The expanding impact of methylglyoxal on behavior-related disorders.

Methylglyoxal (MGO) is a reactive dicarbonyl compound formed as a byproduct of glycolysis. MGO is a major cell-permeant precursor of advanced glycation end products (AGEs), since it readily reacts with basic phospholipids and nucleotides, as well as amino acid residues of proteins, such as arginine, cysteine, and lysine. The AGEs production induced by MGO are widely associated with several pathologies, including neurodegenerative diseases. However, the impact of MGO metabolism and AGEs formation in the central nervous system (particularly in neurons, astrocytes and oligodendrocytes) on behavior and psychiatric diseases is not fully understood. Here, we briefly present background information on the biological activity of MGO in the central nervous system. It was gathered the available information on the role of MGO metabolism at the physiological processes, as well as at the neurobiology of psychiatry diseases, especially pain-related experiences, anxiety, depression, and cognition impairment-associated diseases. To clarify the role of MGO on behavior and associated diseases, we reviewed primarily the main findings at preclinical studies focusing on genetic and pharmacological approaches. Since monoamine neurotransmitter systems are implicated as pivotal targets on the pathophysiology and treatment of psychiatry and cognitive-related diseases, we also reviewed how MGO affects these neurotransmission systems and the implications of this phenomenon for nociception and pain; learning and cognition; and mood. In summary, this review highlights the pivotal role of glyoxalase 1 (Glo1) and MGO levels in modulating behavioral phenotypes, as well as related cellular and molecular signaling. Conclusively, this review signals dopamine as a new neurochemical MGO target, as well as highlights how MGO metabolism can modulate the pathophysiology and treatment of pain, psychiatric and cognitive-related diseases.

Role of heme oxygenase-1 in the antidepressant-like effect of ursolic acid in the tail suspension test.

OBJECTIVES: This study investigated the involvement of heme oxygenase-1 (HO-1) in the antidepressant-like effects of ursolic acid (UA), a plant-derived compound with neuroprotective and antidepressant-like properties. METHODS: Mice received intracerebroventricular injections of zinc protoporphyrin IX (ZnPP) or cobalt protoporphyrin IX (CoPP) to inhibit or induce HO-1, respectively, together with effective (0.1 mg/kg, p.o.) or sub-effective (0.01 mg/kg, p.o.) doses of UA or fluoxetine (10 mg/kg, p.o.). Immobility time was assessed using the tail suspension test (TST) and the ambulatory behaviour with the open field test. HO-1 immunocontent was evaluated in mice hippocampus and prefrontal cortex. KEY FINDINGS: ZnPP prevented the anti-immobility effects of UA and fluoxetine. Combined treatment with a sub-effective dose of CoPP and UA synergistically exerted antidepressant-like effects in the TST. Acute administration of UA or CoPP, but not fluoxetine, increased the HO-1 immunocontent in the hippocampus. None of the treatments altered the HO-1 immunocontent in the prefrontal cortex. CONCLUSIONS: In conclusion, this work shows that increased hippocampal HO-1 content and activity mediate the antidepressant-like effect of UA in the TST.

Aerobic exercise ameliorates survival, clinical score, lung inflammation, DNA and protein damage in septic mice.

BACKGROUND AND OBJECTIVE: Sepsis is a potentially deadly organic dysfunction, and one of the main causes of mortality in intensive care units (ICU). Aerobic exercise (AE) is a preventive intervention in the establishment of inflammatory conditions, such as chronic lung diseases, but its effects on sepsis remain unclear. Therefore, this study aimed to evaluate the effects of AE on health condition, mortality, inflammation, and oxidative damage in an experimental model of pneumosepsis induced by Klebsiella pneumoniae (K.p). METHODS: Animals were randomly allocated to Control; Exercise (EXE); Pneumosepsis (PS) or Exercise + Pneumosepsis (EPS) groups. Exercised animals were submitted to treadmill exercise for 2 weeks, 30 min/day, prior to pneumosepsis induced by K.p tracheal instillation. RESULTS: PS produced a striking decrease in the health condition leading to massive death (85%). AE protected mice, as evidenced by better clinical scores and increased survival (70%). AE alleviated sickness behavior in EPS mice as evaluated in the open field test, and inflammation (nitrite + nitrate, TNF-α and IL-1ß levels) in broncoalveolar fluid. Catalase activity, oxidative damage to proteins and DNA was increased by sepsis and prevented by exercise. CONCLUSION: Overall, the beneficial effects of exercise in septic animals encompassed a markedly improved clinical score and decreased mortality, along with lower inflammation markers, less DNA and protein damage, as well as preserved antioxidant enzyme activity. Neural network risk analysis revealed exercise had a considerable effect on the overall health condition of septic mice.

