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Reelin, a large extracellular glycoprotein, plays critical roles in neuronal development and synaptic plasticity in the central nervous system (CNS). Recent studies have revealed non-neuronal functions of plasma Reelin in inflammation by promoting endothelial–leukocyte adhesion through its canonical pathway in endothelial cells (via ApoER2 acting on NF-κB), as well as in vascular tone regulation and thrombosis. In this study, we have investigated the safety and efficacy of selectively depleting plasma Reelin as a potential therapeutic strategy for chronic inflammatory diseases. We found that Reelin expression remains stable throughout adulthood and that peripheral anti-Reelin antibody treatment with CR-50 efficiently depletes plasma Reelin without affecting its levels or functionality within the CNS. Notably, this approach preserves essential neuronal functions and synaptic plasticity. Furthermore, in mice induced with experimental autoimmune encephalomyelitis (EAE), selective modulation of endothelial responses by anti-Reelin antibodies reduces pathological leukocyte infiltration without completely abolishing diapedesis. Finally, long-term Reelin depletion under metabolic stress induced by a Western diet did not negatively impact the heart, kidney, or liver, suggesting a favorable safety profile. These findings underscore the promising role of peripheral anti-Reelin therapeutic strategies for autoimmune diseases and conditions where endothelial function is compromised, offering a novel approach that may avoid the immunosuppressive side effects associated with conventional anti-inflammatory therapies. [ABSTRACT FROM AUTHOR]

Cognitive function plays an important role in athletic performance, and it seems that brain functioning can be influenced by nutrition and dietary components. Thus, the central nervous system might be manipulated through changes in diet or supplementation with specific nutrients including branched-chain amino acids, tyrosine, carbohydrates, and caffeine. Despite some evidence that branched-chained amino acids can influence ratings of perceived exertion and mental performance, several well-controlled studies have failed to demonstrate a positive effect on exercise performance. Evidence of an ergogenic benefit of tyrosine supplementation during prolonged exercise is limited. There is evidence that mild dehydration can impair cognitive performance and mood. The beneficial effect of carbohydrate supplementation during prolonged exercise could relate to increased substrate delivery for the brain, with numerous studies indicating that hypoglycemia affects brain function and cognitive performance. Caffeine can enhance performance and reduce perception of effort during prolonged exercise and will influence specific reward centers of the brain. Plant products and herbal extracts such as polyphenols, ginseng, ginkgo biloba, etc. are marketed as supplements to enhance performance. In several animal studies, positive effects of these products were shown, however the literature on their effects on sports performance is scarce. Polyphenols have the potential to protect neurons against injury induced by neurotoxins, suppress neuroinflammation, and to promote memory, learning, and cognitive function. In general, there remains a need for controlled randomized studies with a strong design, sufficient statistical power, and well-defined outcome measures before "claims" on its beneficial effects on brain functioning can be established. [ABSTRACT FROM AUTHOR]

Historically, pancreatic islet beta cells have been viewed as principal regulators of glycemia, with type 2 diabetes (T2D) resulting when insulin secretion fails to compensate for peripheral tissue insulin resistance. However, glycemia is also regulated by insulin-independent mechanisms that are dysregulated in T2D. Based on evidence supporting its role both in adaptive coupling of insulin secretion to changes in insulin sensitivity and in the regulation of insulin-independent glucose disposal, the central nervous system (CNS) has emerged as a fundamental player in glucose homeostasis. Here, we review and expand upon an integrative model wherein the CNS, together with the islet, establishes and maintains the defended level of glycemia. We discuss the implications of this model for understanding both normal glucose homeostasis and T2D pathogenesis and highlight centrally targeted therapeutic approaches with the potential to restore normoglycemia to patients with T2D. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the neuromuscular and perceptual fatigue responses of elite rugby players during the inaugural Under-18 (U18) Six Nations Festival. One hundred and thirty-three male players from five national squads (73 forwards, 60 backs) were examined during the competition. Each national squad was involved in three matches separated by 96 h each. Over the competition, players completed a daily questionnaire to monitor perceived well-being (WB) and performed daily countermovement jumps (CMJ) to assess neuromuscular function (NMF). Reductions in WB were substantial 24 h after the first and second match in forwards (d=0.77±0.21, p<0.0001; d=0.84±0.22, p< 0.001) and backs (d=0.89±0.22, p <0.0001; d=0.58±0.23, p<0.0001) but reached complete recovery in time for the subsequent match. Reductions in CMJ height were substantial 24 h after the first and second match for forwards (d=0.31±0.15, p=0.001; d=0.25±0.17, p=0.0205) and backs (d=0.40±0.17, p=0.0001; d=0.28±0.17, p=0.0062) and recovered at 48 h after match-play. Average WB and CMJ height attained complete recovery within matchday cycles in the investigated international competition. The findings of this study can be useful for practitioners and governing bodies involved with fixture scheduling and training prescription during competitive periods. [ABSTRACT FROM AUTHOR]

Meal ingestion provokes the release of hormones and transmitters, which in turn regulate energy homeostasis and feeding behavior. One such hormone, glucagon-like peptide-1 (GLP-1), has received significant attention in the treatment of obesity and diabetes due to its potent incretin effect. In addition to the peripheral actions of GLP-1, this hormone is able to alter behavior through the modulation of multiple neural circuits. Recent work that focused on elucidating the mechanisms and outcomes of GLP-1 neuromodulation led to the discovery of an impressive array of GLP-1 actions. Here, we summarize the many levels at which the GLP-1 signal adapts to different systems, with the goal being to provide a background against which to guide future research. • GLP-1 synthesis, metabolism, and the expression of the receptor show diversity across tissues. • Bile acid signaling may represent a novel target for enhancing GLP-1 action. • The diversity and complexity of GLP-1 signaling in the brain points to the multiple regulatory roles of GLP-1 in the CNS. [ABSTRACT FROM AUTHOR]

Background/Aims. Despite the wide use of acupuncture for the management of visceral pain and the growing interest in the pathophysiology of visceral pain, there is no conclusive elucidation of the mechanisms behind the effects of acupuncture on visceral pain. This systematic review aims to provide an integrative understanding of the treatment mechanism of acupuncture for visceral pain. Methods. Electronic and hand searches were conducted to identify studies that involved visceral pain and acupuncture. Results. We retrieved 192 articles, out of which 46 studies were included in our review. The results of our review demonstrated that visceral pain behaviors were significantly alleviated in response to acupuncture treatment in groups treated with this intervention compared to in sham acupuncture or no-treatment groups. Changes in the concentrations of β-endorphin, epinephrine, cortisol, and prostaglandin E2 in plasma, the levels of c-Fos, substance P, corticotropin-releasing hormone, P2X3, acetylcholinesterase (AchE), N-methyl-D-aspartate (NMDA) receptors, and serotonin in the gut/spinal cord, and the neuronal activity of the thalamus were associated with acupuncture treatment in visceral pain. Conclusions. Acupuncture reduced visceral pain behavior and induced significant changes in neuronal activity as well as in the levels of pain/inflammation-related cytokines and neurotransmitters in the brain-gut axis. Further researches on the thalamus and on a standard animal model are warranted to improve our knowledge on the mechanism of acupuncture that facilitates visceral pain modulation. [ABSTRACT FROM AUTHOR]

