Administration Of Glatiramer Acetate Research Articles

Preparation, characterization and in-vivo efficacy study of glatiramer acetate (GA)-hydrogel-microparticles as novel drug delivery system for GA in RRMS

Relapsing Remitting Multiple Sclerosis is a chronic Central nervous system autoimmune disease. There is no absolute treatment for MS and the available remedies are called disease modifying therapies (DMTs). Glatiramer acetate (GA) is one of the FDA approved DMTs. Currently, injection-site problems and unfavorable daily injection are the most common milestones in administration of GA. So that, the design of improved drug delivery systems with sustained release profile seem necessary and helpful in order to minimize GA adverse effects and improve patients’ compliance. In this study, we have manufactured a novel chitosan-PLGA (poly (lactic-co-glycolic acid)) hydrogel-microparticles containing GA by double emulsion method. Hydrogel-microparticles’ properties including size, morphology and GA loading were investigated. In-vitro drug release was studied during 30 days. In vivo efficacy of GA-hydrogel-microparticles was evaluated in experimental autoimmune encephalomyelitis (EAE) as an established animal model for MS. Pathological studies were performed through H&E (Hematoxylin and Eosin) staining of brain, spine, liver, skin and kidney tissues. Luxol fast blue staining of brain tissue was also done. The obtained results were applied for safety and efficacy evaluations. GA loading and Entrapment efficiency (EE %) of 60% and 95% were achieved, respectively. In- vitro release studies confirms a sustained release profile for GA-hydrogel-microparticles. Mean clinical scores and mean body weights obtained from EAE animal model for GA-hydrogel-microparticles were compared to the outcomes achieved from conventional Iranian brand-generic injection solution of GA (Copamer®, 20 mg/ml). EAE outcomes and pathological studies confirm similar therapeutic efficacy with longer dosing intervals possibility, improved safety through decreased adverse effects and elimination of site injection reactions for GA-hydrogel-microparticles. Further studies on pharmacokinetic and pharmacodynamics in human volunteers are still required to thoroughly examine different aspects of this newly developed GA- hydrogel-microparticles.

Evaluating Effects of Glatiramer Acetate Treatment on Amyloid Deposition and Tau Phosphorylation in the 3xTg Mouse Model of Alzheimer's Disease.

Neuroinflammation driven by the accumulation of amyloid β (Aβ) can lead to neurofibrillary tangle formation in Alzheimer’s Disease (AD). To test the hypothesis that an anti-inflammatory immunomodulatory agent might have beneficial effects on amyloid and tau pathology, as well as microglial phenotype, we evaluated glatiramer acetate (GA), a multiple sclerosis drug thought to bias type 2 helper T (Th2) cell responses and alternatively activate myeloid cells. We administered weekly subcutaneous injections of GA or PBS to 15-month-old 3xTg AD mice, which develop both amyloid and tau pathology, for a period of 8 weeks. We found that subcutaneous administration of GA improved behavioral performance in novel object recognition and decreased Aβ plaque in the 3xTg AD mice. Changes in tau phosphorylation were mixed with specific changes in phosphoepitopes seen in immunohistochemistry but not observed in western blot. In addition, we found that there was a trend toward increased microglia complexity in 3xTg mice treated with GA, suggesting a shift toward homeostasis. These findings correlated with subtle changes in the microglial transcriptome, in which the most striking difference was the upregulation of Dcstamp. Lastly, we found no evidence of changes in proportions of major helper T cell (Th) subtypes in the periphery. Overall, our study provides further evidence for the benefits of immunomodulatory therapies that alter the adaptive immune system with the goal of modifying microglia responses for the treatment of Alzheimer’s Disease.