The role of vitamin C in stress-related disorders.

Stress-related disorders, such as depression and anxiety, present marked deficits in behavioral and cognitive functions related to reward. These are highly prevalent disabling conditions with high social and economic costs. Furthermore, a significant percentage of affected individuals cannot benefit from clinical intervention, opening space for new treatments. Although the literature data have reported limited and variable results regarding oxidative stress-related endpoints in stress-related disorders, the possible neuroprotective effect of antioxidant compounds, such as ascorbic acid (vitamin C), emerges as a possible therapy strategy for psychiatric diseases. Here, we briefly present background information on biological activity of ascorbic acid, particularly functions related to the CNS homeostasis. Additionaly, we reviewed the available information on the role of ascorbic acid in stress-related diseases, focusing on supplementation and depletion studies. The vitamin C deficiency is widely associated to stress-related diseases. Although the efficacy of this vitamin in anxiety spectrum disorders is less stablished, several studies showed that ascorbic acid supplementation produces antidepressant effect and improves mood. Interestingly, the modulation of monoaminergic and glutamatergic neurotransmitter systems is postulated as pivotal target for the antidepressant and anxiolytic effects of this vitamin. Given that ascorbic acid supplementation produces fast therapeutic response with low toxicity and high tolerance, it can be considered as a putative candidate for the treatment of mood and anxiety disorders, especially those that are refractory to current treatments. Herein, the literature was reviewed considering the potential use of ascorbic acid as an adjuvant in the treatment of anxiety and depression.

The effect of voluntary wheel running on the antioxidant status is dependent on sociability conditions.

Voluntary wheel running is widely used as a physical activity (PA) model in rodents, but most studies investigate the beneficial effects of this intervention in socially isolated mice. Social isolation stress (SIS) is associated with vulnerability to oxidative stress and reduced mitochondrial activity. Thus, the aim of this study was to investigate the effects of free access to a running wheel for 21 days on the various markers of the cellular redox/antioxidant status as well as mitochondrial function of mice subjected to SIS or maintained in groups of 3 in the homecage. SIS increased thiobarbituric acid reactive substance (TBARS) levels in the cerebral cortex, and PA intervention was not able to reverse such alteration. PA reduced TBARS levels in the liver of grouped mice and gastrocnemius of socially isolated mice. PA increased nonprotein thiol (NPSH) levels in the cerebral cortex of grouped mice. Furthermore, socially isolated mice presented lower glutathione peroxidase (GPx) activity in the cerebellum and gastrocnemius, and glutathione reductase (GR) activity in the cerebral cortex and liver. By contrast, SIS induced higher GPx activity in the cerebral cortex and heart. PA reduced GPx (cerebral cortex) and GR (cerebral cortex and liver) activities of socially isolated mice. SIS caused higher activity of mitochondrial complexes I and II in the cerebral cortex, and the PA paradigm was not able to alter this effect. Interestingly, the PA produced antidepressant-like effect at both SIS and control groups. In conclusion, the results showed the influence of SIS for the effects of PA on the antioxidant status, but not on the mitochondrial function and emotionality.

Antidepressant-like and pro-neurogenic effects of physical exercise: the putative role of FNDC5/irisin pathway.

