Miracle-dz/UniFAR-FTUs huggingface dataset:
CaMKII activity is essential for improvement of memory‐related behaviors by chronic rivastigmine treatment

Because the cholinergic system is down‐regulated in the brain of Alzheimer's disease patients, cognitive deficits in Alzheimer's disease patients are significantly improved by rivastigmine treatment. To address the mechanism underlying rivastigmine‐induced memory improvements, we chronically treated olfactory bulbectomized (OBX) mice with rivastigmine. The chronic rivastigmine treatments for 12–13 days starting at 10 days after OBX operation significantly improved memory‐related behaviors assessed by Y‐maze task, novel object recognition task, passive avoidance task, and Barnes maze task, whereas the single rivastigmine treatment failed to improve the memory. Consistent with the improved memory‐related behaviors, long‐term potentiation in the hippocampal CA1 region was markedly restored by rivastigmine treatments. In immunoblotting analyses, the reductions of calcium/calmodulin‐dependent protein kinase II (CaMKII) autophosphorylation and calcium/calmodulin‐dependent protein kinase IV (CaMKIV) phosphorylation in the CA1 region in OBX mice were significantly restored by rivastigmine treatments. In addition, phosphorylation of AMPAR subunit glutamate receptor 1 (GluA1) (Ser‐831) and cAMP‐responsive element‐binding protein (Ser‐133) as downstream targets of CaMKII and CaMKIV, respectively, in the CA1 region was also significantly restored by chronic rivastigmine treatments. Finally, we confirmed that rivastigmine‐induced improvements of memory‐related behaviors and long‐term potentiation were not obtained in CaMKIIα+/− mice. On the other hand, CaMKIV−/− mice did not exhibit the cognitive impairments. Taken together, the stimulation of CaMKII activity in the hippocampus is essential for rivastigmine‐induced memory improvement in OBX mice.
Triheptanoin partially restores levels of tricarboxylic acid cycle intermediates in the mouse pilocarpine model of epilepsy

Triheptanoin, the triglyceride of heptanoate, is anticonvulsant in various epilepsy models. It is thought to improve energy metabolism in the epileptic brain by re‐filling the tricarboxylic acid (TCA) cycle with C4‐intermediates (anaplerosis). Here, we injected mice with [1,2‐13C]glucose 3.5–4 weeks after pilocarpine‐induced status epilepticus (SE) fed either a control or triheptanoin diet. Amounts of metabolites and incorporations of 13C were determined in extracts of cerebral cortices and hippocampal formation and enzyme activity and mRNA expression were quantified. The percentage enrichment with two 13C atoms in malate, citrate, succinate, and GABA was reduced in hippocampal formation of control‐fed SE compared with control mice. Except for succinate, these reductions were not found in triheptanoin‐fed SE mice, indicating that triheptanoin prevented a decrease of TCA cycle capacity. Compared to those on control diet, triheptanoin‐fed SE mice showed few changes in most other metabolite levels and their 13C labeling. Reduced pyruvate carboxylase mRNA and enzyme activity in forebrains and decreased [2,3‐13C]aspartate amounts in cortex suggest a pyruvate carboxylation independent source of C‐4 TCA cycle intermediates. Most likely anaplerosis was kept unchanged by carboxylation of propionyl‐CoA derived from heptanoate. Further studies are proposed to fully understand triheptanoin's effects on neuroglial metabolism and interaction.
Inhibition of Rho‐kinase protects cerebral barrier from ischaemia‐evoked injury through modulations of endothelial cell oxidative stress and tight junctions

Ischaemic strokes evoke blood–brain barrier (BBB) disruption and oedema formation through a series of mechanisms involving Rho‐kinase activation. Using an animal model of human focal cerebral ischaemia, this study assessed and confirmed the therapeutic potential of Rho‐kinase inhibition during the acute phase of stroke by displaying significantly improved functional outcome and reduced cerebral lesion and oedema volumes in fasudil‐ versus vehicle‐treated animals. Analyses of ipsilateral and contralateral brain samples obtained from mice treated with vehicle or fasudil at the onset of reperfusion plus 4 h post‐ischaemia or 4 h post‐ischaemia alone revealed these benefits to be independent of changes in the activity and expressions of oxidative stress‐ and tight junction‐related parameters. However, closer scrutiny of the same parameters in brain microvascular endothelial cells subjected to oxygen–glucose deprivation ± reperfusion revealed marked increases in prooxidant NADPH oxidase enzyme activity, superoxide anion release and in expressions of antioxidant enzyme catalase and tight junction protein claudin‐5. Cotreatment of cells with Y‐27632 prevented all of these changes and protected in vitro barrier integrity and function. These findings suggest that inhibition of Rho‐kinase after acute ischaemic attacks improves cerebral integrity and function through regulation of endothelial cell oxidative stress and reorganization of intercellular junctions.
Macrophages and CNS remyelination

