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Background Oral octreotide capsules (OOC) are a treatment option for patients with acromegaly in the United States. The MPOWERED trial (NCT02685709) showed that OOC were noninferior to injectable somatostatin receptor ligands (iSRLs; octreotide or lanreotide) in maintenance of biochemical control in patients previously responding to both treatments, as well as demonstrated improvements in patient-reported outcomes among patients receiving OOC. Objective Report long-term safety and efficacy outcomes with OOC from the open-label extension (OLE) of MPOWERED. Methods Patients were eligible for and could voluntarily enroll into the OLE if they had completed the 15-month core treatment phase of MPOWERED (6-month Run-in phase plus 9-month randomized controlled treatment [RCT] phase or, for OOC nonresponders during/at end of Run-in at participating sites, combination sub-study evaluating OOC in combination with cabergoline) and were adequately biochemically controlled per investigator assessment. Maintenance of response (definition: IGF-I Results Sixty patients elected to enroll in the OLE (35 who received OOC and 19 who received iSRLs in the RCT phase, 6 from the combination sub-study). Median and maximal OOC exposure durations in the OLE were 2.2 and 3.5 years, respectively. A total of 94%, 90%, and 93% of patients receiving OOC monotherapy maintained biochemical response at the end of years 1, 2, and 3 of the OLE, respectively (using last observation carried forward imputation). Of patients switching from iSRLs to OOC during the OLE, 79% reported very good (47%) or excellent (32%) symptom control at the end of the OLE, compared with 47% (42% very good, 5% excellent) at the end of the RCT phase while receiving iSRLs. Patients switching from iSRLs also experienced significant improvements in the treatment convenience and treatment satisfaction domains (both P Conclusions The OLE of MPOWERED demonstrated a high percentage (≥90%) of patients maintaining biochemical response while receiving OOC monotherapy with a favorable long-term safety profile of OOC. Those who switched from iSRLs to OOC demonstrated improvements in symptom control, treatment convenience, and treatment satisfaction. Presentation: Sunday, June 12, 2022 1:12 p.m. - 1:17 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Background: Injectable somatostatin receptor ligands (iSRLs) have been a mainstay in acromegaly treatment. Oral octreotide capsules (OOC; MYCAPSSA®) were recently approved in the United States. Results from the placebo-controlled CHIASMA OPTIMAL and open-label CH-ACM-01 studies showed an OOC safety profile consistent with that of iSRLs with no new or unexpected safety signals. Results of the MPOWERED trial have enabled a comparison of OOC safety and efficacy with iSRLs. Methods: To enter MPOWERED, patients must have the following: acromegaly diagnosis, biochemical control of acromegaly (insulin-like growth factor I Results: In the RCT, incidence of treatment-emergent adverse events (TEAEs) was similar between groups; 39 patients (70.9%) in the OOC group and 26 (70.3%) in the iSRL group had ≥1 TEAE. 19 patients (34.5%) in the OOC and 15 (40.5%) in the iSRL group had treatment-related TEAEs. Occurrence was similar for serious AEs (OOC, 5.5%; iSRL, 8.1%) as well as TEAEs classified as severe (OOC, 9.1%; iSRL, 10.8%). One patient in the OOC group discontinued due to a TEAE. The most common gastrointestinal TEAEs were flatulence (OOC, 25.5%; iSRL, 21.6%), nausea (OOC, 20.0%; iSRL, 8.1%), diarrhea (OOC, 10.9%; iSRL, 13.5%), abdominal pain (OOC, 9.1%; iSRL, 8.1%), and constipation (OOC, 5.5%; iSRL, 13.5%). AEs of interest were infrequent, including cholelithiasis (OOC, n=0; iSRL, n=1 [2.7%]) and secondary hypothyroidism (OOC, n=1 [1.8%]; iSRL, n=0). In the iSRL group, 32.4% of patients reported injection site reactions (ISRs) during the RCT, and 47% of patients reported ISRs as part of the Acromegaly Treatment Satisfaction Questionnaire, a newly validated patient-reported outcome tool.1 Conclusion: Safety results from MPOWERED align with prior trials, showing that the OOC safety profile is consistent with that of iSRLs as well as the acromegaly disease burden. No new or unexpected safety signals were identified during the trial. Safety results were mostly similar between OOC and iSRLs, although patients in the OOC group did not experience any ISRs. 1Fleseriu M, et al. Pituitary. 2020 Aug;23(4):347-358.