Physical exercise has been shown to exert antidepressant effects, but the mechanisms underlying this effect are not completely elucidated. Therefore, we aimed at investigating the antidepressant, pro-neurogenic, and neuroprotective effects of physical exercise and the possible role of FNDC5/irisin for this effect. Treadmill running was used as a protocol of physical exercise (45 min/day/5 days/week for 4 weeks) in female Swiss mice. Immobility time was registered in the tail suspension test (TST) and forced swim test (FST). Immunohistochemical analyses to evaluate hippocampal cell proliferation, neuronal survival, and neuronal commitment and maturation, as well as expression of FNDC5 C-terminal fragment were performed in the entire, dorsal, and ventral dentate gyrus (DG) of the hippocampus. Fluoro-Jade B staining was performed to evaluate degenerating neurons in DG. FNDC5 C-terminal and FNDC5/irisin immunocontents were analyzed by western blot. Exposure to physical exercise reduced the immobility time both in the TST and the FST. This antidepressant-like effect was accompanied by an increase in hippocampal cell proliferation, hippocampal neuronal differentiation, and neuronal survival in the dorsal and ventral DG. Fluoro-Jade B staining was reduced in entire and dorsal DG in exercised mice. Finally, physical exercise also resulted in increased number of FNDC5-positive cells in the hippocampal DG as well as elevated FNDC5 C-terminal and FNDC5/irisin immunocontent in the entire hippocampus. The results suggest that the FNDC5 C-terminal fragment/irisin pathway may be implicated in the antidepressant-like, pro-neurogenic, and neuroprotective effects of treadmill running.

The possible beneficial effects of creatine for the management of depression.

Depression, a highly prevalent neuropsychiatric disorder worldwide, causes a heavy burden for the society and is associated with suicide risk. The treatment of this disorder remains a challenge, since currently available antidepressants provide a slow and, often, incomplete response and cause several side effects that contribute to diminish the adhesion of patients to treatment. In this context, several nutraceuticals have been investigated regarding their possible beneficial effects for the management of this neuropsychiatric disorder. Creatine stands out as a supplement frequently used for ergogenic purpose, but it also is a neuroprotective compound with potential to treat or mitigate a broad range of central nervous systems diseases, including depression. This review presents preclinical and clinical evidence that creatine may exhibit antidepressant properties. The focus is given on the possible molecular mechanisms underlying its effects based on the results obtained with different animal models of depression. Finally, evidence obtained in animal models of depression addressing the possibility that creatine may produce rapid antidepressant effect, similar to ketamine, are also presented and discussed.

Subchronic administration of creatine produces antidepressant-like effect by modulating hippocampal signaling pathway mediated by FNDC5/BDNF/Akt in mice.

Creatine has been shown to play a significant role in the pathophysiology and treatment of major depressive disorder (MDD) in preclinical and clinical studies. However, the biological mechanisms underlying its antidepressant effect is still not fully elucidated. This study investigated the effect of creatine (p.o.) administered for 21 days in the behavior of mice submitted to tail suspension test (TST), a predictive test of antidepressant activity. Creatine reduced the immobility time in the TST (1-10 mg/kg), without affecting locomotor activity, a finding consistent with an antidepressant profile. Creatine administration increased the ubiquitous creatine kinase (uCK) and creatine kinase brain isoform (CK-B) mRNA in the hippocampus of mice. Taking into account that PGC-1α induces FNDC5/irisin expression mediating BDNF-dependent neuroplasticity, the effect of creatine administration (1 mg/kg, p. o.) on the hippocampal PGC-1α, FNDC5 and BDNF gene expression was investigated. Creatine treatment increased PGC-1α, FNDC5 and BDNF mRNA in the hippocampus as well as BDNF immunocontent. The involvement of BDNF downstream intracellular signaling pathway mediated by Akt, proapoptotic proteins BAX and BAD and antiapoptotic proteins Bcl2 and Bcl-xL was also investigated following creatine treatment. Creatine increased Akt phosphorylation (Ser 473), and Bcl2 mRNA and protein levels, and Bcl-xL mRNA, whereas BAD mRNA was decreased following creatine administration in the hippocampus. Altogether these results indicate that creatine antidepressant-like effect may be dependent on Akt activation and increased expression of the neuroprotective proteins in the hippocampus of mice. The obtained data reinforce the antidepressant property of creatine and highlight the role of these molecular targets in the pathophysiology of MDD.

Antidepressant effects of creatine on amyloid ß1-40-treated mice: The role of GSK-3ß/Nrf2 pathway.

