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.     

Cysteamine-related agents could be potential antidepressants through increasing central BDNF levels

Major depressive disorder (MDD) is a common mental disease, but with an unknown etiology. Antidepressants are the main biological treatment for MDD. However, current antidepressive agents have a slow onset of effect and a substantial proportion of MDD patients do not clinically improve, despite maximal medication. Thus, the exploration for new antidepressants with novel strategies may help to develop faster and more effective antidepressant agents. Studies in the recent decades have demonstrated that antidepressants increase central brain-derived neurotrophic factor (BDNF) levels and activating the BDNF-signaling pathway may play an important role in their therapeutic mechanism. Cysteamine is a natural product of cells and constitutes the terminal region of the CoA molecule. Recent work has found that cysteamine and a related agent, cystamine, have neuroprotective effects in Huntington's disease (HD) mice, through enhancing central BDNF levels. Furthermore, cystamine or cysteamine injection could increase serum BDNF levels in wild-type mice as well as HD mice. Since activation of the BDNF-dependent pathway plays an important role in the mechanism of antidepressant therapeutic action, cystamine or its derivatives could have potential antidepressant therapeutic effects. Among these agents, pantethine may be one of the most promising agents. It is a naturally occurring compound which can be administered orally with negligible side effects, and is metabolized to cysteamine. Further evaluation of the therapeutic and toxic effects of these cysteamine-related antidepressant agents in MDD animal models is needed before any clinical application.     

Down-regulation of the Trk-B signal pathway: the possible pathogenesis of major depression

Major depressive disorder (MDD) is a common mental disease with unknown etiology. Recent studies have suggested that decreased brain-derived neurotrophic factor (BDNF) may be implicated in the pathogenesis of MDD. Instead of a decrease in central BDNF, however, studies utilizing genetic depression animal models have found elevated levels of the factor. In the brain, BDNF exerts its influence chiefly by signaling through tyrosine receptor kinase B (Trk-B). In this report, it is suggested that Trk-B pathway down-regulation may be the major pathogenesis for MDD, while stress, which may reduce central BDNF, acts as a precipitation factor to further dampen central BDNF activity and contribute to the development of depression. Further, several possible mechanisms of Trk-B pathway down-regulation, and the implications for this down-regulation in MDD are discussed.     

Association study of p11 gene with major depressive disorder, suicidal behaviors and treatment response

The p11 protein (also called S100A10), which plays a pivotal role in the dynamic modulation of serotonergic 1B receptor function, has been implicated in the pathogenesis of major depressive disorder (MDD) and the therapeutic mechanisms of antidepressant action. Humans and mice with depression have lower central p11 levels, and treatment with antidepressant agents raises p11 levels in animals. Furthermore, brain p11 mRNA expression is lower in post mortem brains from patients who were suffering from depression and had committed suicide compared with control subjects who had died from other causes. From the above findings, the p11 gene may be considered a candidate gene for the investigation of MDD susceptibility, response to antidepressants or the likelihood of attempting suicide. Three p11 polymorphisms were genotyped in 470 patients with MDD and 447 normal controls. No significant association with MDD was discovered in single locus or haplotype analyses. The analysis for genotypic effects showed no significant association between any of the three p11 single nucleotide polymorphisms (SNPs) and MDD therapeutic response. With regard to the risk of suicide attempt, 51 of the 470 MDD patients were found to have attempted suicide in the depressive episode during which they were monitored. No significant association with suicide attempt was shown in both the alleles and genotypes of single loci or of haplotypes constructed from these three p11 polymorphisms. Our findings suggest that p11 genetic variants do not play a major role in the MDD susceptibility, antidepressant therapeutic response or the risk of suicide attempt in MDD.     

Is dysfunction of the tissue plasminogen activator (tPA)-plasmin pathway a link between major depression and cardiovascular disease?