Background: In clinical practice, most patients responding to injectable somatostatin receptor ligands exhibit IGF-I variability around the upper limit of normal (ULN) during long-term follow up. These fluctuations are thought to result from various factors such as assay variability, nutrition, comorbid conditions, concomitant medications and other unknown factors. The magnitude of this variability, and the factors affecting it, is not well understood in patients with acromegaly treated with injectable SRLs. Methods: IGF-I levels of patients responding to and stably treated with injectable SRLs were measured over time in the CHIASMA OPTIMAL phase III study. Two time periods were assessed - Period 1, three assessments during screening phase before randomization to octreotide capsules (N=56), and Period 2 - multiple assessments up to week 36, in patients rescued with SRL injections for at least 12 weeks (N=21). The time from the last injection to each of the 3 assessments in period 1 [Screening visits 1 and 2 (SV1 & SV2), and Baseline (BL)], was on average 6.8 ± 10.7 (SD), 15.8 ± 2.7, and 29.0 ± 1.8 days respectively. Correlation with various demographics and Baseline characteristics, including age, gender, weight, BMI and residual tumor size to IGF-I variability was assessed. Percent change for each individual patient from Minimal to Maximal IGF-I values within each period was computed and the overall population mean was calculated (lowest value was used as the denominator and all other values were expression as a positive % above this value). Results: The overall mean within-patient percent change of IGF-I levels during Period 1 was 20.48 ± 15.56 (range: 0.6-81). Mean IGF-I levels for SV1, SV2 and BL were 0.78 ± 0.18, 0.79 ± 0.18, and 0.85 ± 0.22 x ULN respectively. The overall increase in mean IGF-I levels from SV1 to BL (longest time interval) was statistically significant (p=0.0002; paired T-test). Analysis of IGF-I levels in patients during Period 2, revealed that the overall mean within-patient percent change of IGF-I levels was 15.27 ± 12.20 (range: 0-41.5). The mean duration of follow up during this period, after patients were already treated for ≥12 weeks with injectable SRL, was 1.72 (± 1.29) months. The variability observed in Period 2 was similar to that observed in the entire sample evaluated in Period 1. No significant differences were found in the mean IGF-I percent change between any demographic or baseline characteristic subgroup examined. Conclusion: IGF-I levels fluctuate in patients with acromegaly who are responsive to injectable SRLs. These fluctuations are wide and can be up to 81% higher than the lowest (most controlled) value, with an average increase of approximately 20%. Significant IGF-I increases were observed at the end of the long acting SRL injection interval. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Background: MPOWERED, a large phase 3 trial, assessed maintenance of response to oral octreotide capsules (OOC; MYCAPSSA®) compared to injectable somatostatin receptor ligands (iSRLs) in patients with acromegaly who responded to OOC and iSRLs (octreotide or lanreotide). OOC were recently approved in the US for patients with acromegaly who responded to and tolerated iSRLs. Methods: Eligibility criteria included age 18-75 years at screening, acromegaly diagnosis, disease evidence, biochemical control (insulin-like growth factor I [IGF-I] Results: Of 146 enrolled patients, 92 entered the RCT (OOC, n=55; iSRLs, n=37). Both arms were well balanced for age, sex, and acromegaly duration. OOC demonstrated noninferiority to iSRLs in maintaining biochemical response, with 91% (CI, 80%-97%) of OOC and 100% (CI, 91%-100%) of iSRL groups maintaining control during the RCT. Of those responding at end of Run-in, 96% of patients on OOC maintained response during RCT. Using nonresponse imputation, 89% of OOC and 95% of iSRL groups were biochemically controlled in RCT. Landmark analysis of those respnding at end of Run-in showed that 94% of patients in each group maintained response at RCT end. In both groups, IGF-I levels were stable in the RCT, average IGF-I at baseline and RCT end being 0.9 × ULN (OOC) and 0.8 × ULN (iSRL). Mean change in GH from RCT start to RCT end was -0.03 ng/mL (OOC) and +0.29 ng/mL (iSRL). Safety data were mostly similar between groups; the OOC group did not experience injection site reactions. Conclusion: In this noninferiority trial in patients with acromegaly, OOC demonstrated maintenance of biochemical response compared to iSRLs. Results support the efficacy of OOC as a possible iSRL alternative.