Alzheimer's disease (AD) is characterized by progressive synaptic dysfunction and neuronal lost in specific brain areas including hippocampus, resulting in memory/learning deficits and cognitive impairments. In addition, non-cognitive symptoms are reported in AD patients, such as anxiety, apathy and depressed mood. The current antidepressant drugs present reduced efficacy to improve depressive symptoms in AD patients. Here, we investigated the ability of creatine, a compound with neuroprotective and antidepressant properties, to counteract amyloid ß1-40 peptide-induced depressive-like behavior in mice. Moreover, we addressed the participation of the intracellular signaling pathway mediated by glycogen synthase kinase-3ß (GSK-3ß)/nuclear factor erythroid-2-related factor 2 (Nrf2) in the creatine effects. Aß1-40 administration (400 pmol/mouse, i.c.v.) increased the immobility time in the tail suspension test and decreased the grooming time and increased latency to grooming in the splash test, indicative of depressive-like behavior. These impairments were attenuated by creatine (0.01 and 10 mg/kg, p.o.) and fluoxetine (10 mg/kg, p.o., positive control). No significant alterations on locomotor performance were observed in the open field. Aß1-40 administration did not alter hippocampal phospho-GSK-3ß (Ser9)/total GSK-3ß, total GSK-3ß and heme oxygenase-1 (HO-1) immunocontents. However, Aß1-40-infused mice treated with creatine (0.01 mg/kg) presented increased phosphorylation of GSK-3ß(Ser9) and HO-1 immunocontent in the hippocampus. Fluoxetine per se increased GSK-3ß(Ser9) phosphorylation, but did not alter HO-1 levels. In addition, Aß1-40 administration increased hippocampal glutathione (GSH) levels as well as glutathione reductase (GR) and thioredoxin reductase (TrxR) activities, and these effects were abolished by creatine and fluoxetine. This study provides the first evidence of the antidepressive-like effects of creatine in Aß1-40-treated mice, which were accompanied by hippocampal inhibition of GSK-3ß and modulation of antioxidant defenses. These findings indicate the potential of creatine for the treatment of depression associated with AD.

Central irisin administration affords antidepressant-like effect and modulates neuroplasticity-related genes in the hippocampus and prefrontal cortex of mice.

Evidence has indicated that the practice of physical exercise has antidepressant effects that might be associated with irisin release and BDNF signaling. In this study we investigated the effects of the central administration of irisin or BDNF in predictive tests of antidepressant properties paralleled with the gene expression of peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α), fibronectin type III domain-containing protein 5 (FNDC5) and brain-derived neurotrophic factor (BDNF) in the hippocampus and prefrontal cortex of mice. Irisin (0.5-1 ng/mouse, i.c.v.) reduced the immobility time in the tail suspension test (TST) and forced swim test (FST), without altering locomotion in the open field test (OFT). Irisin reduced the immobility time in the TST up to 6 h after its administration. Irisin administration (6 h) increased PGC-1α mRNA in the hippocampus and prefrontal cortex and reduced (1 h) PGC-1α mRNA in the prefrontal cortex. FNDC5 and BDNF mRNA expression was decreased (1 h) in both structures and remained reduced up to 6 h in the prefrontal cortex. Moreover, BDNF administered at 0.25 µg/mouse, i.c.v. (1 and 6 h before the test) reduced the immobility time in the TST. BDNF administration reduced PGC-1α mRNA in the hippocampus (6 h) and prefrontal cortex (1 and 6 h). It also increased FNDC5 mRNA expression in the hippocampus (1 and 6 h), but reduced the expression of this gene and also BDNF mRNA in the prefrontal cortex (1 and 6 h). None of the treatments altered BDNF protein levels in both structures. In conclusion, irisin presents a behavioral antidepressant profile similar to BDNF, an effect associated with the modulation of gene expression of PGC-1α, FNDC5 and BDNF, reinforcing the pivotal role of these genes in mood regulation.

The APPswe/PS1A246E mutations in an astrocytic cell line leads to increased vulnerability to oxygen and glucose deprivation, Ca2+ dysregulation, and mitochondrial abnormalities.