Alicapistat is an orally active selective inhibitor of calpain 1 and 2 whose overactivation has been linked to Alzheimer disease (AD). Three studies were conducted in healthy subjects (18‐55 years), 1 in healthy elderly subjects (≥65 years), and 1 in patients with mild to moderate AD. Four studies assessed pharmacokinetics, 1 study in healthy subjects assessed pharmacodynamics (sleep parameters, particularly rapid eye movement [REM], as a measure of central nervous system [CNS] penetration and activity), and all studies assessed safety. Participants received single doses or multiple twice‐daily doses of alicapistat for up to 14 days. Maximum alicapistat plasma concentrations were reached in 2 to 5 hours; half‐life was 7 to 12 hours postdose. Alicapistat exposure was dose proportional in the alicapistat 50‐ to 1000‐mg dose range. Exposure of the alicapistat R,S diastereomer was approximately 2‐fold greater than exposure of the R,R diastereomer in healthy young and elderly subjects and patients with AD. Alicapistat at 400‐ or 800‐mg twice‐daily doses had no effect on REM sleep parameters, whereas the active control, donepezil at 10 mg twice daily, affected sleep parameters. Across all trials, the incidence of treatment‐emergent adverse events was similar in the placebo and alicapistat groups. There were no clinically significant changes in vital signs and laboratory measurements. The lack of an effect of alicapistat on sleep suggests that concentrations in the CNS were inadequate or that preclinical studies do not predict alicapistat effects in humans. [ABSTRACT FROM AUTHOR]

Pain can trigger central amplification called central sensitization, which ultimately results in hyperalgesia and/or allodynia. Many reports have showed acupuncture has an analgesic effect. We searched the related article on PubMed database and Cochrane database to discover central sensitization pathway in acupuncture analgesia. We summarized that acupuncture enhances the descending inhibitory effect and modulates the feeling of pain, thus modifying central sensitization. The possible mechanisms underlying the analgesic effects of acupuncture include segmental inhibition and the activation of the endogenous opioid, adrenergic, 5-hydroxytryptamine, and N-methyl-D-aspartic acid, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate pathways. Moreover, acupuncture can locally reduce the levels of inflammatory mediators. In clinical settings, acupuncture can be used to treat headache, neuropathic pain, low back pain, osteoarthritis, and irritable bowel syndrome. These mechanisms of acupuncture analgesia may be involved in the alleviation of central sensitization. [ABSTRACT FROM AUTHOR]

Overactive bladder (OAB) is a symptom complex characterised by urinary urgency, with or without urgency incontinence, usually associated with increased daytime frequency and nocturia. This article discusses our current understanding of OAB and its recommended management. [ABSTRACT FROM AUTHOR]

Analgesia and temporary inhibition of motor activity without interfering with central nervous function have been the essential merits of local anesthesia. Local anesthetics originated from cocaine have played a major role in local analgesia. However, the relatively short duration of action of local anesthetics has been a concern in intra- and post-operative analgesia. From the early age of modern local anesthesia, physicians and medical scientists had been struggling to control the active duration of local anesthetics. Such approach includes: development of long-acting local anesthetics, with physical tourniquet techniques, co-administration of other medicines such as vaso-constrictive agents or analgesics, development of mechanical devices to continuously or intermittently administer local anesthetics, and utilization of pharmaceutical drug delivery systems. In this review, the historical sequence of studies that have been performed in an effort to elongate the action of local anesthetics is presented, referring to epoch-making medical and scientific studies. [ABSTRACT FROM AUTHOR]

Aim of the study was evaluation of anxiolytic, antidepressant, anticonvulsant and analgesic activity in a series of a consistent group of compounds. A series of eleven new N -(phenoxyalkyl)- or N -{2-[2-(phenoxy)ethoxy]ethyl}piperazine derivatives has been obtained. Their affinity towards 5-HT 1A , 5-HT 2A , 5-HT 6 , 5-HT 7 , D 2 and α 1 receptors has been assessed, and then functional assays were performed. The compounds were evaluated in mice, i.p. for their antidepressant-like (forced swim test), locomotor, anxiolytic-like (four-plate test) activities as well as – at higher doses – for anticonvulsant potential (MES) and neurotoxicity (rotarod). Two compounds ( 3 , 6 ) were also evaluated for their analgesic activity in neuropathic pain models (streptozocin test, oxaliplatin test) and they were found active against allodynia in diabetic neuropathic pain at 30 mg/kg. Among the compounds, anxiolytic-like, anticonvulsant or analgesic activity was observed but antidepressant-like activity was not. One of the two most interesting compounds is 1-{2-[2-(2,4,6-trimethylphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazine dihydrochloride ( 9 ), exhibiting anxiolytic and anticonvulsant activity in mice, i.p. 30 min after administration (at 2.5 mg/kg and ED 50  = 26.33 mg/kg, respectively), which can be justified by the receptor profile: 5-HT 1A K i  = 5 nM (antagonist), 5-HT 7 K i  = 70 nM, α 1 K i  = 15 nM, D 2 K i  = 189 nM (antagonist). Another interesting compound is 1-[3-(2,4,6-trimethylphenoxy)propyl]-4-(4-methoxyphenyl)piperazine dihydrochloride ( 3 ), exhibiting anxiolytic, anticonvulsant and antiallodynic activity in mice, i.p. , 30 min after administration (at 10 mg/kg, ED 50  = 23.50 mg/kg, at 30 mg/kg, respectively), which can be related with 5-HT 1A weak antagonism (K i  = 146 nM), or other possible mechanism of action, not evaluated within presented study. Additionally, for the most active compound in the four-plate test ( 7 ), molecular modeling was performed (docking to receptors 5-HT 1A , 5-HT 2A , 5-HT 7 , D 2 and α 1A ). [ABSTRACT FROM AUTHOR]

Neuronal signaling together with synapse activity in the central nervous system requires a precisely regulated microenvironment. Recently, the blood-brain barrier is considered as a “neuro-glia-vascular unit,” a structural and functional compound composed of capillary endothelial cells, glial cells, pericytes, and neurons, which plays a pivotal role in maintaining the balance of the microenvironment in and out of the brain. Tight junctions and adherens junctions, which function as barriers of the blood-brain barrier, are two well-known kinds in the endothelial cell junctions. In this review, we focus on the less-concerned contribution of gap junction proteins, connexins in blood-brain barrier integrity under physio-/pathology conditions. In the neuro-glia-vascular unit, connexins are expressed in the capillary endothelial cells and prominent in astrocyte endfeet around and associated with maturation and function of the blood-brain barrier through a unique signaling pathway and an interaction with tight junction proteins. Connexin hemichannels and connexin gap junction channels contribute to the physiological or pathological progress of the blood-brain barrier; in addition, the interaction with other cell-cell-adhesive proteins is also associated with the maintenance of the blood-brain barrier. Lastly, we explore the connexins and connexin channels involved in the blood-brain barrier in neurological diseases and any programme for drug discovery or delivery to target or avoid the blood-brain barrier. [ABSTRACT FROM AUTHOR]