Multiple sclerosis and immune system biomarkers: Novel comparison in glatiramer acetate and interferon beta-1a-treated patient groups

BackgroundMultiple sclerosis (MS) is a chronic, demyelinating disease of the central nervous system (CNS). T cells and B lymphocytes are involved in the development of this disease. MethodsThe following biomarkers were determined in peripheral blood in 28 patients treated with glatiramer acetate (GA) and 21 patients treated with interferon beta 1-a (IFN): IL-10, BAFF, Mx1, IgG, IgG1, IgG2, IgG3 and IgG4 (at baseline and after 6 months of treatment). All participants had confirmed MS diagnosis. ObjectivesThe primary objective is to assess a percentual change of biomarkers after 6 months since the first-line treatment initiation with GA or IFN. The secondary objective is to explore correlations between the baseline biomarkers‘ values (levels). ResultsA positive trend was observed in the increase in IL-10 concentration by 30.33 % (IFN) and by 15.65 % (GA). In the IFN group, we observed a statistically significant increase in the BAFF protein concentration by 29.9% (P < 0.001). We found that Mx1 protein levels did not change with the administration of GA, which can be explained by the different mechanisms of action of GA. The serum levels of IgG immunoglobulins and both IgG1 and IgG4 subclasses in both groups of patients were increased. Thus, our data were in accordance with the generally accepted assumption that both IFN and GA are capable of modulating the B cell system. ConclusionsOur results suggest that treatment with IFN and GA has a more pronounced influence on the B cell system of MS.

Immediate reactions with glatiramer acetate: Diagnosis of allergy and desensitization protocols.

Diverse adverse events have been associated with administration of glatiramer acetate (GA), mainly local reactions at the injection site. Other, less frequent generalized reactions include isolated postinjection reactions and anaphylaxis, which may lead to discontinuation of GA. Close collaboration between the allergy and neurology departments is needed to study adverse reactions to GA. The allergy study should include a detailed history and skin prick and intradermal tests with GA and, if possible, determination of specific IgE levels. Furthermore, the implication of other drugs should be ruled out. An accurate diagnosis of reactions to GA is essential if we are to confirm or rule out allergy to GA. When an allergy diagnosis is confirmed or firmly suspected based on clinical evidence, desensitization protocols are increasingly seen as safe methods for reintroduction of GA.

Glatiramer Acetate modulates ion channels expression and calcium homeostasis in B cell of patients with relapsing-remitting multiple sclerosis

To investigate the effects of Glatiramer Acetate (GA) on B cells by an integrated computational and experimental approach. GA is an immunomodulatory drug approved for the treatment of multiple sclerosis (MS). GA effect on B cells is yet to be fully elucidated. We compared transcriptional profiles of B cells from treatment-naïve relapsing remitting MS patients, treated or not with GA for 6 hours in vitro, and of B cells before and after six months of GA administration in vivo. Microarrays were analyzed with two different computational approaches, one for functional analysis of pathways (Gene Set Enrichment Analysis) and one for the identification of new drug targets (Mode-of-action by Network Analysis). GA modulates the expression of genes involved in immune response and apoptosis. A differential expression of genes encoding ion channels, mostly regulating Ca2+ homeostasis in endoplasmic reticulum (ER) was also observed. Microfluorimetric analysis confirmed this finding, showing a specific GA effect on ER Ca2+ concentration. Our findings unveils a GA regulatory effect on the immune response by influencing B cell phenotype and function. In particular, our results highlight a new functional role for GA in modulating Ca2+ homeostasis in these cells.

Effect of glatiramer acetate on short-term memory impairment induced by lipopolysaccharide in male mice.