Aims In previous studies, the histamine-3 receptor antagonist CEP-26401 had a subtle effect on spatial working memory, with the best effect seen at the lowest dose tested (20 μg), and a dose-dependent disruption of sleep. In the current study, 3 low-dose levels of CEP-26401 were compared with modafinil and donepezil. Methods In this double-blind, placebo- and positive-controlled, randomized, partial 6-way cross-over study, 40 healthy subjects received single doses of placebo, CEP-26401 (5, 25 or 125 μg) or modafinil 200 mg or donepezil 10 mg. Pharmacokinetic and pharmacodynamic measurements were performed predose and at designated time points postdose. Results The main endpoint between-errors of the spatial working memory-10-boxes task only improved for the 125 μg dose of CEP-26401 with a difference of 2.92 (confidence interval [CI] -1.21 to 7.05), 3.24 (CI -1.57 to 8.04) and 7.45 (CI 2.72 to 12.19) for respectively the 5, 25 and 125 μg dose of CEP-26401, -1.65 (CI -0.572 to 1.96) for modafinil and - 3.55 (CI -7.13 to 0.03) for donepezil. CEP-26401 induced an improvement of adaptive tracking, saccadic peak velocity and reaction time during N-back, but a dose-related inhibition of sleep and slight worsening of several cognitive parameters at the highest dose. CEP-26401 significantly changed several subjective visual analogue scales, which was strongest at 25 μg, causing the same energizing and happy feeling as modafinil, but with a more relaxed undertone. Discussion Of the doses tested, the 25 μg dose of CEP-26401 had the most optimal balance between favourable subjective effects and sleep inhibition. Whether CEP-26401 can have beneficial effects in clinical practice remains to be studied.

Glatiramer acetate (GA) is approved for relapsing-remitting multiple sclerosis in 57 countries worldwide, with more than 2 million patient-years of exposure and over 20 years of continuous clinical use without new safety concerns. GA has an overall favorable risk-benefit profile: 30% reduced annual relapse rate and decreased brain lesion activity. In clinically definite MS or clinically isolated syndrome, GA slows brain atrophy, which may be related to its unique anti-inflammatory and neuroprotective mechanisms of action. Early treatment with GA delays the onset of clinically definite MS more effectively than late treatment in clinically isolated syndrome. GA is not associated with immunosuppression, autoimmune disease, infections or development of neutralizing antibodies. A new three-times-weekly formulation of GA is available to potentially reduce the incidence of injection-related side effects. Other safety advantages of GA include its pregnancy rating (Category B) and limited uncontrolled data suggesting that tolerability is similar in children with MS.

Human plasma butyrylcholinesterase (BChE) contributes to cocaine metabolism and has been considered for use in treating cocaine addiction and cocaine overdose. TV-1380 is a recombinant protein composed of the mature form of human serum albumin fused at its amino terminus to the carboxy-terminus of a truncated and mutated BChE. In preclinical studies, TV-1380 has been shown to rapidly eliminate cocaine in the plasma thus forestalling entry of cocaine into the brain and heart. Two randomized, blinded phase I studies were conducted to evaluate the safety, pharmacokinetics, and pharmacodynamics of TV-1380, following single and multiple administration in healthy subjects. TV-1380 was found to be safe and well tolerated with a long half-life (43-77 hours) and showed a dose-proportional increase in systemic exposure. Consistent with preclinical results, the ex vivo cocaine hydrolysis, TV-1380 activity clearly increased upon treatment in a dose-dependent manner. In addition, there was a direct relationship between ex vivo cocaine hydrolysis (kel ) and TV-1380 serum concentrations. There was no evidence that TV-1380 affected heart rate, the uncorrected QT interval, or the heart-rate-corrected QTcF interval. TV-1380, therefore, offers a safe once-weekly therapy to increase cocaine hydrolysis.

Parkinson's disease (PD) and related synucleinopathies are characterized by extensive neuronal cell loss, which is potentially triggered by α-synuclein misfolding and aggregation. Therefore it is reasonable to suggest that treatments targeting α-synuclein could reduce its levels and toxicity, rescue neuronal cells and halt the neurodegeneration process. Several approaches to decrease α-synuclein levels were employed thus far, mainly by using β-synuclein, another protein from the same family, or immunotherapies. These treatments demonstrated some positive results in preclinical studies, which may pave the road to the development of new promising disease-modifying therapies (DMTs). This approach should be further examined in preclinical and clinical settings, together with a clear process in order to advance candidates, enable the ability to define when there are target engagements and to detect what is a meaningful pharmacological response, and how it will be translated in clinical efficacy.

It is believed that oxidative stress (OS) plays an important role in the loss of dopaminergic nigrostriatal neurons in Parkinson's disease (PD) and that treatment with antioxidants might be neuroprotective. However, most currently available antioxidants cannot readily penetrate the blood brain barrier after systemic administration. We now report that AD4, the novel low molecular weight thiol antioxidant and the N-acytel cysteine (NAC) related compound, is capable of penetrating the brain and protects neurons in general and especially dopaminergic cells against various OS-generating neurotoxins in tissue cultures. Moreover, we found that treatment with AD4 markedly decreased the damage of dopaminergic neurons in three experimental models of PD. AD4 suppressed amphetamine-induced rotational behaviour in rats with unilateral 6-OHDA-induced nigral lesion. It attenuated the reduction in striatal dopamine levels in mice treated with 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP). It also reduced the dopaminergic neuronal loss following chronic intrajugular administration of rotenone in rats. Our findings suggest that AD4 is a novel potential new neuroprotective drug that might be effective at slowing down nigral neuronal degeneration and illness progression in patients with PD.