Microglia are the resident macrophages of the central nervous system that survey the microenvironment for signals of injury or infection. The response to such signals induces an inflammatory response involving macrophages derived from both resident microglia and recruited circulating monocytes. Although implicated as contributors to autoimmune‐mediated injury, microglia/ macrophages have recently been shown to be critical for the important central nervous system regenerative process of remyelination. This functional dichotomy may reflect their ability to be polarized along a continuum of activation states including the well‐characterized cytotoxic M1 and regenerative M2 phenotypes. Here, we review the roles of microglia, monocytes and the macrophages which they give rise to in creating lesion environments favourable to remyelination, highlighting the specific roles of M1 and M2 phenotypes and how the pro‐regenerative role of the innate immune system is altered by ageing.
Relationships between serotonergic and cannabinoid system in depressive‐like behavior: a PET study with [11C]‐DASB

Chronic stress represents a major environmental risk factor for mood disorders in vulnerable individuals. The neurobiological mechanisms underlying these disorders involve serotonergic and endocannabinoid systems. In this study, we have investigated the relationships between these two neurochemical systems in emotional control using genetic and imaging tools. CB1 cannabinoid receptor knockout mice (KO) and wild‐type littermates (WT) were exposed to chronic restraint stress. Depressive‐like symptoms (anhedonia and helplessness) were produced by chronic stress exposure in WT mice. CB1 KO mice already showed these depressive‐like manifestations in non‐stress conditions and the same phenotype was observed after chronic restraint stress. Chronic stress similarly impaired long‐term memory in both genotypes. In addition, brain levels of serotonin transporter (5‐HTT) were assessed using positron emission tomography. Decreased brain 5‐HTT levels were revealed in CB1 KO mice under basal conditions, as well as in WT mice after chronic stress. Our results show that chronic restraint stress induced depressive‐like behavioral alterations and brain changes in 5‐HTT levels similarly to those revealed in CB1 KO mice in non‐stressed conditions. These results underline the relevance of chronic environmental stress on serotonergic and endocannabinoid transmission for the development of depressive symptoms.
HIV‐1 protein Tat produces biphasic changes in NMDA‐evoked increases in intracellular Ca2+ concentration via activation of Src kinase and nitric oxide signaling pathways

HIV‐associated neurocognitive disorders afflict about half of HIV‐infected patients. HIV‐infected cells shed viral proteins, such as the transactivator of transcription (Tat), which can cause neurotoxicity by over activation of NMDA receptors. Here, we show that Tat causes a time‐dependent, biphasic change in NMDA‐evoked increases in intracellular Ca2+ concentration ([Ca2+]i). NMDA‐evoked responses were potentiated following 2‐h exposure to Tat (50 ng/mL). Tat‐induced potentiation of NMDA‐evoked increases in [Ca2+]i peaked by 8 h and then adapted by gradually reversing to baseline by 24 h and eventually dropping below control by 48 h. Tat‐induced potentiation of NMDA‐evoked responses was blocked by inhibition of lipoprotein receptor‐related protein (LRP) or Src tyrosine kinase. Potentiation was unaffected by inhibition of nitric oxide synthase (NOS). However, NOS activity was required for adaptation. Adaptation was also prevented by inhibition of soluble guanylate cyclase (sGC) and cyclic guanosine monophosphate‐dependent protein kinase G (PKG). Together, these findings indicate that Tat potentiates NMDA‐evoked increases in [Ca2+]i via LRP‐dependent activation of Src and that this potentiation adapts via activation of the NOS/sGC/PKG pathway. Adaptation may protect neurons from excessive Ca2+ influx and could reveal targets for the treatment of HIV‐associated neurocognitive disorders.
Heat shock protein 70 induction by valproic acid delays photoreceptor cell death by N‐methyl‐N‐nitrosourea in mice

