RESUMO
Neuroinflammation refers to a highly complicated reaction of the central nervous system (CNS) to certain stimuli such as trauma, infection, and neurodegenerative diseases. This is a cellular immune response whereby glial cells are activated, inflammatory mediators are liberated and reactive oxygen and nitrogen species are synthesized. Neuroinflammation is a key process that helps protect the brain from pathogens, but inappropriate, or protracted inflammation yields pathological states such as Parkinson's disease, Alzheimer's, Multiple Sclerosis, and other neurodegenerative disorders that showcase various pathways of neurodegeneration distributed in various parts of the CNS. This review reveals the major neuroinflammatory signaling pathways associated with neurodegeneration. Additionally, it explores promising therapeutic avenues, such as stem cell therapy, genetic intervention, and nanoparticles, aiming to regulate neuroinflammation and potentially impede or decelerate the advancement of these conditions. A comprehensive understanding of the intricate connection between neuroinflammation and these diseases is pivotal for the development of future treatment strategies that can alleviate the burden imposed by these devastating disorders.
RESUMO
As a non-classical post-translational modification, O-linked ß-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) is widely found in human organ systems, particularly in our brains, and is indispensable for healthy cell biology. With the increasing age of the global population, the incidence of neurodegenerative diseases is increasing, too. The common characteristic of these disorders is the aggregation of abnormal proteins in the brain. Current research has found that O-GlcNAcylation dysregulation is involved in misfolding or aggregation of these abnormal proteins to mediate disease progression, but the specific mechanism has not been defined. This paper reviews recent studies on O-GlcNAcylation's roles in several neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, Machado-Joseph's disease, and giant axonal neuropathy, and shows that O-GlcNAcylation, as glucose metabolism sensor, mediating synaptic function, participating in oxidative stress response and signaling pathway conduction, directly or indirectly regulates characteristic pathological protein toxicity and affects disease progression. The existing results suggest that targeting O-GlcNAcylation will provide new ideas for clinical diagnosis, prevention, and treatment of neurodegenerative diseases.
Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Humanos , Doenças Neurodegenerativas/metabolismo , Processamento de Proteína Pós-Traducional , Proteínas/metabolismo , Doença de Alzheimer/patologia , Acetilglucosamina/metabolismo , Progressão da Doença , N-Acetilglucosaminiltransferases/metabolismoRESUMO
BACKGROUND: Individuals with chronic kidney disease (CKD) are at a substantially higher risk for stroke, which may predispose individuals to cognitive impairment. However, the association of low estimated glomerular filtration rate (eGFR) and albuminuria with poorer cognitive performance in patients with stroke is not fully understood, and the current evidence for this association is contradictory. Our aim was to retrospectively investigate whether low eGFR and albuminuria, as indicated by the urine albumin-creatinine ratio (UACR), are independently or jointly associated with worse cognitive performance in patients with ischemic stroke. METHODS: This retrospective study included 608 patients with acute ischemic stroke. Their UACR and eGFR values were obtained from inpatient medical records. Global cognitive function was assessed with the mini-mental state exam (MMSE) and Montreal Cognitive Assessment (MoCA) one month after hospital discharge. The relationship between renal measures and cognitive performance was assessed using univariate and multiple linear regression analyses. Potential confounders included age, gender, BMI, education, diabetes and hypertension history, NIHSS score, smoking and alcohol consumption status, serum total cholesterol, triglyceride, fasting glucose, uric acid, homocysteine, systolic blood pressure, and either eGFR or UACR. RESULTS: Patients had an average age of 66.6±4.1 years, and 48% were females. Average eGFR and UACR were 88.4±12.9 ml/min/1.73m2 and 83.6±314.2 mg/g, respectively. The number of patients with eGFR ≥90, 60-89, and <60 ml/min/1.73 m2 was 371 (61%), 207 (34%), and 30 (5%), respectively, and the percentage of patients with UACR <30 mg/g, 30-300 mg/g, and >300 mg/g was 56%, 39%, and 5%, respectively. Multivariate adjusted models showed that eGFR was independently associated with MMSE (ß = -0.4; 95% CI = -0.5,-0.4; p <0.001) and MoCA (ß = -0.6; 95% CI = -0.7,-0.5; p <0.001). However, UACR was not significantly correlated with MMSE or MoCA. CONCLUSION: In patients with ischemic stroke, reduced eGFR but not albuminuria was associated with lower cognitive performance. These results show that the eGFR decline could be an effective indicator of cognitive impairment after a stroke. Therefore, regular monitoring and early detection of mild renal dysfunction in patients with acute ischemic stroke might be needed.