Glatiramer acetate (GA) demonstrates neuroprotective, neurogenesis, and anti-inflammatory properties. This study examines the probable protective effect of acute GA on lipopolysaccharide (LPS)-induced memory impairment in male mice and further explores which routes of administration [subcutaneous (s.c.) or intracerebroventricular (i.c.v.)] exert optimum effect. Memory performance was evaluated in two-trial recognition Y-maze and passive-avoidance tasks evaluating special recognition memory and fear memory, respectively. Memory impairment was induced by LPS [100 μg/kg, intraperitoneally (i.p.)], 4 h before training. In Y-maze, GA (10, 2.5, 0.625, 0.153, and 0.03 mg/kg, s.c.; 250 μg/mouse; i.c.v.) was administered 10 min following LPS, and special memory was assayed in Y-maze apparatus. In passive avoidance, LPS (100, 250 μg/kg; i.p.) was injected 4 h before receiving foot shock, and GA (10, 2.5; s.c.) or (250 μg/mouse; i.c.v.) was administered 4 h before the shock. Following 24 h, the fear memory was evaluated. Memory impaired significantly following LPS (100, 250 μg/kg; i.p.) in Y-maze and passive-avoidance tasks, P < 0.001 and P < 0.05, respectively. The data revealed that GA (250 μg/mouse, i.c.v.) and GA (10, 2.5 mg/kg; s.c.) in Y-maze reversed memory impairment (LPS 100 μg/kg, i.p.) (P < 0.01). In passive-avoidance task, GA (2.5, 10 mg/kg; s.c.) reversed LPS-induced impairment and the mice showed significantly longer latency times during the retention trial (P < 0.01). GA improved memory impairment both centrally and systemically. It improved spatial recognition memory increasing the average time in the novel arm and improved fear memory increasing latency time. GA administration improved memory impairment profoundly through both systemic and central routs.

OP23 – 2759: Pharmacological treatment of Rett syndrome with glatiramer acetate (Copaxone)

Background Glatiramer Acetate (GA) represents a collection of synthetic polypeptides approved for the treatment of relapsing–remitting multiple sclerosis, for patients who are 18 years or older. Its high safety profile has been documented in large cohorts of patients 10 or older. Quantitative immunofluorescence assays showed about twofold increase in neuronal expression of BDNF following GA treatment. It causes elevation of BDNF expression up to the level in naive control mice in several cortical areas in the Mecp2 mutated mouse brain. The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression (Chang et al. 2006). Objective Increase in BDNF levels, caused by GA administration will lead to amelioration of RTT related symptoms. Hypothesis: The experimental treatment will be well tolerated and result in at least 20% improvement in at least one of the Rett syndrome related symptoms. Methods Study design: Phase II, dose-escalating trial. Inclusion criteria Female, ambulatory patients with genetically confirmed RTT who are 10 or more years old. Outcome measures: Gait, respiratory function, attention and memory, EEG. Objectives • Primary: To assess primary efficacy of GA in improving gait speed in patients with RTT. • Secondary: a. To evaluate secondary efficacy of GA in improving cognition (visual attention, memory and visual pursuit), autonomic (respiratory) function, encephalopathy (EEG), and quality of life. b. To assess safety and maximally tolerated dosage. Results Treatment with GA lead to significant improvement in gait speed, breath hold index and recognition memory. Seven of 10 treated girls exhibited the improvement. There was no difference in age, genetic status or Rett syndrome severity scores between those who did and who did not improve. Conclusion Treatment with GA was well-tolerated and lead to significant improvements in girls with RTT.

IgE-Mediated Allergic Reactions after the First Administration of Glatiramer Acetate in Patients with Multiple Sclerosis

Background: Immediate adverse reactions to glatiramer acetate (GA), a drug used in the treatment of patients with multiple sclerosis (MS), have been poorly investigated. We studied 3 MS patients who presented adverse reactions following GA administration. Two of them experienced severe anaphylactic reactions after the first administration and the other an eyelid edema upon reintroduction 6 months after GA withdrawal. Methods: Skin prick tests (SPT) to GA and mannitol were performed on all 3 patients and in 10 atopic controls. Specific IgE (sIgE) levels to GA, myelin basic protein (MBP) and MBP fragments were assessed in all 3 patients, 6 MS patients treated with GA for more than 6 month and 10 healthy donors. Specific IgG (sIgG) to GA was also quantified in the three study groups. Both sIgE and sIgG were determined by means of the UniCAP 100 assay. Results: SPT and sIgE to GA were positive only in the 3 patients with adverse reactions while sIgE to mannitol was negative in all. sIgE tests against MBP and its fragments were negative in all individuals. Similar levels of sIgG to GA were found in all studied subjects. Conclusion: These results demonstrate the significance of sIgE in allergic reactions to GA presented by these patients and suggest the importance of strict surveillance during administration of the first GA doses.