Epidemiological, genetic and clinical studies have demonstrated an association between major depressive disorder (MDD) and cardiovascular disease (CVD). For example, MDD is a risk factor for the development of CVD, while around one fifth of patients with CVD have MDD and a significantly larger percentage have subsyndromal symptoms of depression. Furthermore, patients with CVD and depression have an increased risk of future cardiac events compared to similar cohorts without depression, independent of baseline cardiac dysfunction. Despite evidence that CVD and MDD are epidemiologically linked, the cause of this correlation is still unknown. Several risk factors including physical and psychological stress, smoking, physical inactivity and inflammation have been proposed to mediate the interaction between MDD and CVD. The tissue-type plasminogen activator (tPA)-plasminogen proteolytic cascade is widely expressed in the brain. Accumulating evidence from preclinical and clinical studies suggests that tPA and its inhibitor, plasminogen activator inhibitor-1, are related to stress reaction and depression. In addition, brain-derived neurotrophic factor (BDNF) is important for the pathogenesis of MDD and the tPA-plasminogen proteolytic cascade has been implicated in the cleavage of proBDNF to BDNF in the brain, by which the direction of BDNF action is controlled. Thus, it is proposed that tPA-plasmin pathway dysfunction may play a role in the link between MDD and CVD. Future study of the components in the tPA-plasminogen system in CVD patients comorbid with MDD may lead to new, potentially important insights into the link between MDD and CVD, and might also contribute to novel strategies for the management of these two common and devastating diseases.     

The P11, tPA/plasminogen system and brain-derived neurotrophic factor: Implications for the pathogenesis of major depression and the therapeutic mechanism of antidepressants

Major depressive disorder (MDD) is a common disabling psychiatric illness with an unknown etiology. Evidence from animal and human studies suggests that a disturbance in serotonergic (5-HT) activity and/or brain-derived neurotrophic factor (BDNF) signaling may be implicated in the pathogenesis of MDD. Recently, a protein, p11, has been found to increase the number of 5-HT(1B) receptors on the surface of cells and enhance 5-HT(1B) receptor function. Furthermore, mice over-expressing p11 acted as if they were undergoing treatment with antidepressants and p11 knockout mice exhibit a depression-like phenotype and reduced behavioural reactions to an antidepressant. As tissue-type plasminogen activator (tPA)/plasminogen proteolytic cascade is implicated in the cleavage of proBDNF to BDNF, and p11, a component of the Annexin II, which can greatly enhance the activation of plasmin by tPA, it is proposed that p11 may act through the tPA/plasminogen/BDNF pathway to achieve its antidepressant effect. Attempts to confirm this hypothesis may lead to new directions in the study of the pathogenesis of MDD and the development of a novel intervention for this disorder. In addition, BDNF is also implicated in several psychiatric diseases such as schizophrenia, bipolar disorder, attention-deficit hyperactivity disorder and Alzheimer's disease; whether p11 and other components related to the tPA/plasminogen pathway may be related to the pathogenesis of these diseases needs further exploration.     

Major depressive disorder: probiotics may be an adjuvant therapy

Major depressive disorder (MDD) is an extremely complex and heterogeneous condition. Emerging research suggests that nutritional influences on MDD are currently underestimated. MDD patients have been shown to have elevated levels of pro-inflammatory cytokines, increased oxidative stress, altered gastrointestinal (GI) function, and lowered micronutrient and omega-3 fatty acid status. Small intestinal bacterial overgrowth (SIBO) is likely contributing to the limited nutrient absorption in MDD. Stress, a significant factor in MDD, is known to alter GI microflora, lowering levels of lactobacilli and bifidobacterium. Research suggests that bacteria in the GI tract can communicate with the central nervous system, even in the absence of an immune response. Probiotics have the potential to lower systemic inflammatory cytokines, decrease oxidative stress, improve nutritional status, and correct SIBO. The effect of probiotics on systemic inflammatory cytokines and oxidative stress may ultimately lead to increased brain derived neurotrophic factor (BDNF). It is our contention that probiotics may be an adjuvant to standard care in MDD.     

Sipatrigine could have therapeutic potential for major depression and bipolar depression through antagonism of the two-pore-domain K+ channel TREK-1

Major depressive disorder (MDD) is a chronic, recurring and potentially life-threatening mental illness. Current treatments are inadequate - many depression medications, although safe and effective, generally have a slow onset of clinical benefit and around half of the MDD patients do not show full remission with optimized treatment. Therefore, there is still a need for the development of faster-acting and more effective medication for MDD. Recent studies have demonstrated that the TREK-1 protein, one of the 17 members of the two-pore domain K+ (K2P) potassium channel family, is inhibited by the antidepressant fluoxetine. Deletion of TREK-1 in mice caused a substantially reduced elevation of corticosterone levels under stress, and produced behaviour similar to that of naive animals treated with fluoxetine in various behavioural tests. These findings suggested that the blocker of the TREK-1 channel might potentially be a new type of antidepressant. Sipatrigine (BW619C89), a neuroprotective agent, has been found to be a potent antagonist of TREK-1. Its related compound, lamotrigine, has been approved for the treatment of bipolar depression and is used to supplement antidepressant medication in patients with treatment-resistant depression. Furthermore, in addition to its antagonistic effect on TREK-1, sipatrigine is also a glutamate release inhibitor. Excessive glutamatergic neurotransmission is associated with depressive-like behaviours and inhibiting glutamate neurotransmission may be implicated in antidepressant therapeutic mechanisms. From the above findings of the effects of sipatrigine on TREK-1 and glutamate neurotransmission, it is hypothesised that sipatrigine could have potential therapeutic effects for MDD or bipolar depression. Further evaluation of its antidepressant therapeutic and toxic effects in animal models is needed before clinical application.     

