani inbrední LEW MeSH
- proteiny nervové tkáně metabolismus MeSH
- radikulopatie chemicky indukované chirurgie MeSH
- regulace genové exprese účinky léků genetika MeSH
- tkáňová adheziva toxicita MeSH
- viabilita buněk účinky léků genetika MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
AMPA receptors (AMPARs) are responsible for fast excitatory neurotransmission, and their prolonged activation can result in the generation and spread of epileptic seizures. At early stages of postnatal development, the majority of AMPARs are permeable to both Na(+) and Ca(2+) ions. This permeability, which increases neuronal excitability, is due to the lack of the GluA2 subunit, encoded by the GRIA2A gene, and/or the presence of an unedited GluA2 subunit Q/R site (glutamine instead of arginine). Lithium chloride- and pilocarpine-induced status epilepticus (LiCl/Pilo-SE) in rodents represents a model of severe seizures that result in development of temporal lobe epilepsy (TLE). The aim of this study was to determine how LiCl/Pilo-SE induced early in life (at postnatal day 12; P12) alters normal expression of the GRIA2A gene and GluA2 protein. SE was interrupted by an injection of paraldehyde (Para). Control groups were 1) naïve animals, and 2) siblings of SE rats receiving only LiCl and paraldehyde (LiCl/Para). The expression profile of GRIA2A mRNA was determined via qPCR, and GluA2 protein levels were measured by western blotting. The analysis was performed at 3h (protein levels), and then 3-, 6-, 13-, and 60days, following LiCl/Pilo-SE or LiCl/Para injection (i.e. at P12, P15, P18, P25, P72 respectively). Six different brain regions were analyzed: frontal (CXFR), parietal (CXPAR), and occipital (CXOC) cortex, dorsal (HD) and ventral (HV) hippocampus, and thalamus (TH). There was a significant increase in GRIA2A mRNA expression in the CXFR, CXPAR, and CXOC of P18 SE animals. In CXFR and HD, increased expression of GluA2 AMPAR subunit protein was detected, as well as a surge in GRIA2A mRNA and GluA2 protein expression especially at P18. In HD the surge was detected not only during development (P18), but also later in life (P72). Since high levels of GluA2 can be neuroprotective (by decreasing Ca(2+) permeability), our data suggest that the neocortex and dorsal hippocampus are able to activate endogenous antiepileptic mechanisms. A marked decrease in the overall expression of GluA2 protein in the HV in the LiCl/Pilo-SE and LiCl/Para rats, suggests that the HV is predisposed to excitotoxicity, not only during development, but even in adulthood. Interestingly, LiCl in combination with paraldehyde can also strongly alter the normal ontogeny of GRIA2A mRNA as well as GluA2 subunit protein expression.
- MeSH
- AMPA receptory genetika metabolismus MeSH
- chlorid lithný toxicita MeSH
- fluoresceiny farmakokinetika MeSH
- konvulzíva toxicita MeSH
- krysa rodu rattus MeSH
- messenger RNA metabolismus MeSH
- modely nemocí na zvířatech MeSH
- mozek účinky léků růst a vývoj metabolismus MeSH
- novorozená zvířata MeSH
- pilokarpin toxicita MeSH
- potkani Wistar MeSH
- status epilepticus chemicky indukované metabolismus patologie MeSH
- věkové faktory MeSH
- vývojová regulace genové exprese účinky léků fyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Identifying the steps involved in striatal development is important both for understanding the striatum in health and disease, and for generating protocols to differentiate striatal neurons for regenerative medicine. The most prominent neuronal subtype in the adult striatum is the medium spiny projection neuron (MSN), which constitutes more than 85% of all striatal neurons and classically expresses DARPP-32. Through a microarray study of genes expressed in the whole ganglionic eminence (WGE: the developing striatum) in the mouse, we identified the gene encoding the transcription factor Forkhead box protein P1 (FoxP1) as the most highly up-regulated gene, thus providing unbiased evidence for the association of FoxP1 with MSN development. We also describe the expression of FoxP1 in the human fetal brain over equivalent gestational stages. FoxP1 expression persisted through into adulthood in the mouse brain, where it co-localised with all striatal DARPP-32 positive projection neurons and a small population of DARPP-32 negative cells. There was no co-localisation of FoxP1 with any interneuron markers. FoxP1 was detectable in primary fetal striatal cells following dissection, culture, and transplantation into the adult lesioned striatum, demonstrating its utility as an MSN marker for transplantation studies. Furthermore, DARPP-32 expression was absent from FoxP1 knock-out mouse WGE differentiated in vitro, suggesting that FoxP1 is important for the development of DARPP-32-positive MSNs. In summary, we show that FoxP1 labels MSN precursors prior to the expression of DARPP-32 during normal development, and in addition suggest that FoxP1 labels a sub-population of MSNs that are not co-labelled by DARPP-32. We demonstrate the utility of FoxP1 to label MSNs in vitro and following neural transplantation, and show that FoxP1 is required for DARPP-32 positive MSN differentiation in vitro.