Accumulating data from experimental studies indicate that oxidative stress has a major role in the pathogenesis of multiple sclerosis (MS). It has been suggested that local production of reactive oxygen species, probably by macrophages, mediates axonal damage in both MS patients and the mouse model experimental autoimmune encephalomyelitis (EAE). We have shown previously that our novel brain-penetrating antioxidant, N-acetylcysteine amide (AD4), reduces the clinical and pathological symptoms, including inflammation and axonal damage in myelin oligodendrocyte glycoprotein (MOG)-induced chronic EAE in mice. The aim of this study was to examine the molecular mechanism by which AD4 exerts protection in MOG-induced EAE mice. Therefore, we analyzed gene-expression profile in the spinal cords of MOG-induced chronic EAE mice and compared them with MOG-induced mice treated with AD4, using a cDNA microarray. We found that MOG treatment up-regulated genes encoding growth factors, cytokines, death receptors, proteases, and myelin structure proteins, whereas MOG- and AD4-treated mice demonstrated gene expression profiles similar to that seen in naive healthy mice. In conclusion, our study shows that chronic AD4 administration suppresses the induction of various pathological pathways that play a role in EAE and probably in MS.

Accumulating data indicate that oxidative stress (OS) plays a major role in the pathogenesis of multiple sclerosis (MS). Reactive oxygen species (ROS), leading to OS, generated in excess primarily by macrophages, have been implicated as mediators of demyelination and axonal damage in both MS and experimental autoimmune encephalomyelitis (EAE), its animal model. ROS cause damage to cardinal cellular components such as lipids, proteins and nucleic acids (e. g., RNA, DNA), resulting in cell death by necrosis or apoptosis. In addition, weakened cellular antioxidant defense systems in the central nervous system (CNS) in MS, and its vulnerability to ROS effects may increase damage. Thus, treatment with antioxidants might theoretically prevent propagation of tissue damage and improve both survival and neurological outcome. Indeed, several experimental studies have been performed to see whether dietary intake of several antioxidants prevents or reduces the progression of EAE. Although a few antioxidants showed some efficacy in these studies, little information is available on the effect of treatments with such compounds in patients with MS. Well-designed clinical studies using antioxidant intake, as well as investigations based on larger cohorts studied over a longer periods of time, are needed in order to assess whether antioxidant intake together with other conventional treatments, might be beneficial in treating MS.

Parkinson's disease is a chronic neurodegenerative disease of the extrapyramidal system associated with dopaminergic neuronal loss in the basal ganglia. However, several other neurotransmitters, such as serotonin, gamma-amino-butyric acid and glutamate, are also related to the symptoms of Parkinson's disease patients and their response to levodopa treatment. The co-expression of cannabinoid and dopamine receptors in the basal ganglia suggests a potential role for endocannabinoids in the control of voluntary movement in Parkinson's disease. In the present study we treated unilaterally 2,4,5-trihydroxyphenethylamine (6-hydroxydopamine)-lesioned rats with the enantiomers of the synthetic cannabinoid 7-hydroxy-delta6-tetrahydrocannabinol 1,1-dimethylheptyl. Treatment with its (-)- (3R, 4R) enantiomer (code-name HU-210), a potent cannabinoid receptor type 1 agonist, reduced the rotations induced by levodopa/carbidopa or apomorphine by 34% and 44%, respectively. In contrast, treatment with the (+)- (3S, 4S) enantiomer (code-name HU-211), an N-methyl-D-aspartate antagonist, as well as the psychotropically inactive cannabis constituent: cannabidiol and its primary metabolite, 7-hydroxy-cannabinol, did not show any reduction of rotational behavior. Our results indicate that activation of the CB1 stimulates the dopaminergic system ipsilaterally to the lesion, and may have implications in the treatment of Parkinson's disease.