Growing evidence suggests a close relationship between Alzheimer's Disease (AD) and cerebral hypoxia. Astrocytes play a key role in brain homeostasis and disease states, while some of the earliest changes in AD occur in astrocytes. We have therefore investigated whether mutations associated with AD increase astrocyte vulnerability to ischemia. Two astroglioma cell lines derived from APPSWE /PS1A246E (APP, amyloid precursor protein; PS1, presenilin 1) transgenic mice and controls from normal mice were subjected to oxygen and glucose deprivation (OGD), an in vitro model of ischemia. Cell death was increased in the APPSWE /PS1A246E line compared to the control. Increasing extracellular calcium concentration ([Ca2+ ]) exacerbated cell death in the mutant but not in the control cells. In order to explore cellular Ca2+ homeostasis, the cells were challenged with ATP or thapsigargin and [Ca2+ ] was measured by fluorescence microscopy. Changes in cytosolic Ca2+ concentration ([Ca2+ ]c ) were potentiated in the APPSWE /PS1A246E transgenic line. Mitochondrial function was also altered in the APPSWE /PS1A246E astroglioma cells; mitochondrial membrane potential and production of reactive oxygen species were increased, while mitochondrial basal respiratory rate and ATP production were decreased compared to control astroglioma cells. These results suggest that AD mutations in astrocytes make them more sensitive to ischemia; Ca2+ dysregulation and mitochondrial dysfunction may contribute to this increased vulnerability. Our results also highlight the role of astrocyte dyshomeostasis in the pathophysiology of neurodegenerative brain disorders.

Ursolic acid affords antidepressant-like effects in mice through the activation of PKA, PKC, CAMK-II and MEK1/2.

BACKGROUND: Ursolic acid has been shown to display antidepressant-like effects in mice through the modulation of monoaminergic systems. In this study, we sought to investigate the involvement of signaling pathways on the antidepressant-like effects of ursolic acid. METHODS: Mice were treated orally with ursolic acid (0.1mg/kg) and, 45min later they received the followings inhibitors by intracerebroventricular route: H-89 (PKA inhibitor, 1µg/mouse), KN-62 (CAMK-II inhibitor, 1µg/mouse), chelerythrine (PKC inhibitor, 1µg/mouse), U0126 (MEK1/2 inhibitor, 5µg/mouse), PD98059 (MEK1/2 inhibitor, 5µg/mouse), wortmannin (PI3K irreversible inhibitor, 0.1µg/mouse) or LY294002 (PI3K inhibitor, 10 nmol/mouse). Immobility time of mice was registered in the tail suspension test (TST). RESULTS: The anti-immobility effect of ursolic acid in the TST was abolished by the treatment of mice with H-89, KN-62, chelerythrine, U0126 or PD98059, but not with wortmannin or LY294002. CONCLUSIONS: These results suggest that activation of PKA, PKC, CAMK-II, MEK1/2 may underlie the antidepressant-like effects of ursolic acid.

Evidence for the involvement of heme oxygenase-1 in the antidepressant-like effect of zinc.

BACKGROUND: Considering that heme oxygenase-1 (HO-1) and the brain-derived neurotrophic factor (BDNF)-mediated pathway are involved in the pathophysiology of depression and that zinc has been shown to exert beneficial effects in the management of depression, this study investigated the influence of these targets on the antidepressant-like effect of zinc. METHODS: Mice were treated with sub-effective or effective doses of zinc chloride (ZnCl2, 10mg/kg, po), and 45min later, they received intracerebroventricular (icv) injections of sub-effective doses of either zinc protoporphyrin IX (ZnPP, 10µg/mouse, HO-1 inhibitor), cobalt protoporphyrin IX (CoPP, 0.01µg/mouse, HO-1 inducer) or K-252a (1µg/mouse, TrkB receptor antagonist). Immobility time and locomotor activity were evaluated through the tail suspension test (TST) and open-field test (OFT), respectively. HO-1 immunocontents were evaluated in the prefrontal cortex and hippocampus 60min after ZnCl2 (10mg/kg, po) treatment. RESULTS: The antidepressant-like effect of ZnCl2 was prevented by the treatment with ZnPP and K-252a. Furthermore, sub-effective doses of CoPP and ZnCl2 produced a synergistic antidepressant-like effect in the TST. None of the treatments altered locomotor activity. ZnCl2 administration increased HO-1 immunocontents only in the prefrontal cortex. CONCLUSIONS: The results indicate that the antidepressant-like effect of ZnCl2 in the TST may depend on the induction of HO-1, and activation of TrkB receptor.

MPP+-Lesioned Mice: an Experimental Model of Motor, Emotional, Memory/Learning, and Striatal Neurochemical Dysfunctions.