Involvement of nitric oxide in improving stress-induced behavioural alteration by glatiramer acetate treatment in female BALB/c mice

Oxidative stress and neurotrophins are among the most important factors involved in several pathophysiological brain processes. In addition, long-term exposure to stressful situations has deleterious effects on behaviour. We have previously shown that stressed female BALB/c mice show poor learning performance and that this behaviour is reversed by glatiramer acetate (GA) treatment. We investigated the involvement of the hippocampal oxidative status and neurotrophin levels in cognitive deficit and the improvement of this deficit by GA treatment in chronic stressed BALB/c mice. Female BALB/c mice were exposed to a chronic mild stress (CMS) model for 9 weeks. During the last 3 weeks of the stress exposure, one group of mice was subcutaneously injected four times with 100 μg GA/mouse. Following this period, behavioural studies were performed. The mice were then sacrificed, and biochemical studies were performed on the hippocampus. The stressed mice exhibited a significant decline in their performance in the open-field and in object-in-place tasks. This decline was accompanied by an increase in reactive oxygen species (ROS) and a decrease in nitric oxide (NO) production by neuronal nitric oxide synthase (nNOS). Neither antioxidant defences nor neurotrophin protein levels were involved in this process. Interestingly, the administration of GA re-established the normal levels of ROS, restored nNOS activity and improved learning performance. The GA treatment improved learning and memory in female BALB/c mice under chronic stress through a mechanism that involves the regulation of NO production, which in turn modulates the ROS levels.

Glatiramer acetate desensitisation in multiple sclerosis patients ‐ the case report

Background Glatiramer acetate (GA) is immunomodulatory drug widely prescribed for the treatment of multiple sclerosis (MS). GA treatment is frequently associated with local site reactions and generalized urticaria. The systemic reaction approximately occurs in 10% of patients. The desensitization could help to return GA to MS treatment. Objective Our aim was to evaluate the safety and efficiency of GA desensitisation. Eight days of the GA treatment MS female patient came with adverse reactions. Twelve hours after GA administration itching in the injection site, feeling of swelling tongue, swallowing difficulty and cough appeared. Methods

Quality of Life, Depression, Sexual Dysfunction and Work Absenteeism in Relapsing-Remitting Multiple Sclerosis Patients Starting Glatiramer Acetate as First-Line Treatment: A Prospective Cohort Study

Introduction: Quality of life (QoL) has gained increasing importance in multiple sclerosis (MS). We aimed to assess QoL and potentially associated factors such as depression, sexual dysfunction and work absenteeism in patients starting glatiramer acetate (GA) in clinical practice. Methods: A prospective cohort study carried out in relapsing-remitting MS patients starting GA as first-line treatment. Patient information on QoL (Multiple Sclerosis Quality of Life-54 [MSQoL-54]), depression (Beck Depression Inventory), sexual dysfunction (Multiple Sclerosis Intimacy and Sexuality Questionnaire-19) and work absenteeism was assessed from starting GA to week 96. Results: Ninety-eight evaluable patients were enrolled in the study (mean age, 38.0 ± 8.4 years; female, 69.4%; mean MS duration, 42.6 ± 62.9 months; annual relapse rate since MS diagnosis, 0.4), and followed up at weeks 24 (n=96), 48 (n=94), 72 (n=89) and 96 (n=80). Patient QoL was preserved during the study, with improvements on the MSQoL-54 subscales of change in health (p<0.05) and health distress (p<0.05). Depression, primary and secondary sexual dysfunction remained stable, but the number of patients with tertiary sexual dysfunction decreased at week 96 (p<0.05). Work absenteeism also decreased over the study (p<0.01). Depression, sexual dysfunction and work absenteeism affected MSQoL-54 physical and mental health composites (p<0.05). Conclusion: QoL of our patients was preserved during the 96-week administration of GA. Though depression, sexual dysfunction and work absenteeism impair patient QoL, they remained stable or even improved during the study.