Free radicals are highly reactive molecules generated predominantly during cellular respiration and normal metabolism. Imbalance between cellular production of free radicals and the ability of cells to defend against them is referred to as oxidative stress (OS). OS has been implicated as a potential contributor to the pathogenesis of acute central nervous system (CNS) injury. After brain injury by ischemic or hemorrhagic stroke or trauma, the production of reactive oxygen species (ROS) may increase, sometimes drastically, leading to tissue damage via several different cellular molecular pathways. Radicals can cause damage to cardinal cellular components such as lipids, proteins, and nucleic acids (e.g., DNA), leading to subsequent cell death by modes of necrosis or apoptosis. The damage can become more widespread due to weakened cellular antioxidant defense systems. Moreover, acute brain injury increases the levels of excitotoxic amino acids (such as glutamate), which also produce ROS, thereby promoting parenchymatous destruction. Therefore, treatment with antioxidants may theoretically act to prevent propagation of tissue damage and improve both the survival and neurological outcome. Several such agents of widely varying chemical structures have been investigated as therapeutic agents for acute CNS injury. Although a few of the antioxidants showed some efficacy in animal models or in small clinical studies, these findings have not been supported in comprehensive, controlled trials in patients. Reasons for these equivocal results may include, in part, inappropriate timing of administration or suboptimal drug levels at the target site in CNS. Better understanding of the pathological mechanisms of acute CNS injury would characterize the exact primary targets for drug intervention. Improved antioxidant design should take into consideration the relevant and specific harmful free radical, blood brain barrier (BBB) permeability, dose, and time administration. Novel combinations of drugs providing protection against various types injuries will probably exploit the potential synergistic effects of antioxidants in stroke.

Oxidative stress (OS) has been implicated in the pathophysiology of many neurological, particularly neurodegenerative diseases. OS can cause cellular damage and subsequent cell death because the reactive oxygen species (ROS) oxidize vital cellular components such as lipids, proteins, and DNA. Moreover, the brain is exposed throughout life to excitatory amino acids (such as glutamate), whose metabolism produces ROS, thereby promoting excitotoxicity. Antioxidant defense mechanisms include removal of O(2), scavenging of reactive oxygen/nitrogen species or their precursors, inhibition of ROS formation, binding of metal ions needed for the catalysis of ROS generation and up-regulation of endogenous antioxidant defenses. However, since our endogenous antioxidant defenses are not always completely effective, and since exposure to damaging environmental factors is increasing, it seems reasonable to propose that exogenous antioxidants could be very effective in diminishing the cumulative effects of oxidative damage. Antioxidants of widely varying chemical structures have been investigated as potential therapeutic agents. However, the therapeutic use of most of these compounds is limited since they do not cross the blood brain barrier (BBB). Although a few of them have shown limited efficiency in animal models or in small clinical studies, none of the currently available antioxidants have proven efficacious in a large-scale controlled study. Therefore, any novel antioxidant molecules designed as potential neuroprotective treatment in acute or chronic neurological disorders should have the mandatory prerequisite that they can cross the BBB after systemic administration.

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS), often beginning in late adolescence and early adult life. The etiology of MS has not yet been fully elucidated, and it is attributed to both genetic and environmental causes. Accumulating data indicate that oxidative stress (OS) plays a major role in the pathogenesis of MS. Reactive oxygen species (ROS), leading to OS, generated in excess primarily by macrophages, have been implicated as mediators of demyelination and axonal damage in both MS and its animal model: experimental autoimmune encephalomyelitis (EAE). ROS cause damage to cardinal cellular components such as lipids, proteins, and nucleic acids, thereby resulting in cell death. Weakened cellular antioxidant defense systems in the CNS of MS patients resulting in increased vulnerability to ROS effects may increase CNS damage. This chapter reviews the current knowledge on OS in MS and possible antioxidant treatments.

western world, resulting in chronic disability in many cases. Although huge efforts have been made in the search for effective treatment, so far results have been quite disappointing. Recently, cell replacement therapy has emerged as an experimental approach aiming to restore brain function, which is impaired in several neurodegenerative diseases, as well as in stroke. Porcine fetal cells, neuronal progenitor cells (NPCs), embryonic stem cells (ESCs), immortalized cell lines, bone marrow stromal cells (BMSCs), and umbilical cord blood cells (UCBCs) have been introduced as potential sources for neuronal cells in experimental and clinical stroke trials. However, limited knowledge about their biology (including long-term safety) and insufficient data regarding several issues such as the preferred stroke type and its severity, specific location of the injection, and the preferred cell type restrict their potential clinical use. Therefore, further research on the molecular mechanisms of stroke, the candidate cell lines for transplantation, and bioengineering strategies, is needed before this technique can be implemented safely and effectively in stroke victims.