Background Anti‑ N ‑methyl‑ d ‑aspartate receptor (NMDAR) encephalitis is a relatively common autoimmune neurological disease of the central nervous system (CNS). Neuron-specific enolase (NSE) and S100 calcium-binding protein B (S100B) are structural proteins of the central nervous system (CNS). In patients with CNS injury accompanied by nervous tissue and cellular damage, these structural proteins are released from cells; their extracellular concentrations, including those in cerebrospinal fluid (CSF) and blood, subsequently increase. Methods Thirty-six patients with anti-NMDAR encephalitis were prospectively recruited. The CSF NSE and S100B concentrations were measured in 19 and 17 patients, respectively. The CSF NSE and S100B concentrations were measured in 21 patients with noninflammatory neurological disease as controls. All measurements were performed using enzyme-linked immunosorbent assays. Results The CSF NSE and S100B concentrations were remarkably higher in the patients with anti-NMDAR encephalitis than in the controls. The early NSE or S100B concentrations in CSF were associated with the mRS. Conclusion CSF NSE and S100B concentration in patients with anti-NMDAR encephalitis is higher than in patients with non-inflammatory neurological disease. The early NSE or S100B concentrations in CSF were associated with the mRS and we can use it to determine the prognosis of the disease. [ABSTRACT FROM AUTHOR]

Central nervous system aspergillosis is rare with reported mortality rate of 13-50% involving foci in paranasal sinuses and even higher mortality rates (80-100%) in patients of immune-compromised status. Modern day imaging offers an opportunity for early diagnosis, but findings are minimal. A typical finding is that of a space occupying mass lesion with iso-hypointense signal on T1-weighted sequences and extreme hypointense appearance on T2-weighted. This results from the concentration of ferromagnetic substances (iron/zinc/magnesium/manganese) within the lesion. Gadolinium enhancement pattern varies from homogeneous to peripheral ring enhancement. The immune-competent hosts present with homogeneous enhancement while those with immune compromise bear more variable radiological appearance. Due to such radiological appearance, meningioma or tuberculoma is considered in differential earlier than fungal granuloma, if not for the hypointense appearance on T2-weighted sequences which strongly points to fungal granuloma. Through this case report, we attempt to highlight the unusual radiological presentation of the entity. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs), which are regarded as promising candidates for cell replacement therapies, are able to regulate immune responses after traumatic brain injury (TBI). Secondary immune response following the mechanical injury is the essential factor leading to the necrosis and apoptosis of neural cells during and after the cerebral edema has subsided and there is lack of efficient agent that can mitigate such neuroinflammation in the clinical application. By means of three molecular pathways (prostaglandin E2 (PGE2), tumor-necrosis-factor-inducible gene 6 protein (TSG-6), and progesterone receptor (PR) and glucocorticoid receptors (GR)), MSCs induce the activation of macrophages/microglia and drive them polarize into the M2 phenotypes, which inhibits the release of pro-inflammatory cytokines and promotes tissue repair and nerve regeneration. The regulation of MSCs and the polarization of macrophages/microglia are dynamically changing based on the inflammatory environment. Under the stimulation of platelet lysate (PL), MSCs also promote the release of pro-inflammatory cytokines. Meanwhile, the statue of macrophages/microglia exerts significant effects on the survival, proliferation, differentiation and activation of MSCs by changing the niche of cells. They form positive feedback loops in maintaining the homeostasis after TBI to relieving the secondary injury and promoting tissue repair. MSC therapies have obtained great achievements in several central nervous system disease clinical trials, which will accelerate the application of MSCs in TBI treatment. [ABSTRACT FROM PUBLISHER]

The hypothalamic neuropeptide oxytocin (OT) has attracted the attention both of the scientific community and a general audience because of its prosocial effects in mammals, and OT is now seen as a facilitator of mammalian species propagation. Furthermore, OT is a candidate for the treatment of social deficits in several neuropsychiatric and neurodevelopmental conditions. Despite such possibilities and a long history of studies on OT behavioral effects, the mechanisms of OT actions in the brain remain poorly understood. In the present review, based on anatomical, biochemical, electrophysiological, and behavioral studies, we propose a novel model of local OT actions in the central nervous system (CNS) via focused axonal release, which initiates intracellular signaling cascades in specific OT-sensitive neuronal populations and coordinated brain region-specific behaviors. [ABSTRACT FROM AUTHOR]

Many college students underestimate or ignore the side-effects associated with nonmedical use of prescription stimulants (NMUPS) and are motivated by hopes of academic enhancement. The present study measured the effect a placebo stimulant and personal expectancies have on subjective physiological changes and cognitive enhancement. Undergraduate college students participated in a two-phase study. Phase 1 (n = 305) involved completing an online survey to gather distal study variables and individual stimulant expectancy data. Phase 2 (n = 166) required students to attend an in-person session where they completed physiological and neuropsychological measures (e.g., Physical Symptom Checklist, Digit Span, Passage Comprehension). Students were randomized to receive a placebo stimulant medication (experimental) or no medication (control). Following a 30-minute absorption period, participants completed another set of physiological and neuropsychological measures. Experimental participants reported significant increases in positive symptoms resulting from the placebo stimulant. Expectancies moderated the impact of the placebo stimulant on Passage Comprehension performance; no other neuropsychological task performance was impacted. Despite subjective reports of feeling the effects of stimulants, task performance was unaffected. Moreover, expectancies may play a small role in perceptions of the effects of stimulants. [ABSTRACT FROM PUBLISHER]

Fetal repair of myelomeningocele (MMC) has been proven to be beneficial for the central nervous system development; however, the effect of fetal MMC repair on bladder function remains controversial. The objective of the present study was to establish an early timepoint for in utero MMC repair using a rat model, and to investigate the changes in bladder development subsequent to that intervention. Sprague Dawley rats were divided into the MMC, MMC repair and control groups. MMC rat fetus models were created by treating pregnant rats with all-trans retinoic acid. The MMC defect was then repaired in utero at embryonic day 17 (E17) using a chitosan-gelatin membrane patch. Fetal rat bladders were removed at E19 and E21 in each group, as well as at stage E17 in the MMC and control groups. Differential expression of ß-III-tubulin, a-smooth muscle actin (a-SMA), nerve growth factor (NGF) and acetylcholinesterase (AChE) mRNA, and ß-III-tubulin and a-SMA protein in the bladder following fetal repair was measured and compared among the three groups. In addition, the expression of NGF mRNA was significantly elevated at E21 in the MMC group compared with that of the control group, however, the level decreased in the repair group at stage E21. The expression of a-SMA mRNA significantly increased at E19 and then decreased at E21 in the repair group compared with that of the MMC group; however, there were no significant changes in a-SMA protein following the repair. Furthermore, the repair enhanced ß-III-tubulin mRNA expression at E19, but ameliorated the decrease of ß-III-tubulin protein at E21. The expression of AChE mRNA increased in the MMC group at E19 and E21 compared with that of the control group, although it was not significantly altered following repair as compared with that of the MMC group. In conclusion, in the current study, abnormal neuromuscular development was observed in the MMC bladder, which enabled a certain degree of improvement in the in utero MMC repair. [ABSTRACT FROM AUTHOR]