Assuntos
AVC Isquêmico , Insuficiência Renal Crônica , Acidente Vascular Cerebral , Feminino , Humanos , Pessoa de Meia-Idade , Idoso , Masculino , AVC Isquêmico/complicações , Estudos Retrospectivos , Albuminúria/complicações , Rim , Taxa de Filtração Glomerular/fisiologia , Insuficiência Renal Crônica/complicações , Acidente Vascular Cerebral/complicações , Cognição , CreatininaRESUMO
Neuroinflammation plays a crucial role in the development of epilepsy, and suppressing neuroinflammation can delay epileptogenesis. Recent reports have demonstrated that (+)-borneol has neuroprotective effects in several brain disorders by reducing neuroinflammation. However, its effects on epilepsy have not been reported. In this research, we first studied the effect of different doses of (+)-borneol (3, 6, and 12 mg/kg) on neuroinflammation in a pilocarpine model of epileptogenesis by detecting IL-1ß, TNF-α, and COX-2 expression. We demonstrated that different doses of (+)-borneol decreased IL-1ß, TNF-α, and COX-2 levels, with 12 mg/kg having the most substantial effect. Furthermore, we examined the effects of 12 mg/kg (+)-borneol on neuronal damage, glial cell activation, and apoptosis in the hippocampus at different time points (1, 3, and 7 days) after SE. We found that (+)-borneol significantly ameliorated neuronal injury, decreased glial cell activation, and attenuated apoptosis. We also found that (+)-borneol inhibited the NF-κB pathway activation induced by SE. In conclusion, our results indicated that (+)-borneol reduces neuroinflammation by inhibiting the NF-κB pathway activation, exerts neuroprotective effects, and may have an inhibitory effect in epileptogenesis.
Assuntos
Epilepsia , Fármacos Neuroprotetores , Ratos , Animais , NF-kappa B/metabolismo , Pilocarpina/toxicidade , Fármacos Neuroprotetores/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Doenças Neuroinflamatórias , Ciclo-Oxigenase 2 , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológicoRESUMO
The GLP-1 receptor agonist exendin-4 has recently shown good effects in a phase II clinical trial in Parkinson's disease (PD) patients. Here, a comparison of the new GLP-1/GIP dual receptor agonist DA5-CH and NLY01, a 40 kDa pegylated form of exendin-4, on motor impairments and reducing inflammation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) PD mouse model is provided. The drug groups received either DA5-CH or NLY01 (25 nmol/kg) i.p. after daily MPTP intraperitoneal injection. Both drugs showed improvements in motor activity, open field experiments, rotarod tests, and gait analysis, but DA5-CH was more potent. Tyrosine hydroxylase expression in dopaminergic neurons was much reduced by MPTP and improved by DA5-CH, while NLY01 showed weak effects. When analyzing levels of α-synuclein (α-Syn), DA5-CH reduced levels effectively while NLY01 had no effect. When measuring the levels of the inflammation markers Toll-like receptor 4 (TLR4), specific markers of microglia activation (Iba-1), the marker of astrocyte activation glial fibrillary acidic protein (GFAP), nuclear factor-κB (NF-κB), tumor necrosis factor (TNF-α), and transforming growth factor ß1 (TGF-ß1), DA5-CH was very effective in reducing the chronic inflammation response, while NLY01 did not show significant effects. Levels of key growth factors such as Glial cell-derived neurotrophic factor (GDNF) and Brain-derived neurotrophic factor (BDNF) were much reduced by MPTP, and DA5-CH was able to normalize levels in the brain, while NLY01 showed little effect. The levels of pro-inflammatory cytokines (IL-6 and IL-Iß) were much reduced by DA5-CH, too, while NLY01 showed no effect. In a separate experiment, we tested the ability of the two drugs to cross the blood-brain barrier. After injecting fluorescin-labelled peptides peripherally, the fluorescence in brain tissue was measured. It was found that the pegylated NLY01 peptide did not cross the BBB in meaningful quantities while exendin-4 and the dual agonist DA5-CH did. The results show that DA5-CH shows promise as a therapeutic drug for PD.