The Effect of Methylprednisolone, Interferon Beta and Glatiramer Acetate Treatment on the Levels of Leptin, Adiponectin and Resistin in Multiple Sclerosis Patients

Objective: Adipocytokines are cytokine-like mediators that link adipose tissue function with inflammatory and autoimmune processes, and have a suggested role in the pathogenesis of multiple sclerosis (MS). The aim of this study was to analyze the effects of methylprednisolone, interferon-1b (INF) and glatiramer acetate (GA) on leptin, resistin, and adiponectin concentrations in relapsing-remitting MS (RRMS) patients. Methods: The study included 154 RRMS patients who were hospitalized in the Department of Neurology, Poznan University of Medical Sciences. The comparison group included 31 patients with myasthenia gravis (MG) and 39 healthy controls. Serum levels of leptin, adiponectin, and resistin were evaluated before treatment initiation. In the RRMS patients treated with methylprednisolone, adipocytokine evaluation was performed one day after the therapy. Patients treated with INF or GA were evaluated at 1 month and 6 months. Routine neurological examination and expanded disability status scale (EDSS) scoring were performed, and MRI scans were analyzed for the localization of demyelinating plaques. Body mass index, glycemia, and insulin levels were evaluated and homeostatic model assessment insulin resistance index (HOMA-IR) was calculated. Results: Adiponectin and resistin levels in RRMS and MG patients were increased compared to controls, but adiponectin levels were lower in RRMS than MG patients. Intravenous methylprednisolone in RRMS with relapse caused an elevation of leptin concentration. INF treatment caused a significant, time-dependent effect on resistin concentration. GA administration influenced only resistin concentration as a long-term effect. No relationship between adipocytokines and metabolic status or insulin resistance was found. Conclusions: We identified resistin as the most important adipocytokine associated with RRMS. Its concentrations are reduced by first line immunomodulatory treatment, which produces a milieu of beneficial inflammatory and metabolic processes. On the other hand, the routine treatment of MS relapses with methylprednisolone induces harmful metabolic and inflammatory effects that may be mediated by elevated leptin levels.

Glatiramer Acetate administration does not reduce damage after cerebral ischemia in mice

Inflammation plays a key role in ischemic stroke pathophysiology: microglial/macrophage cells and type-1 helper cells (Th1) seem deleterious, while type-2 helper cells (Th2) and regulatory T cells (Treg) seem protective. CD4 Th0 differentiation is modulated by microglial cytokine secretion. Glatiramer Acetate (GA) is an immunomodulatory drug that has been approved for the treatment of human multiple sclerosis by means of a number of mechanisms: reduced microglial activation and pro-inflammatory cytokine production, Th0 differentiation shifting from Th2 to Th2 and Treg with anti-inflammatory cytokine production and increased neurogenesis.We induced permanent (pMCAo) or transient middle cerebral artery occlusion (tMCAo) and GA (2mg) or vehicle was injected subcutaneously immediately after cerebral ischemia. Mice were sacrificed at D3 to measure neurological deficit, infarct volume, microglial cell density and qPCR of TNFα and IL-1β (pro-inflammatory microglial cytokines), IFNγ (Th2 cytokine), IL-4 (Th2 cytokine), TGFβ and IL-10 (Treg cytokines), and at D7 to evaluate neurological deficit, infarct volume and neurogenesis assessment.We showed that in GA-treated pMCAo mice, infarct volume, microglial cell density and cytokine secretion were not significantly modified at D3, while neurogenesis was enhanced at D7 without significant infarct volume reduction. In GA-treated tMCAo mice, microglial pro-inflammatory cytokines IL-1β and TNFα were significantly decreased without modification of microglial/macrophage cell density, cytokine secretion, neurological deficit or infarct volume at D3, or modification of neurological deficit, neurogenesis or infarct volume at D7.In conclusion, Glatiramer Acetate administered after cerebral ischemia does not reduce infarct volume or improve neurological deficit in mice despite a significant increase in neurogenesis in pMCAo and a microglial pro-inflammatory cytokine reduction in tMCAo.