Cofilin is a ubiquitous protein which cooperates with many other actin-binding proteins in regulating actin dynamics. Cofilin has essential functions in nervous system development including neuritogenesis, neurite elongation, growth cone pathfinding, dendritic spine formation, and the regulation of neurotransmission and spine function, components of synaptic plasticity essential for learning and memory. Cofilin's phosphoregulation is a downstream target of many transmembrane signaling processes, and its misregulation in neurons has been linked in rodent models to many different neurodegenerative and neurological disorders including Alzheimer disease (AD), aggression due to neonatal isolation, autism, manic/bipolar disorder, and sleep deprivation. Cognitive and behavioral deficits of these rodent models have been largely abrogated by modulation of cofilin activity using viral-mediated, genetic, and/or small molecule or peptide therapeutic approaches. Neuropathic pain in rats from sciatic nerve compression has also been reduced by modulating the cofilin pathway within neurons of the dorsal root ganglia. Neuroinflammation, which occurs following cerebral ischemia/reperfusion, but which also accompanies many other neurodegenerative syndromes, is markedly reduced by peptides targeting specific chemokine receptors, which also modulate cofilin activity. Thus, peptide therapeutics offer potential for cost-effective treatment of a wide variety of neurological disorders. Here we discuss some recent results from rodent models using therapeutic peptides with a surprising ability to cross the rodent blood brain barrier and alter cofilin activity in brain. We also offer suggestions as to how neuronal-specific cofilin regulation might be achieved. [ABSTRACT FROM AUTHOR]

Background: Despite multiple risk factors for neurodevelopmental vulnerability, few studies have assessed neurodevelopmental performance of Australian Aboriginal children. An important risk factor for neurodevelopmental vulnerability is prenatal alcohol exposure (PAE), which places children at risk for Fetal Alcohol Spectrum Disorder (FASD).Aims: This study assesses neurodevelopment outcomes in a population of Australian Aboriginal children with and without PAE.Methods and Procedures: Children born in 2002/2003, and living in the Fitzroy Valley, Western Australia between April 2010 and November 2011, were eligible (N=134). Sociodemographic and antenatal data, including PAE, were collected by interview with 127/134 (95%) consenting parents/caregivers. Maternal/child medical records were reviewed. Neurodevelopment was assessed by clinicians blinded to PAE in 108/134 (81%) children and diagnoses on the FASD spectrum were assigned.Outcomes and Results: Neurodevelopmental disorder was documented in 34/108 children (314.8 per 1000). Any diagnosis on the FASD spectrum was made in 21/108 (194.4 per 1000) children (95% CI=131.0-279.0).Conclusions and Implications: Neurodevelopmental impairment with or without PAE is highly prevalent among children in the Fitzroy Valley. Rates of diagnoses on the FASD spectrum are among the highest worldwide. Early intervention services are needed to support developmentally vulnerable children in remote communities. [ABSTRACT FROM AUTHOR]

This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M 4 antagonists, based on a 4,6-disubstituted core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at both human and rat M 4 (IC 50 s < 300 nM), with no substantial species differences noted. Moreover, CNS penetration proved attractive for this series (brain:plasma K p,uu = 0.87), while other DMPK attributes were addressed in the course of the optimization effort, providing low in vivo clearance in rat (CL p = 5.37 mL/min/kg). Surprisingly, this series displayed pan -muscarinic antagonist activity across M 1–5 , despite the absence of the prototypical basic or quaternary amine moiety, thus offering a new chemotype from which to develop a next generation of pan -muscarinic antagonist agents. [ABSTRACT FROM AUTHOR]

Laquinimod is currently being tested as a therapeutic drug in multiple sclerosis. However, its exact mechanism of action is still under investigation. Tracking of fluorescently-tagged encephalitogenic T cells during experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, revealed that laquinimod significantly reduces the invasion of pathogenic effector T cells into the CNS tissue. T-cell activation, differentiation and amplification within secondary lymphoid organs after immunization with myelin antigen, their migratory capacity and re-activation within the nervous tissue were either only mildly affected or remained unchanged. Instead, laquinimod directly impacted the functionality of the CNS vasculature. The expression of tight junction proteins p120 and ZO-1 in human brain endothelial cells was up-regulated upon laquinimod treatment, resulting in a significant increase in the transendothelial electrical resistance of confluent monolayers of brain endothelial cells. Similarly, expression of the adhesion molecule activated leukocyte cell adhesion molecule (ALCAM) and inflammatory chemokines CCL2 and IP-10 was suppressed, leading to a significant reduction in the migration of memory T H 1 and T H 17 lymphocytes across the blood brain barrier (BBB). Our data indicate that laquinimod exerts its therapeutic effects by tightening the BBB and limiting parenchymal invasion of effector T cells, thereby reducing CNS damage. [ABSTRACT FROM AUTHOR]

Nerve growth factor (NGF) promotes the survival and differentiation of neurons. NGF is initially synthesized as a precursor, proNGF, which is the predominant form in the central nervous system. NGF and proNGF bind to TrkA/p75NTR to mediate cell survival and to sortilin/p75NTR to promote apoptosis. The ratio of TrkA to p75NTR affects whether proNGF and mature NGF signal cell survival or apoptosis. The purpose of this study was to determine whether the loss of TrkA influences p75NTR or sortilin expression levels, and to establish whether proNGF and mature NGF have a similar ability to switch between cell survival and cell death. We systematically altered TrkA receptor levels by priming cells with NGF, using small interfering RNA, and using the mutagenized PC12nnr5 cell line. We found that both NGF and proNGF can support cell survival in cells expressing TrkA, even in the presence of p75NTR and sortilin. However, when TrkA is reduced, proNGF signals cell death, while NGF exhibits no activity. In the absence of TrkA, proNGF-induced cell death occurs, even when p75NTR and sortilin levels are reduced. These results show that proNGF can switch between neurotrophic and apoptotic activity in response to changes in TrkA receptor levels, whereas mature NGF cannot. These results also support the model that proNGF is neurotrophic under normal circumstances, but that a loss in TrkA in the presence of p75NTR and sortilin, as occurs in neurodegenerative disease or injury, shifts proNGF, but not NGF, signalling from cell survival to cell death. [ABSTRACT FROM AUTHOR]