BACKGROUND Tardive dyskinesia (TD), characterized by abnormal movements, is the major late-onset chronic side effect of antipsychotic treatment found in about 30% of those patients. The association of oxidative stress and the release of free radicals is one of the hallmarks of dopaminergic malfunctions and is one of the leading theories suggested for the pathophysiology of TD. To this day, no brain-targeted antioxidant has been tested as a potential treatment of TD. In light of this assumption, the authors chose a novel, low-molecular weight thiol antioxidant, N-acetyl cysteine amide (AD4), that crosses the blood-brain barrier as a possible treatment of TD. OBJECTIVE To examine the protective effects of the novel brain-penetrating antioxidant AD4 on TD experimental models. METHODS The typical vacuous chewing movement occurs in rats following chronic haloperidol injections (1.5 mg/kg/day intraperitoneally for 21 days). This purposeless mouth opening in the vertical plane is similar to TD symptoms in humans. The authors tested rats treated with haloperidol without or with AD4 in the drinking water (1 g/kg orally). Thiobarbituric acid reactive substances and anticarbonyl antibodies were used to measure oxidation of membranes and proteins. RESULTS Haloperidol increased the vacuous chewing movements to 66.5 +/- 7.6 movements/5 minutes compared with 16.4 +/- 2.4 movements/5 minutes in untreated rats (P < 0.01). Coadministration of haloperidol and AD4 decreased the vacuous chewing movements level to 42.1 +/- 6.7 movements/5 minutes (P < 0.05). Haloperidol also increased the level of lipid peroxidation and protein oxidation in the rat brain, whereas coadministration with AD4 preserved their normal levels. CONCLUSION Haloperidol causes behavioral abnormalities associated with oxidative stress in rats, similar to TD. AD4, the brain-targeted potent antioxidant, reduces the cellular oxidation markers and improves the typical clinical behavior. Hence, AD4 is a potential new treatment of antipsychotic-induced TD.

There is a vast amount of evidence indicating that neurotrophic factors play a major role in the development, maintenance, and survival of neurons and neuron-supporting cells such as glia and oligodendrocytes. In addition, it is well known that alterations in levels of neurotrophic factors or their receptors can lead to neuronal death and contribute to the pathogenesis of neurodegenerative diseases such as Parkinson disease, Alzheimer disease, Huntington disease, amyotrophic lateral sclerosis, and also aging. Although various treatments alleviate the symptoms of neurodegenerative diseases, none of them prevent or halt the neurodegenerative process. The high potency of neurotrophic factors, as shown by many experimental studies, makes them a rational candidate co-therapeutic agent in neurodegenerative disease. However, in practice, their clinical use is limited because of difficulties in protein delivery and pharmacokinetics in the central nervous system. To overcome these disadvantages and to facilitate the development of drugs with improved pharmacotherapeutic profiles, research is underway on neurotrophic factors and their receptors, and the molecular mechanisms by which they work, together with the development of new technologies for their delivery into the brain.

It is believed that oxidative stress (OS) plays an important role in the loss of dopaminergic nigrostriatal neurons in Parkinson's disease (PD) and that treatment with antioxidants might be neuroprotective. However, most currently available antioxidants cannot readily penetrate the blood brain barrier after systemic administration. We now report that AD4, the novel low molecular weight thiol antioxidant and the N-acytel cysteine (NAC) related compound, is capable of penetrating the brain and protects neurons in general and especially dopaminergic cells against various OS-generating neurotoxins in tissue cultures. Moreover, we found that treatment with AD4 markedly decreased the damage of dopaminergic neurons in three experimental models of PD. AD4 suppressed amphetamine-induced rotational behaviour in rats with unilateral 6-OHDA-induced nigral lesion. It attenuated the reduction in striatal dopamine levels in mice treated with 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP). It also reduced the dopaminergic neuronal loss following chronic intrajugular administration of rotenone in rats. Our findings suggest that AD4 is a novel potential new neuroprotective drug that might be effective at slowing down nigral neuronal degeneration and illness progression in patients with PD.

Accumulating data from experimental studies indicate that oxidative stress has a major role in the pathogenesis of multiple sclerosis (MS). It has been suggested that local production of reactive oxygen species, probably by macrophages, mediates axonal damage in both MS patients and the mouse model experimental autoimmune encephalomyelitis (EAE). We have shown previously that our novel brain-penetrating antioxidant, N-acetylcysteine amide (AD4), reduces the clinical and pathological symptoms, including inflammation and axonal damage in myelin oligodendrocyte glycoprotein (MOG)-induced chronic EAE in mice. The aim of this study was to examine the molecular mechanism by which AD4 exerts protection in MOG-induced EAE mice. Therefore, we analyzed gene-expression profile in the spinal cords of MOG-induced chronic EAE mice and compared them with MOG-induced mice treated with AD4, using a cDNA microarray. We found that MOG treatment up-regulated genes encoding growth factors, cytokines, death receptors, proteases, and myelin structure proteins, whereas MOG- and AD4-treated mice demonstrated gene expression profiles similar to that seen in naive healthy mice. In conclusion, our study shows that chronic AD4 administration suppresses the induction of various pathological pathways that play a role in EAE and probably in MS.