Retinal degenerative diseases (RDs) are a group of inherited diseases characterized by the loss of photoreceptor cells. Selective photoreceptor loss can be induced in mice by an intraperitoneal injection of N‐methyl‐N‐nitrosourea (MNU) and, because of its selectivity, this model is widely used to study the mechanism of RDs. Although it is known that calcium‐calpain activation and lipid peroxidation are involved in the initiation of cell death, the precise mechanisms of this process remain unknown. Heat shock protein 70 (HSP70) has been shown to function as a chaperone molecule to protect cells against environmental and physiological stresses. In this study, we investigated the role of HSP70 on photoreceptor cell death in mice. HSP70 induction by valproic acid, a histone deacetylase inhibitor, attenuated the photoreceptor cell death by MNU through inhibition of apoptotic caspase signals. Furthermore, HSP70 itself was rapidly and calpain‐dependently cleaved after MNU treatment. Therefore, HSP70 induction by valproic acid was dually effective against MNU‐induced photoreceptor cell loss as a result of its anti‐apoptotic actions and its ability to prevent HSP70 degradation. These findings might help lead us to a better understanding of the pathogenic mechanism of RDs.
Avaliação dos resultados da sinovectomia por via artroscópica do cotovelo em pacientes portadores de artrite reumatoide

OBJECTIVE: To review functional outcomes of arthroscopic elbow synovectomy in patients with rheumatoid arthritis. Methods: Between May 1999 and December 2005, 15 patients were submitted to elbow synovectomy using an arthroscopic approach. Three cases were bilateral, totaling 18 elbows. There were two male and 13 female patients. The mean age was 44 years and five months. The mean time of previous diagnosis was six years and eight months. All patients reported preoperative pain, and on seven elbows, instability was present. The mean preoperative values for joint motion were: flexion, 118o; extension, -24o, supine, 80o, and; prone, 71o. Result: The mean postoperative follow-up time was 39 months. The mean postoperative joint motion was 133o for flexion, -20o for extension, 84o supine, and 78o prone. On nine elbows (50%) an improved postoperative range of motion was reported, reaching functional levels. Twelve cases (66.6%) showed pain resolution or improvement to a level not interfering on the activities of daily life. According to Bruce's assessment method, the results were as follows: seven excellent, three good, two fair and six poor results, with an average of 85.5 points. Synovitis recurrence was found in six cases (33.3%), and evolution to osteoarthrosis was found in four (22.2%). CONCLUSION: Arthroscopic elbow synovectomy in patients with rheumatoid arthritis leads to pain improvement in 66.6% of the cases; however, it does not cause a significant range of motion improvement.
Research in the 1980s: World trends in physiotherapy research

A survey of the physiotherapy journals of five major English-speaking countries, namely Physiotherapy (UK), Physical Therapy (USA), Physiotherapy Canada, the Australian Journal of Physiotherapy and the South African Journal of Physiotherapy, was conducted to determine the current areas of, and trends in, physiotherapy research. The period reviewed was from 1980 to 1989. The greatest physiotherapy research interests were the musculoskeletal system/therapy and education/administration. The number of descriptive papers decreased and the number of experimental trials increased. There was an increase, too, in the use of statistical analyses of data. In all the journals reviewed, there was an increase in the number of first authors who were physiotherapists with higher academic qualifications. These findings suggest that there is an increased trend towards more scientifically based experimental trials in physiotherapy research and towards publishing articles written by more highly academically qualified physiot.
α‐synuclein‐induced mitochondrial dysfunction in isolated preparation and intact cells: Implications in the pathogenesis of Parkinson's disease