The possible role of tissue-type plasminogen activator and the plasminogen system in the pathogenesis of major depression

Major depressive disorder (MDD) is one of the most common psychiatric illnesses with an unknown etiology. Evidence from animal and human studies has suggested that brain-derived neurotrophic factor (BDNF) function may be implicated in the pathogenesis of MDD. Tissue-type plasminogen activator (tPA) is a highly specific serine proteinase that catalyses the generation of zymogen plasminogen from the proteinase plasmin. Recent studies have found that the proteolytic cleavage of proBDNF, a BDNF precursor, to BDNF by the plasmin represents a mechanism by which the direction of BDNF action is controlled. Furthermore, studies using mice deficient in tPA has demonstrated that tPA is important for the stress reaction, a common precipitating factor for MDD. A study of the serum levels of the plasminogen activator inhibitor-1 (PAI-1), the major inhibitor of tPA, found that women with MDD had a higher PAI-1 concentration than normal controls. From these findings, it is proposed that the tPA/plasminogen system may play a role in the pathogenesis of MDD. Attempts to confirm the tPA/plasminogen hypothesis may lead to new directions in the study of the pathogenesis of MDD and the development of a novel intervention of this disorder.     

Intranasal insulin-like growth factor I (IGF-I) as a plausible future treatment of depression

Depression remains a highly prevalent and mostly recurrent disorder causing an increased need to optimize and broaden the current therapy options. An enormous body of evidence links the regulation of specific neurotrophic proteins, like the brain-derived neurotrophic factor (BDNF), to depression and it may be assumed that the behavioral effects of antidepressants require functional BDNF signaling in the brain. Another neurotrophin, insulin-like growth factor-I (IGF-I), also produces antidepressant-like behavioral effects. Data have shown that BDNF plus IGF-I are more effective than either neurotrophin alone in activating neurotrophic cascades and promoting survival of hippocampal neurons. In fact, it has been suggested that the increase in hippocampal BDNF following antidepressant treatment or physical exercise in animal models is IGF-I-dependent and that antidepressant treatment increases IGF-I in human cerebrospinal fluid (CSF). Thus, BDNF and IGF-I seem to act synergistically in the same cascade of transmission and neuroplasticity. In order to avoid the pitfalls of systemic application (e.g. possible peripheral side effects) while directly targeting central nervous circuitries, the clinical intranasal administration of IGF-I appears to be a plausible and promising treatment option of depression.     

Killing two birds with one stone: The potential role of aripiprazole for patients with comorbid major depressive disorder and nicotine dependence via altering brain activity in the anterior cingulate cortex

The high comorbidity between major depressive disorder (MDD) and nicotine dependence (ND) is well recognized. Patients with comorbid MDD and ND often have increased suicidal risk and poor outcomes. A dysfunctional dopaminergic brain reward system might be a neurobiological link between MDD and ND. Aripiprazole has been considered as a dopamine stabilizer and was the first atypical antipsychotic agent approved by the US Food and Drug Administration as an adjunctive to the treatment of unipolar MDD. Bupropion is well known as a dual norepinephrine and dopamine reuptake inhibitor, and has been shown to be effective in smoking cessation. One reason bupropion is useful in treating ND is that it enhances the level of dopamine in the brain. Aripiprazole might act as a dopamine agonist similar to the way that bupropion does because of its partial dopamine D2 agonist and 30% intrinsic dopaminergic activity. Several recent studies have applied the unique pharmacodynamic characteristics of aripiprazole to treat patients with ND. Based on neuroimaging findings, aripiprazole can reduce substance cravings by altering brain activity, particularly in the brain regions of the anterior cingulate cortex. Therefore, we hypothesize that adjunctive aripiprazole with antidepressant may be an effective treatment for patients with MDD and ND comorbidity. A new drug invention that combines an antidepressant with an adequate dose of aripiprazole thus should be considered. The neurobiological basis for this combination to treat patients with MDD and ND comorbidity deserves further study.     