Immunological mechanisms underlying delayed-type hypersensitivity reactions to glatiramer acetate

BackgroundDelayed-type hypersensitivity to glatiramer acetate is rare, and the underlying immunological mechanisms are not completely understood. ObjectiveTo study the immunologic response in 2 patients with multiple sclerosis who developed maculopapular exanthema related with the administration of glatiramer acetate. MethodsThe allergologic study included general blood tests, viral serologic tests, and skin tests (patch and intradermal tests). The immunologic study was performed in skin biopsy specimens by immunohistochemistry and in the peripheral blood by flow cytometry and the lymphocyte transformation test. ResultsSkin test results were negative in both patients, and the diagnosis was confirmed by a drug provocation test. The evaluation of the acute phase showed an increase in the percentage of CD8 T lymphocytes (>50%) and the percentage of cells expressing skin-homing receptor (cutaneous lymphocyte–associated antigen) (>70%) and chemokine receptors (CCR4 and CXCR3) at T1. A positive proliferative response was observed in T lymphocytes (stimulation index [SI] = 3.5 in patient 1 and 3.59 in patient 2), especially the CD8+ subpopulation (SI = 5.5 and 4.6 in patients 1 and 2, respectively), and NK lymphocytes (SI = 3.9 and 8.5 in patients 1 and 2, respectively) after glatiramer acetate stimulation. ConclusionThis study demonstrates the important role of TH1 cells expressing skin-homing receptors in delayed-type hypersensitivity reactions to glatiramer acetate. A lymphocyte transformation test revealed a specific glatiramer acetate recognition by T lymphocytes and NK lymphocytes.

Glatiramer acetate reverts stress-induced alterations on adult neurogenesis and behavior. Involvement of Th1/Th2 balance

Long-term exposure to stressful situations has deleterious effects on adult neurogenesis, behavior, and the immune system. We have previously shown that stressed BALB/c mice show poor learning performance, which correlates with an increase in the T helper 1/T helper 2 (Th1/Th2) cytokine balance. Glatiramer acetate (GA) can stimulate autoreactive T cells. In this work we investigated the effects of GA treatment on BALB/c mice exposed to chronic mild stress (CMS). Stressed mice exhibited a significant decline in their performance in the open field and Y-maze tasks, which was accompanied by a reduction in dentate gyrus neurogenesis and an altered Th1/Th2 balance. Interestingly, after 6 weeks of CMS exposure administration of GA reestablished normal levels of adult neurogenesis, restored the Th1/Th2 balance, and improved learning performance. These results demonstrate that GA treatment can reverse the learning impairment induced by stress through a mechanism that likely involves the regulation of the cytokine balance and adult neurogenesis.