This study has shown that purified recombinant human α‐synuclein (20 μM) causes membrane depolarization and loss of phosphorylation capacity of isolated purified rat brain mitochondria by activating permeability transition pore complex. In intact SHSY5Y (human neuroblastoma cell line) cells, lactacystin (5 μM), a proteasomal inhibitor, causes an accumulation of α‐synuclein with concomitant mitochondrial dysfunction and cell death. The effects of lactacystin on intact SHSY5Y cells are, however, prevented by knocking down α‐synuclein expression by specific siRNA. Furthermore, in wild‐type (non‐transfected) SHSY5Y cells, the effects of lactacystin on mitochondrial function and cell viability are also prevented by cyclosporin A (1 μM) which blocks the activity of the mitochondrial permeability transition pore. Likewise, in wild‐type SHSY5Y cells, typical mitochondrial poison like antimycin A (50 nM) produces loss of cell viability comparable to that of lactacystin (5 μM). These data, in combination with those from isolated brain mitochondria, strongly suggest that intracellularly accumulated α‐synuclein can interact with mitochondria in intact SHSY5Y cells causing dysfunction of the organelle which drives the cell death under our experimental conditions. The results have clear implications in the pathogenesis of sporadic Parkinson's disease.
Molecular determinants of transport stimulation of EAAT2 are located at interface between the trimerization and substrate transport domains

Excitatory amino acid transporters (EAATs) regulate glutamatergic signal transmission by clearing extracellular glutamate. Dysfunction of these transporters has been implicated in the pathogenesis of various neurological disorders. Previous studies have shown that venom from the spider Parawixia bistriata and a purified compound (Parawixin1) stimulate EAAT2 activity and protect retinal tissue from ischemic damage. In the present study, the EAAT2 subtype specificity of this compound was explored, employing chimeric proteins between EAAT2 and EAAT3 transporter subtypes and mutants to characterize the structural region targeted by the compound. This identified a critical residue (Histidine‐71 in EAAT2 and Serine‐45 in EAAT3) in transmembrane domain 2 (TM2) to be important for the selectivity between EAAT2 and EAAT3 and for the activity of the venom. Using the identified residue in TM2 as a structural anchor, several neighboring amino acids within TM5 and TM8 were identified to also be important for the activity of the venom. This structural domain of the transporter lies at the interface of the rigid trimerization domain and the central substrate‐binding transport domain. Our studies suggest that the mechanism of glutamate transport enhancement involves an interaction with the transporter that facilitates the movement of the transport domain.
Multiple Forms of the Ehlers-Danlos Syndrome

The Ehlers-Danlos syndrome (or, as we shall attempt to emphasize here, the Ehlers-Danlos syndromes) is characterized mainly by changes in the joints and in the skin. The joint change is hyperextensibility, ie, loose-jointedness. The skin change is classically excessive stretchability, excessive bruisability, and excessive fragility. In the last ten years or so, many genetic disorders that in the past were considered to be a single entity have, on close scrutiny, been found to be a collection of two or more fundamentally distinct disorders. The Ehlers-Danlos syndrome is no exception to this experience. Today at least seven seemingly distinct forms of the Ehlers-Danlos syndrome can be recognized (Table), and this may well not exhaust the heterogeneity within this group. As with other categories of genetic disease, clinical features, genetic factors, and biochemical approaches have been used to distinguish the various forms. Of the three approaches, the biochemical one is the most
Regulation of peroxisome proliferator‐activated receptors (PPAR) α and ‐γ of rat brain astrocytes in the course of activation by toll‐like receptor agonists

Peroxisome proliferator‐activated receptors (PPAR)‐α and ‐γ in astrocytes play important roles in inflammatory brain pathologies. Understanding the regulation of both activity and expression levels of PPARs is an important neuroscience issue. Toll‐like receptor (TLR) agonists are inflammatory stimuli that could modulate PPAR, but the mechanisms of their control in astrocytes are poorly understood. In the present study, we report that lipopolysaccharide, peptidoglycan, and flagellin, which are agonists of TLR4, TLR1/2, and TLR5, respectively, exert time‐ and nuclear factor kappa‐light‐chain‐enhancer of activated B cells‐dependent suppression of mRNA, protein and activity of PPARα and PPARγ. In naïve astrocytes, PPARα and PPARγ mRNA have short turnover time (half‐life about 30 min for PPARα, 75 min for PPARγ) with a nearly two‐fold stabilization after TLR‐activation. p38 inhibition abolished TLR‐induced stabilization. The levels of PPARα and PPARγ mRNA, and protein and DNA‐binding activity could be modified using c‐Jun N‐terminal Kinase and p38 inhibitors. In addition, the expression levels of both PPARα and PPARγ isotypes were induced after inhibition of protein synthesis. This induction signifies participation of additional regulatory proteins with short life‐time. They are p38‐sensitive for PPARα and c‐Jun N‐terminal Kinase‐sensitive for PPARγ. Thus, PPARα and PPARγ are regulated in astrocytes on mRNA and protein levels, mRNA stability, and DNA‐binding activity during TLR‐mediated responses. Astrocytes have the triad of PPARα, PPARβ/δ, and PPARγ in regulation of proinflammatory responses. Activation of Toll‐like receptors (TLR) leads to PPARβ/δ overexpression, PPARα and PPARγ suppression via TLR/NF‐κB pathway on mRNA, protein and activity levels. Mitogen‐activated protein kinases (MAPK) p38 and JNK are involved in regulation of PPAR expression. p38 MAPK plays a special role in stabilization of PPAR mRNA.
Nicotine administration in the wake‐promoting basal forebrain attenuates sleep‐promoting effects of alcohol