Increasing evidence suggests that enhanced production of reactive oxygen species (ROS) activates the MAP kinases, c-Jun N-terminal protein kinase (JNK) and mitogen-activated protein kinase MAPK (p38). These phosphorylated intermediates at the stress-activated pathway induce expression of matrix metalloproteinases (MMPs), leading to inflammatory responses and pathological damages involved in the etiology of multiple sclerosis (MS). Here we report that N-acetylcysteine amide (AD4) crosses the blood-brain barrier (BBB), chelates Cu(2+), which catalyzes free radical formation, and prevents ROS-induced activation of JNK, p38 and MMP-9. In the myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, oral administration of AD4 drastically reduced the clinical signs, inflammation, MMP-9 activity, and protected axons from demylination damages. In agreement with the in vitro studies, we propose that ROS scavenging by AD4 in MOG-treated animals prevented MMP's induction and subsequent damages through inhibition of MAPK pathway. The low toxicity of AD4 coupled with BBB penetration makes this compound an excellent potential candidate for the therapy of MS and other neurodegenerative disorders.

Recent studies suggest that glutamate neurotoxicity is involved in the pathogenesis of multiple sclerosis (MS), and that treatment with glutamate receptor (AMPA/kainate) antagonists inhibits experimental autoimmune encephalomyelitis (EAE), the conventional model of MS. Therefore, we examined whether riluzole, an inhibitor of glutamate transmission, affects the pathogenesis and clinical features of MS-like disease in myelin oligodendrocyte glycoprotein (MOG)-induced EAE in mice. Here we report that riluzole (10 mg/kgx2/day, i.p.), administered before and even after the appearance of clinical symptoms, dramatically reduced the clinical severity of MOG-induced EAE, while all the MOG-immunized control mice developed significant clinical manifestations. Moreover, the riluzole-treated mice demonstrated only mild focal inflammation, and less demyelination, compared to MOG-treated mice, using histological methods. Furthermore, riluzole markedly reduced axonal disruption, as assessed by Bielshowesky's silver staining and by antibodies against non-phosphorylated neurofilaments (SMI-32). No difference was detected in the immune system potency, as T-cell proliferative responses to MOG were similar in both groups. In conclusion, our study demonstrates, for the first time, that riluzole can reduce inflammation, demyelination and axonal damage in the CNS and attenuate the clinical severity of MOG-induced EAE. These results suggest that riluzole, a drug used in amyotrophic lateral sclerosis (ALS), might be beneficial for the treatment of MS.

Glatiramer acetate (GA) is efficacious in reducing demyelinating-associated exacerbations in patients with relapsing-remitting multiple sclerosis (RRMS) and in several experimental autoimmune encephalomyelitis (EAE) models. Here we report that GA reduced the clinical and pathological signs of mice in chronic EAE induced by myelin oligodendrocyte glycoprotein (MOG). GA-treated mice demonstrated only mild focal inflammation, and less demyelination, compared with controls. Moreover, we also found minimal axonal disruption, as assessed by silver staining, antibodies against amyloid precursor protein (APP) and non-phosphorylated neurofilaments (SMI-32), in the GA-treated group. In conclusion, our study demonstrated for the first time that axonal damage is reduced following GA treatment in C57/bl mice with chronic MOG-induced EAE.

Accumulating data from experimental and human studies indicate that oxidative stress (OS) plays a major role in the pathogenesis of Alzheimer's disease (AD). The production of reactive oxygen species (ROS), which leads to OS, can occur very early, even before the appearance of symptoms and molecular events (beta-amyloid plaques and neurofibrillary tangles), leading to tissue damage via several different cellular molecular pathways. ROS can cause damage to cardinal cellular components such as lipids, proteins, and nucleic acids (e.g., RNA, DNA), causing cell death by modes of necrosis or apoptosis. The damage can become more widespread because of the weakened cellular antioxidant defense systems. Therefore, treatment with antioxidants might theoretically act to prevent propagation of tissue damage and improve both survival and neurological outcome. Indeed, several studies preformed to date examined whether dietary intake of several antioxidants, mainly vitamins, might prevent or reduce the progression of AD. Although a few of the antioxidants showed some efficacy in these trials, no answer is yet available as to whether antioxidants are truly protective against AD. Reasons for these results might include, in part, blood-brain barrier (BBB) permeability, inappropriate timing of administration, or suboptimal drug levels at the target site in the central nervous system. Thus, antioxidant cocktails or antioxidants combined with other drugs may have more successful synergistic effects. Further, well-designed intervention, as well as observational investigations based on large cohorts studied over a long period of time with several methods for assessing antioxidant exposure, including relation to BBB penetration, are needed to test this hypothesis.