Background Sphenopalatine ganglion (SPG), an extracranial structure, is connected with the central nervous system (CNS) through sympathetic and parasympathetic nerves. We hypothesized that SPG block through sympathetic nerves anesthesia might decrease blood pressure (BP) in recently diagnosed and never treated middle-aged patients with essential hypertension. Methods We performed SBG block in 22 hypertensive patients (mean age 45 ± 12 years, 15 men). All patients have been subjected to 24 hour ambulatory blood pressure monitoring a week prior the procedure as well as in a period of 21–30 days after the SBG block in order to estimate differences in 24 h average systolic (24 h SBP) and diastolic blood pressure (24 h DBP), daytime, nighttime, pre-awake and early morning SBP and DBP as well as BP load. Results We found that 24 h SBP (p = 0.001) and 24 h DBP (p < 0.001), daytime SBP and DBP (p < 0.001) as well as daytime SBP and DBP load (p = 0.002 and p < 0.001, respectively) were decreased in total population at 21–30 days after SPG block. In 11/22 responders (24 h SBP decrease ≥ 5 mm Hg), SBP and DBP were reduced during overall 24 h and daytime (p < 0.001) and nighttime periods (p = 0.01 and p = 0.06, respectively) while pre-awake SBP (p = 0.09) along with daytime SBP and DBP load (p = 0.07 and p = 0.06, respectively) were also almost decreased. Conclusions SBG block might be a promising, non-invasive, safe, painless and easy to perform therapeutic option of BP decrease. As with renal denervation, SBG should be effective in those hypertensive patients with an activated SNS, so a period of patient selection should precede the application of this procedure. [ABSTRACT FROM AUTHOR]

Neuropeptide Y (NPY) and NPY receptors are widely expressed in the mammalian central nervous system. Studies in both humans and rodent models revealed that brain NPY levels are altered in some neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Machado-Joseph disease. In this review, we will focus on the roles of NPY in the pathological mechanisms of these disorders, highlighting NPY as a neuroprotective agent, as a neural stem cell proliferative agent, as an agent that increases trophic support, as a stimulator of autophagy and as an inhibitor of excitotoxicity and neuroinflammation. Moreover, the effect of NPY in some clinical manifestations commonly observed in Alzheimer's disease, Parkinson's disease, Huntington's disease and Machado-Joseph disease, such as depressive symptoms and body weight loss, are also discussed. In conclusion, this review highlights NPY system as a potential therapeutic target in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Acid-sensing ion channels (ASICs) are involved in numerous physiological and pathological processes in the central nervous system. Development of pharmacological tools capable to inhibit or potentiate these channels is important for our knowledge about roles of ASICs in the neuronal network and can be promising for treatment of some disorders. Recently we described four hydrophobic monoamines that potentiate and inhibit ASICs depending on subunit composition of the channel and peculiarities of the drug structure. In the present work we performed structure-activity relationship analysis using derivatives of adamantane, phenylcyclohexyl and 9-aminoacridine to reveal the main determinants of action of amine-containing compounds on recombinant ASIC1a and ASIC2a homomers expressed in CHO cells. We found that the most active compounds are monocations with protonatable aminogroup. In general, potentiators and inhibitors of ASIC1a we found, but only potentiators for ASIC2a. Flat aromatic structure of the headgroup determines inhibition of ASIC1a while “V-shape” structure of the hydrophobic moiety favors potentiation of ASIC2a. Moreover, for some series of monoamines there was a correlation between action on ASIC1a and ASIC2a, the weaker ASIC1a inhibition, the stronger ASIC2a potentiation. Decay of response was accelerated by ASIC1a inhibitors as well as by potentiators. All compounds potentiating ASIC2a slowed down desensitization. Our results suggest that hydrophobic amines cause complex action on ASICs. [ABSTRACT FROM AUTHOR]

Endogenous levels of the neurosteroid (NS) allopregnanolone (AlloP) during neonatal stages are crucial for the correct development of the central nervous system (CNS). In a recent work we reported that the neonatal administration of AlloP or finasteride (Finas), an inhibitor of the enzyme 5α-reductase needed for AlloP synthesis, altered the voluntary consumption of ethanol and the ventrostriatal dopamine (DA) levels in adulthood, suggesting that neonatal NS manipulations can increase alcohol abuse vulnerability in adulthood. Moreover, other authors have associated neonatal NS alterations with diverse dopaminergic (DAergic) alterations. Thus, the aim of the present work is to analyse if manipulations of neonatal AlloP alter the DAergic response in the nucleus accumbens (NAcc) during alcohol intake in rats. We administered AlloP or Finas from postnatal day (PND) 5 to PND9. At PND98, we measured alcohol consumption using a two-bottle free-choice model (ethanol 10% (v/v) + glucose 3% (w/v), and glucose 3% (w/v)) for 12 days. On the last day of consumption, we measured the DA and 3,4-dihydroxyphenylacetic acid (DOPAC) release in NAcc in response to ethanol intake. The samples were obtained by means of in vivo microdialysis in freely moving rats, and DA and DOPAC levels were determined by means of high-performance liquid chromatography analysis (HPLC). The results revealed that neonatal Finas increased ethanol consumption in some days of the consumption phase, and decreased the DA release in the NAcc in response to solutions (ethanol + glucose) and food presentation. Taken together, these results suggest that neonatal NS alterations can affect alcohol rewarding properties. [ABSTRACT FROM AUTHOR]

Central poststroke pain (CPSP) is one of the most common central neuropathic pain syndromes seen after stroke. It is mainly related with vascular damage at certain brain territory and pain related to corresponding body areas. In the past, it was described as one of the definitive symptoms of thalamic lesion. However, recent findings suggest that it is not only seen after thalamic lesions but also seen after vascular lesions in any part of the central nervous system. Although there are certain hypotheses to explain physiopathologic mechanisms of CPSP, further evidence is needed. The majority of the cases are intractable and unresponsive to analgesic treatment. Electrical stimulation such as deep brain stimulation and repetitive transcranial magnetic stimulation seems to be effective in certain cases. In this systematic review, recent advancements related to CPSP mechanisms have been evaluated. Further investigations are needed in order to reveal the mystery of the pathophysiologic mechanisms of CPSP. [ABSTRACT FROM AUTHOR]

Objective Acupuncture is increasingly used as an alternative to medical therapy for various pain conditions. To study the effect of acupuncture in experimental and clinical studies, a control condition with sham acupuncture is needed. However, as such models have not been established in assessment of acupunctures effect against visceral pain, this study aimed to validate a new method for blinded sham acupuncture in experimental rectal pain. Methods Fifteen subjects underwent a sequence of either sham or real acupuncture in randomized order. In the sham arm, a hollow inner tube with a sharp tip was fitted into an outer tube and subjects were blinded to the stimulations. Before and after the intervention, pain was induced by rectal stimulation with an inflatable balloon distended until the subjects' pain threshold was reached. The resting electroencephalogram ( EEG) was quantified by spectral power analysis to explore the central nervous system effects objectively. Additionally, after the second study day, the subject was asked to indicate the sequence of interventions. Results A significant increase in rectal balloon volume was observed after sham 12 ± 21 mL ( P = 0.049) and acupuncture 17 ± 30 mL ( P = 0.046). However, the change in volume was not different between groups ( P = 0.6). No differences in EEG spectral power distributions between sham and acupuncture were seen (all P > 0.6). The correct sequence of sham and acupuncture was indicated by 36% of the subjects ( P = 0.4). Conclusions The presented sham procedure provides a valid method for blinding of 'sham acupuncture' and may be used in future blinded controlled trials of acupuncture for visceral pain. [ABSTRACT FROM AUTHOR]