Nicotine and alcohol co‐abuse is highly prevalent, although the underlying causes are unclear. It has been suggested that nicotine enhances pleasurable effects of alcohol while reducing aversive effects. Recently, we reported that nicotine acts via the basal forebrain (BF) to activate nucleus accumbens and increase alcohol consumption. Does nicotine suppress alcohol‐induced aversive effects via the BF? We hypothesized that nicotine may act via the BF to suppress sleep‐promoting effects of alcohol. To test this hypothesis, adult male Sprague–Dawley rats were implanted with sleep‐recording electrodes and bilateral guides targeted toward the BF. Nicotine (75 pmol/500 nL/side) or artificial cerebrospinal fluid (ACSF; 500 nL/side) was microinjected into the BF followed by intragastric alcohol (ACSF + EtOH and NiC + EtOH groups; 3 g/kg) or water (NiC + W and ACSF + W groups; 10 mL/kg) administration. On completion, rats were killed and processed to localize injection sites in the BF. The statistical analysis revealed a significant effect of treatment on sleep‐wakefulness. While rats exposed to alcohol (ACSF + EtOH) displayed strong sleep promotion, nicotine pre‐treatment in the BF (NiC + EtOH) attenuated alcohol‐induced sleep and normalized sleep‐wakefulness. These results suggest that nicotine acts via the BF to suppress the aversive, sleep‐promoting effects of alcohol, further supporting the role of BF in alcohol‐nicotine co‐use.
Elevated dopamine concentration in light‐adapted zebrafish retinas is correlated with increased dopamine synthesis and metabolism

Probing zebrafish (Danio rerio) retinal cryostat sections, collected either 8 h into the light or dark cycle, with an antibody against tyrosine hydroxylase (TH) identified a single population of immunopositive cells in the inner retina. However, the observed labeling patterns were not identical in both sets of tissues – label intensity was brighter in light‐adapted tissue. This difference was quantified by probing western blots of retinal homogenates with the same TH antibody, which showed that TH expression increased by 42% in light‐adapted tissue. High‐performance liquid chromatography with electrochemical detection revealed that the concentrations of both dopamine and 3,4‐dihydroxyphenylacetic acid (DOPAC) are also elevated in light‐adapted zebrafish retinal tissue. Dopamine levels increased by 14% and DOPAC levels increased by 25% when measured in retinal homogenates harvested during the light cycle. These results indicate that dopamine levels in zebrafish retina are significantly increased in light‐adapted tissue. The increase in dopamine content is correlated with an increase in both TH and DOPAC, suggesting that changes in dopamine concentration are due to light‐adaptive changes in the synthesis, release and metabolism of dopamine.
Signaling pathways regulating neuron–glia interaction and their implications in Alzheimer's disease

Astrocytes are the most abundant cells in the central nervous system. They play critical roles in neuronal homeostasis through their physical properties and neuron–glia signaling pathways. Astrocytes become reactive in response to neuronal injury and this process, referred to as reactive astrogliosis, is a common feature accompanying neurodegenerative conditions, particularly Alzheimer's disease. Reactive astrogliosis represents a continuum of pathobiological processes and is associated with morphological, functional, and gene expression changes of varying degrees. There has been a substantial growth of knowledge regarding the signaling pathways regulating glial biology and pathophysiology in recent years. Here, we attempt to provide an unbiased review of some of the well‐known players, namely calcium, proteoglycan, transforming growth factor β, NFκB, and complement, in mediating neuron–glia interaction under physiological conditions as well as in Alzheimer's disease.