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces motor and nonmotor dysfunctions resembling Parkinson's disease (PD); however, studies investigating the effects of 1-methyl-4-phenylpyridinium (MPP+), an active oxidative product of MPTP, are scarce. This study investigated the behavioral and striatal neurochemical changes (related to oxidative damage, glial markers, and neurotrophic factors) 24 h after intracerebroventricular administration of MPP+ (1.8-18 µg/mouse) in C57BL6 mice. MPP+ administration at high dose (18 µg/mouse) altered motor parameters, since it increased the latency to leave the first quadrant and reduced crossing, rearing, and grooming responses in the open-field test and decreased rotarod latency time. MPP+ administration at low dose (1.8 µg/mouse) caused specific nonmotor dysfunctions as it produced a depressive-like effect in the forced swim test and tail suspension test, loss of motivational and self-care behavior in the splash test, anxiety-like effect in the elevated plus maze test, and short-term memory deficit in the step-down inhibitory avoidance task, without altering ambulation. MPP+ at doses of 1.8-18 µg/mouse increased tyrosine hydroxylase (TH) immunocontent and at 18 µg/mouse increased α-synuclein and decreased parkin immunocontent. The astrocytic calcium-binding protein S100B and glial fibrillary acidic protein (GFAP)/S100B ratio was decreased following MPP+ administration (18 µg/mouse). At this highest dose, MPP+ increased the ionized calcium-binding adapter molecule 1 (Iba-1) immunocontent, suggesting microglial activation. Also, MPP+ at a dose of 18 µg/mouse increased thiobarbituric acid reactive substances (TBARS) and glutathione (GSH) levels and increased glutathione peroxidase (GPx) and hemeoxygenase-1 (HO-1) immunocontent, suggesting a significant role for oxidative stress in the MPP+-induced striatal damage. MPP+ (18 µg/mouse) also increased striatal fibroblast growth factor 2 (FGF-2) and brain-derived neurotrophic factor (BDNF) levels. Moreover, MPP+ decreased tropomyosin receptor kinase B (TrkB) immunocontent. Finally, MPP+ (1.8-18 µg/mouse) increased serum corticosterone levels and did not alter acetylcholinesterase (AChE) activity in the striatum but increased it in cerebral cortex and hippocampus. Collectively, these results indicate that MPP+ administration at low doses may be used as a model of emotional and memory/learning behavioral deficit related to PD and that MPP+ administration at high dose could be useful for analysis of striatal dysfunctions associated with motor deficits in PD.

Atorvastatin Protects from Aß1-40-Induced Cell Damage and Depressive-Like Behavior via ProBDNF Cleavage.

Intracerebroventricular (icv) amyloid-beta (Aß)1-40 infusion to mice has been demonstrated to cause neurotoxicty and depressive-like behavior and it can be used to evaluate antidepressant and neuroprotective effect of drugs. Atorvastatin is a widely used statin that has demonstrated antidepressant-like effect in predictable animal behavioral models and neuroprotective effect against Aß1-40 infusion. The purpose of this study was to determine the effect of in vivo atorvastatin treatment against Aß1-40-induced changes in mood-related behaviors and biochemical parameters in ex vivo hippocampal slices from mice. Atorvastatin treatment (10 mg/kg, p.o., once a day for seven consecutive days) abolished depressive-like and anhedonic-like behaviors induced by Aß1-40 (400 pmol/site, icv) infusion. Aß1-40-induced hippocampal cell damage was reversed by atorvastatin treatment. Aß1-40 infusion decreased glutamate uptake in hippocampal slices, and atorvastatin did not altered it. Glutamine synthetase activity was not altered by any treatment. Atorvastatin also increased hippocampal mature brain-derived neurotrophic factor (mBDNF)/precursor BDNF (proBDNF) ratio, suggesting an increase of proBDNF to mBDNF cleavage. Accordingly, increased tissue-type plasminogen activator (tPA) and p11 genic expression were observed in hippocampus of atorvastatin-treated mice. Atorvastatin displays antidepressant-like and neuroprotective effects against Aß1-40-induced toxicity, and these effects may involve tPA- and p11-mediated cleavage of proBDNF to mBDNF.

Creatine Prevents Corticosterone-Induced Reduction in Hippocampal Proliferation and Differentiation: Possible Implication for Its Antidepressant Effect.