Glatiramer Acetate Treatment Directly Targets CD11b+Ly6G− Monocytes and Enhances the Suppression of Autoreactive T cells in Experimental Autoimmune Encephalomyelitis

Glatiramer acetate (GA) is used for the treatment of relapsing-remitting multiple sclerosis (MS) and can suppress experimental autoimmune encephalomyelitis in animals. Effective GA treatment is associated with the induction of anti-inflammatory T(H)2 responses and antigen-specific expansion of CD25(+)/Foxp3(+) Tregs through the modulation of antigen-presenting cells. Here, we show that intravenous injection of fluorochrome-labelled GA resulted in rapid and specific binding of GA to CD11b(+) F4/80(lo) Ly6G(-) blood monocytes via an MHC class II-independent mechanism. Intravenous GA treatment enhanced the intrinsic capability of these monocytes to directly suppress T cell proliferation in vitro. The suppressive function correlated with reduced proliferation of myelin-specific T cells in vivo after intravenous GA treatment. In contrast, subcutaneous treatment with GA inhibited the pro-inflammatory IFNγ-producing T cell phenotype rather than suppressing T cell proliferation. These data indicate that (1) GA engages directly with circulating monocytes to induce type II monocyte suppressor function; and (2) the therapeutic efficacy of GA may be expanded by employing different routes of GA administration to engage alternative mechanisms of suppression of autoreactive T cells in MS.

The Strategies Used for Treatment of Experimental Autoimmune Neuritis (EAN): A Beneficial Effect of Glatiramer Acetate Administered Intraperitoneally

Glatiramer acetate (GA) significantly ameliorates multiple sclerosis and was initially discovered through its effects on the animal model experimental autoimmune encephalomyelitis (EAE). Guillain-Barré syndrome (GBS) is a relatively common demyelinating disease of peripheral nerves for which there is a parallel animal model, experimental autoimmune neuritis (EAN). We review the treatments found useful in EAN with special emphasis on the need for quick onset of action and the relevance of treatments used for EAE and multiple sclerosis. We evaluated the effect of GA administered by a novel intraperitoneal route in EAN. GA significantly ameliorated the severity of disease in rats (F = 6.3, p = 0.01 by analysis of variance (ANOVA)) and course of disease (F = 4.9, p = 0.02 by repeated-measures ANOVA with a day x treatment interaction term). Neurophysiology data supported the trend for the beneficial effect of GA. Myelin-induced immune cell proliferation was significantly modulated by GA (p < 0.025). This report describes a novel route of administration of GA and a rapid beneficial effect of GA in EAN. GA may be useful in human diseases, such as GBS, where the intravenous route may offer a rapid onset of drug action.

Glatiramer acetate could be a potential therapeutic agent for Parkinson’s disease through its neuroprotective and anti-inflammatory effects

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. The hallmark pathologic feature of PD is dopamine deficiency, caused by the degeneration of nigrostriatal dopaminergic neurons. Current treatments for PD mainly address the dopaminergic features of the disease; however they do not modify the progression of neurodegeneration. The need for newer and more effective agents is consequently receiving a great deal of attention. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, can promote survival of injured dopaminergic nigrostriatal neurons in the rodent. Postmortem studies have suggested that BDNF deficiency may play a role in PD pathogenesis. This is further supported by the finding that BDNF administration has a therapeutic effect in animal models of PD. Glatiramer acetate (GA) is a collection of synthetic polypeptides approved for the treatment of relapsing-remitting multiple sclerosis. Preclinical studies have demonstrated that peripheral GA administration can enhance central BDNF activity and augment neurogenesis. Furthermore, PD has been associated with an inflammatory process in the brain. Animal studies have demonstrated that GA administration has a central anti-inflammatory effect through the release of anti-inflammatory cytokines. From the above evidence, GA could act as a potential therapeutic agent for PD by increasing central BDNF and by exerting an anti-inflammatory effect. With the recent finding that GA administration can prevent neuronal loss and cognitive decline in Alzheimer's disease double-transgenic mice, early GA treatment may also prevent neurodegeneration and manifestations of PD symptoms in subjects with familial Parkinson's disease.