Statins may enhance the proteolytic cleavage of proBDNF: implications for the treatment of depression

The family of hydroxymethylglutaryl coenzyme A reductase inhibitors, collectively known as statins, are used clinically to reduce plasma cholesterol levels. Recent reports indicate that statin therapy is associated with a reduced risk of depression, although the mechanism underlying this antidepressant effect is unknown. Evidence suggests that increasing central BDNF activity plays an important role in the treatment of major depression. In the nervous system, the proteolytic cleavage of pro-BDNF, a BDNF precursor, to BDNF through the tissue-type plasminogen activator (tPA)-plasmin pathway represents one mechanism that can regulate the action of BDNF. In vitro studies have demonstrated that statins can induce tPA and inhibit plasminogen activator inhibitor-1, the major inhibitor of tPA. It is therefore possible that statins could act through the tPA-plasminogen pathway to increase BDNF and achieve an antidepressant effect. It is suggested that statins could be of therapeutic potential for patients with major depression: especially those that have an abnormality in the tPA-plasminogen pathway or comorbidities relating to cardiovascular disease. Furthermore, BDNF dysfunction has also been implicated in several other neuropsychiatric diseases, such as Alzheimer's disease, attention-deficit hyperactivity disorder and Rett syndrome. The potential use of statins in these diseases may warrant further exploration.     

Is mania caused by overactivity of central brain-derived neurotrophic factor?

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, can modulate synaptic plasticity and neurotransmitter release across multiple neurotransmitter systems, as well as the intracellular signal-transduction pathway. Recent studies had demonstrated that BDNF may play a role in the antidepressant mechanism and the pathogenesis of major depression. These findings implicated that BDNF may involve in mood regulation. In addition, (1). studies found positive association between BDNF genetic polymorphism and bipolar affective disorders; (2). agents which potentially induce manic states also increase BDNF, and (3). increase in mossy fibers were noted for bipolar affective disorder brain and BDNF is related to the induction of aberrant mossy fiber sprouting. From these finding, it is proposed that BDNF overactivity may be implicated in the manic state. The notion of BDNF overactivity in mania suggests that factors associated with increased BDNF activity may proffer the etiological fundamentals for bipolar affective disorder. Further, exploration of this hypothesis can provide a new direction in the treatment of the bipolar affective disorder.     

New antidepressant drugs that do not cross the blood-brain barrier

Stimulation of neurogenesis in the adult brain (i.e. in the hippocampus) has recently been proposed as a putative mechanism of antidepressant action of drugs. This effect of antidepressants may not be achieved by their primary action on proliferating cells, but may involve the drug-triggered mobilization of trophic factors, such as brain-derived neurotrophic factor (BDNF), glia-derived protein S100 beta, or insulin-like growth factor I (IFG-I). Whereas BDNF and S100 beta are produced in the brain, IGF-I is primarily released from peripheral tissues. Administered peripherally, IGF-I increases hippocampal neurogenesis in the adult rat. Because synthesis and release of IGF-I appear to be stimulated by serotonergic mechanisms, we propose that antidepressants that affect serotonergic mechanisms might be rendered more effective by mobilizing IGF-I. Moreover, we suggest that new antidepressant drugs could be designed that would not enter into the brain but would stimulate peripheral mediators such as IGF-I.     

Semax, an analogue of adrenocorticotropin (4-10), is a potential agent for the treatment of attention-deficit hyperactivity disorder and Rett syndrome

Psychostimulants, such as methylphenidate, are currently the most common used drug therapy for children with attention-deficit hyperactivity disorder (ADHD). However, a number of patients with ADHD either fail to respond to these drugs or experience side effects that preclude their use. The heptapeptide Semax is an analogue of the N-terminal fragment (4-10) of adrenocorticotropic hormone, but is completely devoid of any hormonal activity. It has been found to stimulate memory and attention in rodents and humans after intranasal application. Evidence from animal studies revealed that Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis. In addition, Semax could improve selective attention and modulate brain development. Since ADHD is likely to be a neurodevelopmental disorder with disturbance in dopamine and BDNF function, it is proposed in this paper that Semax may have good therapeutic potential in ADHD. Furthermore, increased BDNF activity is found to improve Rett syndrome, a severe neurodevelopmental disorder which is, in the majority of cases, caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MECP2). The potential therapeutic effect of Semax in Rett syndrome by increasing central BDNF activity may be of interest for further exploration in animal models of Rett syndrome.     

The cytokine network in the pathogenesis of major depressive disorder. Close to translation?