- MeSH
- buněčná diferenciace fyziologie MeSH
- corpus striatum * cytologie embryologie růst a vývoj MeSH
- dopaminem a cAMP regulovaný fosfoprotein 32 metabolismus MeSH
- embryo savčí MeSH
- forkhead transkripční faktory genetika metabolismus MeSH
- jaderné proteiny metabolismus MeSH
- kultivované buňky MeSH
- myši knockoutované MeSH
- myši MeSH
- neparametrická statistika MeSH
- nervové kmenové buňky fyziologie transplantace MeSH
- neurony cytologie metabolismus MeSH
- novorozená zvířata MeSH
- plod cytologie MeSH
- proteiny nervové tkáně metabolismus MeSH
- represorové proteiny genetika metabolismus MeSH
- techniky in vitro MeSH
- transportní proteiny metabolismus MeSH
- vývojová regulace genové exprese fyziologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The period around birth is a risky time for stroke in infants, which is associated with two major acute and subacute processes: anatomical damage and seizures. It is unclear as to what extent each of these processes independently contributes to poor outcome. Furthermore, it is unclear whether there is an interaction between the two processes - does seizure activity cause additional brain damage beyond that produced by ischemia and/or does brain damage foster seizures? The model of focal cerebral ischemia induced by the intrahippocampal infusion of endothelin-1 (ET-1) in 12-day-old rat was used to examine the role of the endothelin receptors in the development of focal ischemia, symptomatic acute seizures and neurodegeneration. ET-1 (40pmol/μl) was infused either alone or co-administered with selective antagonists of ETA (BQ123; 70nmol/μl) or ETB receptors (BQ788; 70nmol/1μl). Effects of activation of ETB receptors were studied using selective agonist 4-Ala-ET-1 (40pmol/1μl). Regional cerebral blood flow (rCBF) and tissue oxygenation (pO2) were measured in anesthetized animals with a Doppler-flowmeter and a pO2-sensor, respectively. Seizure development was assessed with video-EEG in freely moving rats. Controls received the corresponding volume of the appropriate vehicle (10mM PBS or 0.01% DMSO-PBS solution; pH7.4). The extent of hippocampal lesion was determined using FluoroJade B staining performed 24h after ET-1 infusion. Infusion of ET-1 or ET-1+ETB receptor antagonist reduced rCBF to ~25% and pO2 to ~10% for about 1.5h, whereas selective ETB agonist, ET-1+ETA antagonist and the PBS vehicle had only negligible effect on the rCBF and pO2 levels. Reduction of rCBF was associated with the development of lesion in the injected hippocampus. In all groups, except sham operated and PBS controls, epileptiform activity was observed after activation of the ETA or the ETB receptors. The data revealed a positive correlation between the severity of morphological damage and all the measured seizure parameters (seizure frequency, average and total seizure duration) in the ET-1 group. In addition, the severity of morphological damage positively correlated with the average seizure duration in animals after infusion of ET-1+ETA receptor antagonist or after infusion of ET-1+ETB receptor antagonist. Our results indicate that the activation of ETA receptors is crucial for ischemia development, however either ETA or ETB receptors mediate the development of seizures following the application of ET-1 in immature rats. The dissociation between the ischemic-producing and seizure-producing processes suggests that damage is not necessary to induce seizures, although it may exacerbate them.
- MeSH
- elektroencefalografie * účinky léků MeSH
- endotelin-1 aplikace a dávkování toxicita MeSH
- hipokampus účinky léků metabolismus MeSH
- injekce intraventrikulární MeSH
- krysa rodu rattus MeSH
- potkani Wistar MeSH
- receptor endotelinu A agonisté metabolismus MeSH
- receptor endotelinu B agonisté metabolismus MeSH
- záchvaty chemicky indukované metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
