RESUMO
Gangliosides are compounds that are abundant throughout the CNS, participating actively in neuroplasticity. We previously described that exogenous GM1 ganglioside pretreatment enhances the rewarding properties of cocaine, evidenced by a lower number of sessions and/or dosage necessary to induce conditioned place preference (CPP). Since GM1 pretreatment did not modify cocaine's pharmacokinetic parameters, we suspected that the increased rewarding effect found might be mediated by BDNF, a neurotrophic factor closely related to cocaine addiction. This study was performed to investigate the possibility that GM1 may induce changes in BDNF levels in the nucleus accumbens (NAc), a core structure in the brain's reward circuitry, of rats submitted to three conditioning sessions with cocaine (10 mg/kg, i.p.). The results demonstrate that GM1 administration, which showed no rewarding effect by itself in the CPP, induced a significant increase of BDNF protein levels in the NAc, which may account for the increased rewarding effect of cocaine shown in the CPP paradigm.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cocaína/farmacologia , Condicionamento Operante/efeitos dos fármacos , Gangliosídeo G(M1)/farmacologia , Núcleo Accumbens/metabolismo , Recompensa , Animais , Gangliosídeo G(M1)/administração & dosagem , Masculino , Ratos , Ratos WistarRESUMO
NOD (non-obese diabetic) mice develop type 1 diabetes mellitus spontaneously and with a strong similarity to the human disease. Differentiation and function of pancreas beta cells are regulated by a variety of hormones and growth factors, including the nerve growth factor (NGF). Gangliosides have multiple immunomodulatory activities with immunosuppressive properties, decreasing lymphoproliferative responses and modulating cytokine production. In the present study, serum, pancreas islets and spleen mononuclear cells from NOD mice treated with monosialic ganglioside GM1 (100 mg/kg/day) and the group control which received saline solution were isolated to investigate the proinflammatory cytokines (IL-1beta, IFN-gamma, IL-12, TNF-alpha), NGF and its high-affinity receptor TrkA, peri-islet Schwann cells components (GFAP, S100-beta) expression and the relationship with diabetes onset and morphological aspects. Our results suggest that GM1 administration to female NOD mice beginning at the 4th week of life is able to reduce the index of inflammatory infiltrate and consequently the expression of diabetes, modulating the expression of proinflammatory cytokines (IL-12, IFN-gamma, TNF-alpha and IL-1beta). Furthermore, GM1 increases GFAP, S-100beta and NGF in pancreas islets, factors involved in beta cell survival.
Assuntos
Citocinas/metabolismo , Diabetes Mellitus Tipo 1/imunologia , Gangliosídeo G(M1)/metabolismo , Camundongos Endogâmicos NOD , Fator de Crescimento Neural/metabolismo , Receptor trkA/metabolismo , Idade de Início , Animais , Citocinas/genética , Feminino , Gangliosídeo G(M1)/administração & dosagem , Proteína Glial Fibrilar Ácida , Humanos , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Fator de Crescimento Neural/genética , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Receptor trkA/genética , Subunidade beta da Proteína Ligante de Cálcio S100 , Proteínas S100/genética , Proteínas S100/metabolismo , Células de Schwann/citologia , Células de Schwann/metabolismo , Baço/citologia , Baço/metabolismoRESUMO
Numerous investigations have been reporting the involvement of GM1 ganglioside in central nervous system development and memory formation. The effects of neonatal treatment with GMI ganglioside on the performance of adult rats in a plus-maze discriminative avoidance task and old rats in a step-down passive avoidance task were investigated. Rats were injected subcutaneously from day 3 to 15 after birth with 10 mg/kg GM1 or saline. GM1 treatment did not modify indicative landmarks of physical and motor development. Behavioural tasks were carried out when the animals were 4 (discriminative avoidance) or 24 (passive avoidance) months old. Discriminative avoidance conditioning was performed in a modified elevated plus-maze. During the training session, the animals received aversive stimulation (light and hot air blow) in one of the enclosed arms. Tests were performed 7, 14 and 21 days after conditioning (tests 1, 2 and 3), in the absence of the aversive stimulation. In all tests, GM1-treated animals spent less time in the aversive arm than in the non-aversive enclosed arm. Control animals, however, spent a shorter time in the aversive arm only in tests 1 and 2. Passive avoidance conditioning was performed in an acrylic box with a grid floor, that was partially covered by an inclined platform. Animals were placed on the platform and received a 0,5 mA foot shock when stepped down. A test was performed 48 hr later. Latency to step down presented by GM 1-treated animals was significantly higher in the test session, whereas no significant increase in latency to step down was found for control animals. The results suggest a possible action of GM1 on the maturation of the central nervous system that persists during adulthood and ageing.
Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Gangliosídeo G(M1)/farmacologia , Memória/efeitos dos fármacos , Análise de Variância , Animais , Animais Recém-Nascidos , Peso Corporal/efeitos dos fármacos , Sistema Nervoso Central/crescimento & desenvolvimento , Feminino , Gangliosídeo G(M1)/administração & dosagem , Injeções Subcutâneas , Masculino , Ratos , Ratos WistarRESUMO
In a previous work, our group reported that Albino Swiss male mice inoculated with T. cruzi to develop acute lethal infection by day 15 decreased parasitemia and survived when treated with total brain gangliosides (GT; 1 mg, daily). In this paper, GT were replaced by GM1 in 0.1 mg dose that caused diminished parasitemia from day 15 to 30 and survival of 80% by day 120 p.i. Treatment with GT 0.15 mg was ineffective. This indicates that GT effect was due to GM1 and that more sialyl residues on the same lipid moiety produces adverse results. GM1 was compared to other sialylated molecules: fetuine and colominic acid. Both of them increased parasitemias and death by day 16 p.i., suggesting that sialic residues favor parasite replication. Asialo-GM1 (0.1 mg daily) was also adverse. This pointed to GM1 not to other ganglioside or sphingolipid or sialoprotein as the active agent. Gangliosides are [Ca+2]i modulators, so GM1 was compared to nifedipine which blocks calcium channels only in the host. Nifedipine treated mice behaved as controls. It is proposed that if GM1 calcium modulation is involved it must be on the parasite rather than on the host. Electrocardiographic (ECG) records show that while infected mice die with bradycardia, treated mice survive and recover normal frequency. Uninfected treated mice showed no electrocardiographic alterations.
Assuntos
Cardiomiopatia Chagásica/tratamento farmacológico , Doença de Chagas/tratamento farmacológico , Gangliosídeo G(M1)/uso terapêutico , Coração/fisiologia , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/fisiopatologia , Doença de Chagas/parasitologia , Doença de Chagas/fisiopatologia , Eletrocardiografia , Gangliosídeo G(M1)/administração & dosagem , Gangliosídeo G(M1)/química , Gangliosídeo G(M1)/farmacologia , Coração/parasitologia , Masculino , Camundongos , Nifedipino/farmacologia , Nifedipino/uso terapêutico , Parasitemia/tratamento farmacológico , Parasitemia/parasitologiaRESUMO
INTRODUCTION: The ganglioside GM1 has been shown to be effective in the treatment of experimental cerebral ischemia. Gangliosides from bovine brain have not been used in the treatment of ischemic cerebral accidents. There is evidence suggesting that they may also be effective. RESULTS: Ten minutes of bilateral occlusion of the carotid arteries of Mongolian gerbils leads a week later to reduced spontaneous exploratory activity, assessed by counting the number of times they stood up in an open field over a period of three minutes, and retarded neuronal death in the pyramidal stratum of the CA1 sector of the hippocampus, evaluated on the density of normal neurons in this region of both hemispheres. Treatment with 30 mg/kg of intra-peritoneal bovine cerebral gangliosides during the first six days following occlusion of the carotid arteries, leads to conservation of both exploratory activity and density of pyramidal neurons observed in the control animals. CONCLUSIONS: Bovine cerebral gangliosides have a short term cytoprotector effect on neurons sensitive to the ischemia-reperfusion phenomenon. This effect may be due to more than one mechanism, in which other gangliosides (together with GM1) may be present due to transient permeability of the blood-brain barrier.
Assuntos
Comportamento Exploratório/efeitos dos fármacos , Gangliosídeo G(M1)/uso terapêutico , Ataque Isquêmico Transitório/tratamento farmacológico , Neurônios/patologia , Animais , Bovinos , Contagem de Células , Morte Celular/efeitos dos fármacos , Gangliosídeo G(M1)/administração & dosagem , Gerbillinae , Injeções Intraperitoneais , Neurônios/efeitos dos fármacosRESUMO
Tubulization repair technique is a useful model to study peripheral nerve regeneration by offering quantifiable parameters to assess the possible effect of exogenously applied substances on nerve repair. In the present study we demonstrated that locally administered GM1 inside a tubular prosthesis at the time of implantation can significantly improve the repair process. The sciatic nerve of 8 male C57BL/6J mice, approximately 3 months old at the time of surgery and divided into two groups of 4 animals each, was transected and the proximal and distal nerve stumps were sutured into a polyethylene tube (PT), 0.76 mm internal diameter (ID), to bridge a nerve gap of 4 mm. The tubes contained 2 microliters of collagen type I (2.4 mg/ml) alone or in combination (1:1 volume ratio) with monosialoganglioside GM1 (10 mg/ml in the final solution). Four additional animals received a PT with 1.14 mm ID filled with 5.5 microliters of collagen/GM1 (at the same ratio and final concentration as above). After 6 weeks the PT with the regenerating nerve cables were processed for total myelinated axon counts with a computer-controlled system. GM1 significantly increased peripheral axon regeneration (3427 +/- 64 myelinated axons for the 0.76-mm PT and 3623 +/- 270 for the 1.14-mm PT, mean +/- SEM) compared to the group receiving collagen alone (2516 +/- 156) and this effect did not depend on tube diameter. This action is possibly due to a stimulating effect of GM1 on neurite outgrowth and sprouting.