Major depressive disorder (MDD) is a common condition that afflicts the general population across a broad spectrum of ages and social backgrounds. MDD has been identified by the World Health Organization as a leading cause of disability worldwide.Approximately 30% of patients are poor responsive to standard of care (SOC) treatment and novel therapeutic approaches are warranted.Since chronic inflammation, as it is often observed in certain cancers, type 2 diabetes, psoriasis and chronic arthritis, are accompanied by depression, it has been suggested that immunoinflammatory processes may be involved in the pathogenesis of MDD.Cytokines are a group of glycoproteins secreted from lymphoid and non-lymphoid cells that orchestrate immune responses. It has been suggested that a dysregulated production of cytokines may be implicated in the pathogenesis and maintenance of MDD. On the basis of their functions, cytokines can be subdivided in pro-inflammatory and anti-inflammatory cytokines. Since abnormal blood and cerebrospinal fluid of both pro and anti-inflammatory cytokines are altered in MDD, it has been suggested that abnormal cytokine homeostasis may be implicated in the pathogenesis of MDD and possibly to induction of therapeutic resistance.We review current data that indicate that cytokines may represent a useful tool to identify MDD patients that may benefit from tailored immunotherapeutic approaches and may represent a potential tailored therapeutic target.     

Possible involvement of brain-derived neurotrophic factor in the antinociceptive effect of antidepressants in neuropathic pain

Neuropathic pain, a chronic pain state caused by injury to the nervous system, usually responds poorly to standard pain treatment. Antidepressants have been used to treat neuropathic pain, and animal and clinical studies have showed beneficial effects. However, the mechanisms underlying antidepressant antinociceptive effect in neuropathic pain are still unknown. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, can modulate synaptic plasticity and neurotransmitter release across multiple neurotransmitter systems. Recent animal and human studies have demonstrated that antidepressants can increase central as well as plasma BDNF levels. In addition: (1) BDNF is produced by a subset of primary sensory neurons that are located in the dorsal root ganglion; (2) BDNF levels change in animal models of neuropathic pain; (3) BDNF can indirectly depress sensory neuron transmission in the dorsal horn. From these findings, it is proposed that BDNF may play an important role in the antidepressant antinociceptive effect in neuropathic pain. The notion of BDNF mediating the therapeutic mechanisms of antidepressant in neuropathic pain may help to select the specific type and the optimal dose of antidepressants for the treatment of neuropathic pain. Exploration of this hypothesis could provide a new direction in the treatment of neuropathic pain, as well as other pain disorders.     

Hippocampal adult neurogenesis is enhanced by chronic eszopiclone treatment in rats

The adult hippocampal dentate gyrus (DG) exhibits cell proliferation and neurogenesis throughout life. We examined the effects of daily administration of eszopiclone (Esz), a commonly used hypnotic drug and γ‐aminobutyric acid (GABA) agonist, compared with vehicle, on DG cell proliferation and neurogenesis, and on sleep–wake patterns. Esz was administered during the usual sleep period of rats, to mimic typical use in humans. Esz treatment for 7 days did not affect the rate of cell proliferation, as measured by 5‐bromo‐2′‐deoxyuridine (BrdU) immunostaining. However, twice‐daily Esz administration for 2 weeks increased survival of newborn cells by 46%. Most surviving cells exhibited a neuronal phenotype, identified as BrdU–neuronal nuclei (NeuN) double‐labeling. NeuN is a marker of neurons. Non‐rapid eye movement sleep was increased on day 1, but not on days 7 or 14 of Esz administration. Delta electroencephalogram activity was increased on days 1 and 7 of treatment, but not on day 14. There is evidence that enhancement of DG neurogenesis is a critical component of the effects of antidepressant treatments of major depressive disorder (MDD). Adult‐born DG cells are responsive to GABAergic stimulation, which promotes cell maturation. The present study suggests that Esz, presumably acting as a GABA agonist, has pro‐neurogenic effects in the adult DG. This result is consistent with evidence that Esz enhances the antidepressant treatment response of patients with MDD with insomnia.     

Attention-deficit hyperactivity disorder and brain-derived neurotrophic factor: a speculative hypothesis

Brain-derived neurotrophic factor (BDNF) is important for normal neuronal development. Attention-deficit hyperactivity disorder (ADHD), a childhood-onset neurodevelopmental disorder, is characterized by inattention and hyperactivity. Psychostimulants and antidepressants are the agents commonly used for the treatment of ADHD and were also found to elevate central BDNF. It is proposed here that BDNF may play a role in the therapeutic action and pathogenesis of ADHD. This hypothesis may provide a new direction for the treatment and the pathogenesis of ADHD.