The benefits of creatine supplementation have been reported in a broad range of central nervous system diseases, including depression, although the mechanisms underlying these effects remain to be understood. In the present study, we investigated the ability of creatine to counteract the morphological and behavioral effects elicited by chronic administration of corticosterone (CORT, 20 mg/kg, p.o.) for 21 days to mice, a pharmacological model of depression that mimics exposure to stress. CORT treatment increased immobility time in the tail suspension test (TST) and forced swim test (FST), as well as latency to immobility in the FST, and decreased the sucrose consumption in the sucrose preference test (SPT). These behavioral effects were associated with decreased hippocampal cell proliferation and neuronal differentiation and increased glial fibrillary acid protein (GFAP) immunostaining (suggestive of astrogliosis) in dentate gyrus (DG) of the hippocampus. These CORT-induced alterations were abolished by treatment with either fluoxetine (a conventional antidepressant) or creatine for 21 days (both 10 mg/kg, p.o.). In addition, fluoxetine, but not creatine, was able to reverse the CORT-induced reduction in serum CORT levels. Collectively, our results suggest that creatine produces morphological alterations that contribute to the improvement of depressive-like behaviors triggered by chronic CORT administration in mice.

Pramipexole, a Dopamine D2/D3 Receptor-Preferring Agonist, Prevents Experimental Autoimmune Encephalomyelitis Development in Mice.

Experimental autoimmune encephalomyelitis (EAE) is the most used animal model of multiple sclerosis (MS) for the development of new therapies. Dopamine receptors can modulate EAE and MS development, thus highlighting the potential use of dopaminergic agonists in the treatment of MS, which has been poorly explored. Herein, we hypothesized that pramipexole (PPX), a dopamine D2/D3 receptor-preferring agonist commonly used to treat Parkinson's disease (PD), would be a suitable therapeutic drug for EAE. Thus, we report the effects and the underlying mechanisms of action of PPX in the prevention of EAE. PPX (0.1 and 1 mg/kg) was administered intraperitoneally (i.p.) from day 0 to 40 post-immunization (p.i.). Our results showed that PPX 1 mg/kg prevented EAE development, abolishing EAE signs by blocking neuroinflammatory response, demyelination, and astroglial activation in spinal cord. Moreover, PPX inhibited the production of inflammatory cytokines, such as IL-17, IL-1ß, and TNF-α in peripheral lymphoid tissue. PPX was also able to restore basal levels of a number of EAE-induced effects in spinal cord and striatum, such as reactive oxygen species, glutathione peroxidase, parkin, and α-synuclein (α-syn). Thus, our findings highlight the usefulness of PPX in preventing EAE-induced motor symptoms, possibly by modulating immune cell responses, such as those found in MS and other T helper cell-mediated inflammatory diseases.

Agmatine attenuates reserpine-induced oral dyskinesia in mice: Role of oxidative stress, nitric oxide and glutamate NMDA receptors.

Dyskinesia consists in a series of trunk, limbs and orofacial involuntary movements that can be observed following long-term pharmacological treatment in some psychotic and neurological disorders such as schizophrenia and Parkinson's disease, respectively. Agmatine is an endogenous arginine metabolite that emerges as neuromodulator and a promising agent to manage diverse central nervous system disorders by modulating nitric oxide (NO) pathway, glutamate NMDA receptors and oxidative stress. Herein, we investigated the effects of a single intraperitoneal (i.p.) administration of different agmatine doses (10, 30 or 100mg/kg) against the orofacial dyskinesia induced by reserpine (1mg/kg,s.c.) in mice by measuring the vacuous chewing movements and tongue protusion frequencies, and the duration of facial twitching. The results showed an orofacial antidyskinetic effect of agmatine (30mg/kg, i.p.) or the combined administration of sub-effective doses of agmatine (10mg/kg, i.p.) with the NMDA receptor antagonists amantadine (1mg/kg, i.p.) and MK801 (0.01mg/kg, i.p.) or the neuronal nitric oxide synthase (NOS) inhibitor 7-nitroindazole (7-NI; 0.1mg/kg, i.p.). Reserpine-treated mice displayed locomotor activity deficits in the open field and agmatine had no effect on this response. Reserpine increased nitrite and nitrate levels in cerebral cortex, but agmatine did not reverse it. Remarkably, agmatine reversed the decrease of dopamine and non-protein thiols (NPSH) levels caused by reserpine in the striatum. However, no changes were observed in striatal immunocontent of proteins related to the dopaminergic system including tyrosine hydroxylase, dopamine transporter, vesicular monoamine transporter type 2, pDARPP-32[Thr75], dopamine D1 and D2 receptors. These results indicate that the blockade of NO pathway, NMDAR and oxidative stress are possible mechanisms associated with the protective effects of agmatine against the orofacial dyskinesia induced by reserpine in mice.