Studies suggest that patients with relapsing-remitting multiple sclerosis (RRMS) who do not benefit from other disease-modifying treatments (DMTs) may benefit from converting to glatiramer acetate (GA). COPTIMIZE was a 24-month observational study designed to assess the disease course of patients converting to GA 20 mg daily from another DMT. Eligible patients had converted to GA and had received prior DMT for 3-6 months, depending on the reasons for conversion. Patients were assessed at baseline and at 6, 12, 18, and 24 months. In total, 672 patients from 148 centers worldwide were included in the analysis. Change of therapy to GA was prompted primarily by lack of efficacy (53.6 %) or intolerable adverse events (AEs; 44.8 %). Over a 24-month period, 72.7 % of patients were relapse free. Mean annual relapse rate decreased from 0.86 [95 % confidence interval (CI) 0.81-0.91] before the change to 0.32 (95 % CI 0.26-0.40; p0.0001) at last observation, while the progression of disability was halted, as the Kurtzke Expanded Disability Status Scale (EDSS) scores remained stable. Patients improved significantly (p0.05) on measures of fatigue, quality of life, depression, and cognition; mobility scores remained stable. The results indicate that changing RRMS patients to GA is associated with positive treatment outcomes.

Background TV‐1380 (AlbuChE) is a novel recombinant fusion protein of mutated butyrylcholinesterase (BChE) that has increased catalytic efficiency for cocaine metabolism compared to wild-type BChE. Methods Intra-muscular injections of TV-1380 (150 mg or 300 mg) or placebo were administered once weekly to participants (n = 66–69 per group) in a randomized, double-blind study to evaluate the ability of TV-1380 to facilitate abstinence in treatment-seeking, cocaine-dependent individuals. The primary endpoint was the proportion of participants achieving abstinence from cocaine during the last three weeks of the 12 week treatment phase, based on daily self-report of “no use” confirmed by urine testing. Results Although there were no significant differences between the TV-1380 treatment groups and placebo for the primary endpoint, 6% of participants in the 150 mg and 300 mg TV-1380 groups and no participants in the placebo group achieved abstinence. For the only declared secondary endpoint, there was a dose-dependent increase in the group mean percentage of urine samples testing negative for cocaine metabolites during weeks 5–12 (8.1% and 14.6% for the 150 mg and 300 mg TV-1380 groups, respectively, compared to 4.7% for the placebo group; p = 0.0056 for 300 mg vs. placebo). No meaningful differences in adverse events were seen between treatment groups. Conclusions While the apparent reduction in cocaine use may be of insufficient magnitude to justify further trials of TV-1380 in cocaine dependence, the results argue for development of improved enzymes with greater catalytic activity.

Background Studies suggest that patients with relapsing–remitting multiple sclerosis (RRMS) who fail to benefit from a disease-modifying treatment (DMT) may benefit from converting to another DMT class. COPTIMIZE was a 24-month observational study designed to assess the disease course of patients converting to glatiramer acetate (GA) 20 mg daily from another DMT and the association of disease characteristics and reasons for converting. This sub-analysis was to determine if any findings varied by three geographic locations: Latin America (LA), Canada and Western Europe (CWE), and Eastern Europe (EE). Methods A total of 668 patients were included (263 LA, 248 CWE, 157 EE) in an analysis of annualized relapse rate (ARR) and annualized rate of deterioration (ARD), as well as secondary endpoints including reason for DMT switch and changes in disability and fatigue scores. Repeated-measures analysis of variance and log transformation were used to analyze ARR and ARD, whereas the Wilcoxon signed rank test was used for secondary endpoints. Results The sub-analysis of treatment outcomes stratified by region showed that Latin American patients had higher ARR before conversion to GA compared with patients from the other two areas and subsequently experienced the largest reduction in ARR. Latin American patients also had higher baseline rates of comorbidities and relapses with incomplete remissions and improved more than those in the other two regions based on measures of fatigue, quality of life, depression, and cognition scores. Latin American patients also generally had a better perception of the benefits associated with their conversion to GA in terms of efficacy and adverse events. Conclusions These findings indicate that, in RRMS patients, converting to GA is associated with positive treatment outcomes regardless of geographic location. However, the reasons for converting and the type and degree of any associated benefits appear to vary depending on various factors, including patients’ geographical location. Electronic supplementary material The online version of this article (doi:10.1186/s12883-015-0448-4) contains supplementary material, which is available to authorized users.