Nowadays, mantle cell lymphoma is considered to have one of the worst prognostic profiles among lymphoid malignancies. Mantle cell lymphoma rarely affects the central nervous system (CNS) as it represents about 0.9% of diagnosis and 4% among recurrent cases. Here, we present the case of a 69-year-old male patient who was diagnosed with mantle cell lymphoma in 2006. The patient relapsed three times, without affecting the CNS, then was treated accordingly, and achieved complete remission three times. Four years after his last complete remission, upon receiving his last dose of treatment, the medical team noted a rapid worsening of the patient’s neurological status followed by a deep coma state causing MCL neurological recurrence by exclusion diagnosis. The patient then received ibrutinib via a nasogastric tube at a dose of 560 mg daily. Two days after receiving his last dose of ibrutinib, the patient regained full consciousness, and 10 days later, he was discharged from the hospital. The patient achieved complete remission and showed no signs of neurological damages for 24 months following his ibrutinib treatment. We believe that the administration of ibrutinib through the nasogastric tube was a determinant factor in this patient’s remission and survival. [ABSTRACT FROM AUTHOR]

Since the introduction of combination antiretroviral therapy (cART), the incidence of severe HIV-associated neurocognitive impairment has declined significantly, whereas the prevalence of the milder forms has increased. Studies suggest that better distribution of cART drugs into the CNS may be important in reducing viral replication in the CNS and in reducing HIV-related brain injury. Correlates of neuropsychological (NP) performance were determined in 417 participants of the Ontario HIV Treatment Cohort Study (OCS). All participants were on three cART drugs for at least 90 days prior to assessment. Multiple logistic and linear regression methods were used. Most participants were Caucasian men with mean age of 47 years. About two thirds had a nadir CD4+ T-cell count below 200 cells/μL and 92 % had an undetectable plasma HIV viral load. The median CNS penetration effectiveness (CPE) score was 7. Sixty percent of participants had neuropsychological impairment. Higher CPE values significantly correlated with lower prevalence of impairment in bivariate and multivariate analyses. In this cross-sectional analysis of HIV+ adults who had a low prevalence of comorbidities and were taking three-drug cART regimens, greater estimated distribution of cART drugs into the CNS was associated with better NP performance. [ABSTRACT FROM AUTHOR]

In neurodegenerative diseases, the inflammatory response is mediated by activated glial cells, mainly microglia, which are the resident immune cells of the central nervous system. Activated microglial cells release proinflammatory mediators and neurotoxic factors that are suspected to cause or exacerbate these diseases. We recently demonstrated that doxycycline protects substantia nigra dopaminergic neurons in an animal model of Parkinson's disease. This effect was associated with a reduction of microglial cell activation, which suggests that doxycycline may operate primarily as an anti-inflammatory drug. In the present study, we assessed the anti-inflammatory potential of doxycycline using lipopolysaccharide (LPS)-activated primary microglial cells in culture as a model of neuroinflammation. Doxycycline attenuated the expression of key activation markers in LPS-treated microglial cultures in a concentration-dependent manner. More specifically, doxycycline treatment lowered the expression of the microglial activation marker IBA-1 as well as the production of ROS, NO, and proinflammatory cytokines (TNF-α and IL-1β). In primary microglial cells, we also found that doxycycline inhibits LPS-induced p38 MAP kinase phosphorylation and NF-kB nuclear translocation. The present results indicate that the effect of doxycycline on LPS-induced microglial activation probably occurs via the modulation of p38 MAP kinase and NF-kB signaling pathways. These results support the idea that doxycycline may be useful in preventing or slowing the progression of PD and other neurodegenerative diseases that exhibit altered glia function. [ABSTRACT FROM AUTHOR]

This study investigated the effect of systemic salicylate on central auditory and non-auditory structures in mice. Since cochlear hair cells are known to be one major target of salicylate, cochlear effects were reduced by using kanamycin to remove or impair hair cells. Neuronal brain activity was measured using the non-invasive manganese-enhanced magnetic resonance imaging technique. For all brain structures investigated, calcium-related neuronal activity was increased following systemic application of a sodium salicylate solution: probably due to neuronal hyperactivity. In addition, it was shown that the central effect of salicylate was not limited to the auditory system. A general alteration of calcium-related activity was indicated by an increase in manganese accumulation in the preoptic area of the anterior hypothalamus, as well as in the amygdala. The present data suggest that salicylate-induced activity changes in the auditory system differ from those shown in studies of noise trauma. Since salicylate action is reversible, central pharmacological effects of salicylate compared to those of (permanent) noise-induced hearing impairment and tinnitus might induce different pathophysiologies. These should therefore, be treated as different causes with the same symptoms. [ABSTRACT FROM AUTHOR]

Objective: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are associated with reduced appetite and body weight. We investigated whether these effects could be mediated by the central nervous system (CNS).Research Design and Methods: We performed a randomized crossover study in obese patients with type 2 diabetes (n = 20, mean age 59.3 ± 4.1 years, mean BMI 32 ± 4.7 kg/m(2)), consisting of two periods of 12-week treatment with either liraglutide 1.8 mg or insulin glargine. Using functional MRI, we determined the effects of treatment on CNS responses to viewing food pictures in the fasted condition and 30 min after meal intake.Results: After 12 weeks, the decrease in HbA1c was larger with liraglutide versus insulin glargine (Δ-0.7% vs. -0.2%, P < 0.001). Body weight decreased during liraglutide versus insulin glargine (Δ-3.3 kg vs. 0.8 kg, P < 0.001). After 10 days, patients treated with liraglutide, compared with insulin glargine, showed decreased responses to food pictures in insula and putamen (P ≤ 0.02). In addition, liraglutide enhanced the satiating effect of meal intake on responses in putamen and amygdala (P ≤ 0.05). Differences between liraglutide and insulin glargine were not observed after 12 weeks.Conclusions: Compared with insulin, liraglutide decreased CNS activation significantly only after short-term treatment, suggesting that these effects of GLP-1RA on the CNS may contribute to the induction of weight loss, but not necessarily to its maintenance, in view of the absence of an effect of liraglutide on CNS activation in response to food pictures after longer-term treatment. [ABSTRACT FROM AUTHOR]

Clinical improvement during pregnancy in multiple sclerosis (MS) patients suggests that sex hormones exert potent regulatory effects on autoimmune function. Our previous studies demonstrated that estrogen- (17β-estradiol; E2) mediated protection against experimental autoimmune encephalomyelitis (EAE), a mouse model for MS, hinges on the B cells, leading to elevated numbers of IL-10 secreting CD1dCD5 B regulatory cells (B) in wild type mice. Our data show that co-administration of E2 and IL-10 B cells ameliorates EAE disease severity and limits CNS infiltrating leukocytes in B cell deficient mice. Additionally, treatment with E2 and B reduces demyelination and dramatically decreases the proportion of CD11bCD45 activated microglia/macrophages found in the CNS of immunized animals compared to vehicle, E2 or B cells alone. Furthermore, mice given E2 and B exhibit increased numbers of peripheral programmed death-1 positive CD4Foxp3 regulatory T cells (T) and up-regulation of programmed death receptor-ligand-1 and CD80 expression on monocytes. Our study suggests IL-10 producing B have powerful therapeutic potential as an agent against EAE when augmented with E2 treatment. [ABSTRACT FROM AUTHOR]