Creatine affords protection against glutamate-induced nitrosative and oxidative stress.

Creatine has been reported to exert beneficial effects in several neurodegenerative diseases in which glutamatergic excitotoxicity and oxidative stress play an etiological role. The purpose of this study was to investigate the protective effects of creatine, as compared to the N-Methyl-d-Aspartate (NMDA) receptor antagonist dizocilpine (MK-801), against glutamate or hydrogen peroxide (H2O2)-induced injury in human neuroblastoma SH-SY5Y cells. Exposure of cells to glutamate (60-80 mM) or H2O2 (200-300 µM) for 24 h decreased cellular viability and increased dichlorofluorescein (DCF) fluorescence (indicative of increased reactive oxygen species, ROS) and nitric oxide (NO) production (assessed by mono-nitrogen oxides, NOx, levels). Creatine (1-10 mM) or MK-801 (0.1-10 µM) reduced glutamate- and H2O2-induced toxicity. The protective effect of creatine against glutamate-induced toxicity involves its antioxidant effect, since creatine, similar to MK-801, prevented the increase on DCF fluorescence induced by glutamate or H2O2. Furthermore, creatine or MK-801 blocked glutamate- and H2O2-induced increases in NOx levels. In another set of experiments, the repeated, but not acute, administration of creatine (300 mg/kg, po) in mice prevented the decreases on cellular viability and mitochondrial membrane potential (assessed by tetramethylrhodamine ethyl ester, TMRE, probe) of hippocampal slices incubated with glutamate (10 mM). Creatine concentration-dependent decreased the amount of nitrite formed in the reaction of oxygen with NO produced from sodium nitroprusside solution, suggesting that its protective effect against glutamate or H2O2-induced toxicity might be due to its scavenger activity. Overall, the results suggest that creatine may be useful as adjuvant therapy for neurodegenerative disease treatments.

Creatine, Similar to Ketamine, Counteracts Depressive-Like Behavior Induced by Corticosterone via PI3K/Akt/mTOR Pathway.

Ketamine has emerged as a novel strategy to treat refractory depression, producing rapid remission, but elicits some side effects that limit its use. In an attempt to investigate a safer compound that may afford an antidepressant effect similar to ketamine, this study examined the effects of the ergogenic compound creatine in a model of depression, and the involvement of phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway in its effect. In order to induce a depressive-like behavior, mice were administered with corticosterone (20 mg/kg, per os (p.o.)) for 21 days. This treatment increased immobility time in the tail suspension test (TST), an effect abolished by a single administration of creatine (10 mg/kg, p.o.) or ketamine (1 mg/kg, i.p.), but not by fluoxetine (10 mg/kg, p.o., conventional antidepressant). Treatment of mice with wortmannin (PI3K inhibitor, 0.1 µg/site, intracerebroventricular (i.c.v.)) or rapamycin (mTOR inhibitor, 0.2 nmol/site, i.c.v.) abolished the anti-immobility effect of creatine and ketamine. None of the treatments affected locomotor activity of mice. The immunocontents of p-mTOR, p-p70S6 kinase (p70S6K), and postsynaptic density-95 protein (PSD95) were increased by creatine and ketamine in corticosterone or vehicle-treated mice. Moreover, corticosterone-treated mice presented a decreased hippocampal brain-derived neurotrophic factor (BDNF) level, an effect abolished by creatine or ketamine. Altogether, the results indicate that creatine shares with ketamine the ability to acutely reverse the corticosterone-induced depressive-like behavior by a mechanism dependent on PI3K/AKT/mTOR pathway, and modulation of the synaptic protein PSD95 as well as BDNF in the hippocampus, indicating the relevance of targeting these proteins for the management of depressive disorders. Moreover, we suggest that creatine should be further investigated as a possible fast-acting antidepressant.