Glatiramer acetate could be a potential antidepressant through its neuroprotective and anti-inflammatory effects

Antidepressants that act by increasing the activity of central serotonergic or noradrenergic systems are the main biological treatments for major depressive disorder (MDD). Although these agents are generally safe and effective, they are far from ideal due to their slow onset and a substantial proportion of MDD patients do not clinically improve, despite maximal dosing. Thus, the development of new antidepressants based on novel theories may help to develop faster and more effective antidepressant agents. Over the last decade, there has been an impressive accumulation of data about non-monoamine systems that might mediate the pathogenesis of, and therapeutic mechanisms in, MDD. For example, MDD has been associated with a decreased central brain-derived neurotrophic factor (BDNF) state and activating the BDNF-signaling pathway may play an important role in the mechanisms of antidepressant therapeutic action. Glatiramer acetate (GA) is a collection of synthetic polypeptides indicated as therapy for relapsing-remitting multiple sclerosis. Both preclinical and clinical studies have demonstrated that peripheral GA administration can enhance central BDNF activity or increase serum BDNF levels. Furthermore, MDD has been associated with an inflammatory process in the brain. Animal studies have demonstrated that GA administration has a central anti-inflammatory effect through the release of interleukin-10. Finally, recent animal studies have suggested that psychosocial stress reduces neurogenesis, whereas antidepressant treatment increases neurogenesis and blocks the effects of stress. Peripheral administration of GA was found to augment neurogenesis, including cell proliferation, migration, and differentiation in rodent brain. From the above evidence, GA could have antidepressant effects by increasing central BDNF, stimulating neurogenesis or through its anti-inflammatory effect. It is also suggested that immediate GA treatment after stress may prevent the development of stress-related psychiatric disorders such as MDD and post-traumatic stress disorder.

Therapy with glatiramer acetate for multiple sclerosis.

Some clinical data have shown that glatiramer acetate (Copaxone), a synthetic amino acid polymer empirically found to suppress experimental allergic encephalomyelitis (EAE), an animal model of MS, might help improve the outcome of patients with multiple sclerosis (MS). We performed a Cochrane review of all randomised, placebo-controlled trials of glatiramer acetate in MS, whatever the disease course. We searched the Cochrane MS Group trials register (June 2003), the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2, 2003), MEDLINE (PubMed) (January 1966 to June 2003), EMBASE (January 1988 to June 2003) and hand searching of symposia reports (1990-2002) from the neurological Associations and MS Societies in both Europe and America. All randomised controlled trials (RCTs) comparing glatiramer acetate and placebo in patients with definite MS, whatever the administration schedule and disease course, were eligible for this review. Both patients with relapsing-remitting (RR) and chronic progressive (CP) MS were analysed. Study protocols were comparable across trials as to patient entry criteria and outcome definition. No major flaws were found in methodological quality. However, efficacy of blinding should be balanced against well-known side effects, including injection-site reactions in glatiramer acetate-treated patients. A total of 646 patients contributed to this review, as it is summarised in Table 01. Glatiramer acetate did not show any significant effect on disease progression, measured as a sustained worsening in the Expanded Disability Status Scale (EDSS). On the other hand, a slight decrease in the mean EDSS score, driven by a major study, should be considered in the light of the limited validity of this outcome measure. No benefit was shown in CP MS patients (progression at two years: RR=0.69, 95% CI [0.33 to 1.46]). The frequency of reported adverse events does not support any major toxicity associated with glatiramer acetate administration. The most common systemic adverse event was a transient and self-limiting patterned reaction of flushing, chest tightness, sweating, palpitations, anxiety (relative risk = 3.40 (95% CI [2.22 to 5.21], p <0.00001]). Local injection-site reactions were observed in up to a half of patients treated with glatiramer acetate, thus making a blind assessment of outcomes questionable. Glatiramer acetate did not show any beneficial effect on the main outcome measures in MS, i.e. disease progression, and it does not substantially affect the risk of clinical relapses. Therefore its routine use in clinical practice is not currently supported. More investigations are needed. Further research should also develop more reliable measures of patient disability over time and include quality of life among primary outcomes.