This study explored differences in the center of pressure in healthy people in a sitting and standing position and with eyes open and closed. With this purpose, 32 healthy participants (16 men, 16 women; M age = 25.2 yr., SD = 10.0, range = 18-55) were measured with an extensiometric force plate. Using a two-way repeated-measures multivariate analysis of variance (MANOVA), the root mean square, velocity, range, and sway, in both visual conditions, had higher values in the standing task than in the sitting task. In the frequency domain, the low-frequency band had higher values during the standing task. For control mechanism variables, mean distance and time were greater when standing while mean peaks were greater when sitting. Thus, stability is worse in the standing position and more neuromuscular activity is required to maintain balance. [ABSTRACT FROM AUTHOR]

Macrophages are important players in the fight against viral, bacterial, fungal and parasitic infections. From a resting state they may undertake two activation pathways, the classical known as M1, or the alternative known as M2. M1 markers are mostly mediators of pro-inflammatory responses whereas M2 markers emerge for resolution and cleanup. Microglia exerts in the central nervous system (CNS) a function similar to that of macrophages in the periphery. Microglia activation and proliferation occurs in almost any single pathology affecting the CNS. Often microglia activation has been considered detrimental and drugs able to stop microglia activation were considered for the treatment of a variety of diseases. Cumulative evidence shows that microglia may undergo the alternative activation pathway, express M2-type markers and contribute to neuroprotection. This review focuses on details about the role of M2 microglia and in the approaches available for its identification. Approaches to drive the M2 phenotype and data on its potential in CNS diseases are also reviewed. [ABSTRACT FROM AUTHOR]

Adenosine is a naturally occurring purine nucleoside in every cell. Many critical treatments such as modulating irregular heartbeat (arrhythmias), regulation of central nervous system (CNS) activity and inhibiting seizural episodes can be carried out using adenosine. Despite the significant potential therapeutic impact of adenosine and its derivatives, the severe side effects caused by their systemic administration have significantly limited their clinical use. In addition, due to adenosine’s extremely short half-life in human blood (<10 s), there is an unmet need for sustained delivery systems to enhance efficacy and reduce side effects. In this article, various adenosine delivery techniques, including encapsulation into biodegradable polymers, cell-based delivery, implantable biomaterials and mechanical-based delivery systems, are critically reviewed and the existing challenges are highlighted. [ABSTRACT FROM PUBLISHER]

In-frame fusion KIF5B (the-kinesin-family-5B-gene)-RET transcripts have been characterized in 1–2% of non-small cell lung cancers and are known oncogenic drivers. The RET tyrosine kinase inhibitor, vandetanib, suppresses fusion-induced, anchorage-independent growth activity. In vitro studies have shown that vandetanib is a high-affinity substrate of breast cancer resistance protein (Bcrp1/Abcg2) but is not transported by P-glycoprotein (P-gp), limiting its blood–brain barrier penetration. A co-administration strategy to enhance the brain accumulation of vandetanib by modulating P-gp/Abcb1- and Bcrp1/Abcg2-mediated efflux with mTOR inhibitors, specifically everolimus, was shown to increase the blood–brain barrier penetration. We report the first bench-to-bedside evidence that RET inhibitor combined with an mTOR inhibitor is active against brain-metastatic RET-rearranged lung cancer and the first evidence of blood–brain barrier penetration. A 74-year-old female with progressive adenocarcinoma of the lung (wild-type EGFR and no ALK rearrangement) presented for therapy options. A deletion of 5′RET was revealed by FISH assay, indicating RET-gene rearrangement. Because of progressive disease in the brain, she was enrolled in a clinical trial with vandetanib and everolimus ( NCT01582191 ). Comprehensive genomic profiling revealed fusion of KIF5B (the-kinesin-family-5B-gene) and RET, in addition to AKT2 gene amplification. After two cycles of therapy a repeat MRI brain showed a decrease in the intracranial disease burden and PET/CT showed systemic response as well. Interestingly, AKT2 amplification seen is a critical component of the PI3K/mTOR pathway, alterations of which has been associated with both de novo and acquired resistance to targeted therapy. The addition of everolimus may have both overcome the AKT2 amplification to produce a response in addition to its direct effects on the RET gene. Our case report forms the first evidence of blood–brain barrier penetration by vandetanib in combination with everolimus. Further research is required in this setting. [ABSTRACT FROM AUTHOR]

The article focuses on the MyoKinesthetic (MYK) System developed by doctor Michael Uriarte, which helps in identifying posture asymmetries that result in pain. Topics include aim of the concept for balancing the nervous system through application of chiropractic treatment, postural analysis by the system with a patient in standing position, the system improving communication between muscles and the central nervous system (CNS) and movements being performed bilaterally under the system.

Human immunodeficiency virus type-1 (HIV-1) invades the central nervous system (CNS) during acute infection which can result in HIV-associated neurocognitive disorders in up to 50 % of patients, even in the presence of combination antiretroviral therapy (cART). Within the CNS, productive HIV-1 infection occurs in the perivascular macrophages and microglia. Astrocytes also become infected, although their infection is restricted and does not give rise to new viral particles. The major barrier to the elimination of HIV-1 is the establishment of viral reservoirs in different anatomical sites throughout the body and viral persistence during long-term treatment with cART. While the predominant viral reservoir is believed to be resting CD4 T cells in the blood, other anatomical compartments including the CNS, gut-associated lymphoid tissue, bone marrow, and genital tract can also harbour persistently infected cellular reservoirs of HIV-1. Viral latency is predominantly responsible for HIV-1 persistence and is most likely governed at the transcriptional level. Current clinical trials are testing transcriptional activators, in the background of cART, in an attempt to purge these viral reservoirs and reverse viral latency. These strategies aim to activate viral transcription in cells constituting the viral reservoir, so they can be recognised and cleared by the immune system, while new rounds of infection are blocked by co-administration of cART. The CNS has several unique characteristics that may result in differences in viral transcription and in the way latency is established. These include CNS-specific cell types, different transcription factors, altered immune surveillance, and reduced antiretroviral drug bioavailability. A comprehensive understanding of viral transcription and latency in the CNS is required in order to determine treatment outcomes when using transcriptional activators within the CNS. [ABSTRACT FROM AUTHOR]

Since the onset of the HIV epidemic, there has been a shift from a deadly diagnosis to the management of a chronic disease. This shift is the result of the development of highly effective drugs that are able to suppress viral replication for years. The availability of these regimens has also shifted the neurocognitive pathology associated with infection from potentially devastating to a much milder phenotype. As the disease outcome has changed significantly with the availability of antiretroviral therapy, there is an opportunity to re-evaluate the currently available models to address the neurocognitive pathology seen in suppressed patients. In the following, we seek to summarize the current literature on humanized mouse models and their utility in understanding how HIV infection leads to changes in the central nervous system (CNS). Also, we identify some of the unanswered questions regarding HIV infection of the CNS as well as the opportunities and limitations of currently existing models to address those questions. Finally, our conclusions indicate that the earlier humanized models used to study HIV infection in the CNS provided an excellent foundation for the type of work currently being performed using novel humanized mouse models. We also indicate the potential of some humanized mouse models that have not been used as of this time for the analysis of HIV infection in the brain. [ABSTRACT FROM AUTHOR]

Too controversial to discuss only a short time ago, achieving a cure for HIV infection has become a priority in HIV research. However, substantial challenges must be overcome. Among key hurdles to be surmounted is the definition of a reliable, validated model in which to test latency reversal agents (LRAs), as current primary cell models differ in their response to such agents. Animal models such as the HIV-infected humanized BLT mouse and SIV-infected macaque will be essential to study LRAs and to quantify their effects in anatomic reservoirs. Of several potential anatomic reservoirs, the central nervous system presents a significant obstacle, as it is known to harbor persistent HIV infection and is difficult to access for study and therapeutic intervention. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic, autoimmune, inflammatory demyelinating disorder of the central nervous system that leads to permanent neurological deficits. Current MS treatment regimens are insufficient to treat the irreversible neurological disabilities. Tremendous progress in the experimental and clinical applications of cell-based therapies has recognized stem cells as potential candidates for regenerative therapy for many neurodegenerative disorders including MS. Mesenchymal stem cells (MSC) and induced pluripotent stem cell (iPSCs) derived precursor cells can modulate the autoimmune response in the central nervous system (CNS) and promote endogenous remyelination and repair process in animal models. This review highlights studies involving the immunomodulatory and regenerative effects of mesenchymal stem cells and iPSCs derived cells in animal models, and their translation into immunomodulatory and neuroregenerative treatment strategies for MS. [ABSTRACT FROM AUTHOR]

Background Mixed cannabinoid receptor 1 and 2 (CB 1 and CB 2 ) agonists such as Δ 9 -tetrahydrocannabinol (Δ 9 -THC) can produce tolerance, physical withdrawal, and unwanted CB 1 -mediated central nervous system side effects. Whether repeated systemic administration of a CB 2 -preferring agonist engages CB 1 receptors or produces CB 1 -mediated side effects is unknown. Methods We evaluated antiallodynic efficacy, possible tolerance, and cannabimimetic side effects of repeated dosing with a CB 2 -preferring agonist AM1710 in a model of chemotherapy-induced neuropathy produced by paclitaxel using CB 1 knockout (CB 1 KO), CB 2 knockout (CB 2 KO), and wild-type (WT) mice. Comparisons were made with the prototypic classic cannabinoid Δ 9 -THC. We also explored the site and possible mechanism of action of AM1710. Results Paclitaxel-induced mechanical and cold allodynia developed to an equivalent degree in CB 1 KO, CB 2 KO, and WT mice. Both AM1710 and Δ 9 -THC suppressed established paclitaxel-induced allodynia in WT mice. In contrast to Δ 9 -THC, chronic administration of AM1710 did not engage CB 1 activity or produce antinociceptive tolerance, CB 1 -mediated cannabinoid withdrawal, hypothermia, or motor dysfunction. Antiallodynic efficacy of systemic administration of AM1710 was absent in CB 2 KO mice and WT mice receiving the CB 2 antagonist AM630, administered either systemically or intrathecally. Intrathecal administration of AM1710 also attenuated paclitaxel-induced allodynia in WT mice, but not CB 2 KO mice, implicating a possible role for spinal CB 2 receptors in AM1710 antiallodynic efficacy. Finally, both acute and chronic administration of AM1710 decreased messenger RNA levels of tumor necrosis factor-α and monocyte chemoattractant protein 1 in lumbar spinal cord of paclitaxel-treated WT mice. Conclusions Our results highlight the potential of prolonged use of CB 2 agonists for managing chemotherapy-induced allodynia with a favorable therapeutic ratio marked by sustained efficacy and absence of tolerance, physical withdrawal, or CB 1 -mediated side effects. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), for which current treatments are unable to prevent disease progression. Based on its neuroprotective and neuroregenerating properties, leukemia inhibitory factor (LIF), a member of the interleukin-6 (IL-6) cytokine family, is proposed as a novel candidate for MS therapy. However, its effect on the autoimmune response remains unclear. In this study, we determined how LIF modulates T cell responses that play a crucial role in the pathogenesis of MS. We demonstrate that expression of the LIF receptor was strongly increased on immune cells of MS patients. LIF treatment potently boosted the number of regulatory T cells (Tregs) in CD4 + T cells isolated from healthy controls and MS patients with low serum levels of IL-6. Moreover, IL-6 signaling was reduced in the donors that responded to LIF treatment in vitro . Our data together with previous findings revealing that IL-6 inhibits Treg development, suggest an opposing function of LIF and IL-6. In a preclinical animal model of MS we shifted the LIF/IL-6 balance in favor of LIF by CNS-targeted overexpression. This increased the number of Tregs in the CNS during active autoimmune responses and reduced disease symptoms. In conclusion, our data show that LIF downregulates the autoimmune response by enhancing Treg numbers, providing further impetus for the use of LIF as a novel treatment for MS and other autoimmune diseases. [ABSTRACT FROM AUTHOR]

The increasing incidence of diseases affecting the central nervous system (CNS) demands the urgent development of efficient drugs. While many of these medicines are already available, the Blood Brain Barrier and to a lesser extent, the Blood Spinal Cord Barrier pose physical and biological limitations to their diffusion to reach target tissues. Therefore, efforts are needed not only to address drug development but specially to design suitable vehicles for delivery into the CNS through systemic administration. In the context of the functional and structural versatility of proteins, recent advances in their biological fabrication and a better comprehension of the physiology of the CNS offer a plethora of opportunities for the construction and tailoring of plain nanoconjugates and of more complex nanosized vehicles able to cross these barriers. We revise here how the engineering of functional proteins offers drug delivery tools for specific CNS diseases and more transversally, how proteins can be engineered into smart nanoparticles or ‘artificial viruses’ to afford therapeutic requirements through alternative administration routes. [ABSTRACT FROM AUTHOR]

Multiple Sclerosis (MS) is a chronic inflammatory neurodegenerative disease of central nervous system (CNS). Although the main cause of MS is not clear, studies suggest that MS is an autoimmune disease which attacks myelin sheath of neurons. There are different therapeutic regimens for MS patients including interferon (IFN)-β, glatiramer acetate (GA), and natalizumab. However, such therapies are not quite effective and are associated with some side effects. So which, there is no complete therapeutic method for MS patients. Regarding the potent immunomodulatory effects of mesenchymal stem cells (MSCs) and their ameliorative effects in experimental autoimmune encephalopathy (EAE), it seems that MSCs may be a new therapeutic method in MS therapy. MSC transplantation is an approach to regulate the immune system in the region of CNS lesions. In this review, we have tried to discuss about the immunomodulatory properties of MSCs and their therapeutic mechanisms in MS patients. [ABSTRACT FROM AUTHOR]