Assuntos
Fármacos Neuroprotetores , Doença de Parkinson , Preparações Farmacêuticas , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Modelos Animais de Doenças , Peptídeo 1 Semelhante ao Glucagon , Humanos , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa BRESUMO
BACKGROUND AND AIMS: Diabetes is one of the most important risk factors and comorbidities of ischemic stroke. Endoplasmic reticulum stress (ERS) is considered to be the major injury mechanism of ischemic stroke with diabetes. Studies have found that incretin can inhibit ERS in ischemia-reperfusion injury of the liver and heart. We aimed to explore the effects of GLP-1/GIP double agonist DA3-CH and GLP-1 single agonist liraglutide on ERS and apoptosis in diabetic rats with cerebral ischemia-reperfusion injury. METHODS AND RESULTS: 72 Sprague-Dawley (SD) male rats were randomly divided into 4 groups: â blank group (Sham group, n = 18); model group (Saline group, n = 18); DA3 treatment group (DA3 group, n = 18); liraglutide treatment group (Lir group, n = 18). The Sham group was not given any treatment and was only raised in the same environment as the other groups. The remaining 3 groups used STZ-induced diabetes models. After the successful membrane formation of diabetes, DA3-CH and liraglutide (10 mmol/kg, once-daily for 14 days) were injected intraperitoneally. Thereafter, rats were subjected to middle cerebral artery occlusion followed by 24-h reperfusion. Animals were evaluated for neurologic deficit score, infarct volume, and biomarker analyses of the brain after ischemia. The DA3-CH-treated and liraglutide-treated groups showed significantly reduced scores of neurological dysfunction and cerebral infarction size, and reduced the expression of ERS markers GRP78, CHOP and Caspase-12, and the expression of apoptosis marker bax. Anti-apoptotic markers bcl-2 and neuronal numbers increased significantly. CONCLUSIONS: DA3-CH and liraglutide have obvious neuroprotective effects in a rat model of cerebral ischemia-reperfusion injury with diabetes, which can reduce the infarct size and the neurological deficit score. Their exert neuroprotective effects in a rat model of cerebral ischemia-reperfusion injury with diabetes by inhibiting endoplasmic reticulum stress and thereby reducing apoptosis. DA3 is better than liraglutide.
Assuntos
Encéfalo/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Incretinas/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Liraglutida/farmacologia , Peptídeos/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Chaperona BiP do Retículo Endoplasmático , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Ratos Sprague-Dawley , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores dos Hormônios Gastrointestinais/metabolismo , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de Sinais , EstreptozocinaRESUMO
Amifostine is a cytoprotective compound that is beneficial in ischaemic stroke cases. However, the neuroprotective effect of amifostine on ischaemia/reperfusion (I/R)-induced brain injury and its underlying mechanism are still poorly understood. Herein, we constructed an animal model of middle cerebral artery occlusion and reperfusion (MCAO/R) injury and an in vitro model of oxygen and glucose deprivation and reperfusion (OGD/R) injury. After administration of amifostine, we found significant improvements in neurological deficits, infarct size, and cerebral oedema. Moreover, amifostine alleviated histopathological alteration and increased the number of surviving neurons. Biochemical analysis showed that treatment with amifostine obviously improved the brain damage of MCAO/R mice, as manifested by a decrease in reactive oxygen species (ROS) and malondialdehyde (MDA) generation, and an increase in superoxide dismutase (SOD) activity. Moreover, amifostine decreased the mitochondrial membrane potential (ïïm) loss, and cytochrome c escaping to cytoplasm, but increased the ATP level. In vitro, amifostine also showed an antioxidant effect, which was reflected by the reduced ROS generation, decreased mitochondrial superoxide generation, increased total SOD, SOD1 (Cu/Zn SOD, cytoplasmic SOD), and SOD2 (mitochondrial SOD) activities, and decreased ïïm loss. Furthermore, amifostine suppressed neuronal apoptosis, accompanied by the reduction of Bax, cleaved caspase-9, cleaved caspase-3, and Bcl-2 upregulation. Amifostine also reduced the expression of p-p38 (Thr 180/Tyr 182) in vivo and in vitro. In short, amifostine exhibits a protective effect on cerebral I/R damage through modulating p38-related oxidative stress, mitochondrial dysfunction, and apoptosis.
Assuntos
Amifostina/farmacologia , Isquemia Encefálica/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/patologia , Animais , Antioxidantes/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologiaRESUMO
AIMS: Glia-mediated neuro-inflammation and oxidative stress-induced neuronal apoptosis can contribute to epileptogenesis. We have demonstrated previously that mimetics of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and dual-GLP-1/GIP receptor agonists protect the brain from inflammation, oxidative stress, apoptosis and neuronal loss in animal models of central nervous system diseases. METHODS: This study investigated for the first time whether the novel dual GLP-1/GIP receptor agonist DA3-CH has neuroprotective effects in the pilocarpine-induced status epilepticus (SE) rat model and the studies the underlying mechanisms. DA3-CH was administered once daily at 10 nmol/kg ip. following SE induction. The effect of DA3-CH was evaluated by immunohistochemistry and western blot at 12 h, 1 d, 3 d, 7 d after kindling. RESULTS: Our findings show that DA3-CH reduced the chronic inflammation response (astrogliosis and microgliosis), and the associated release of the pro-inflammatory cytokines interleukin-1ß (IL-ß) and tumor necrosis factor-α (TNF-α) in the hippocampal CA1 area. Furthermore, DA3-CH reduced the expression of the mitochondrial pro-apoptotic protein Bax, while increasing the expression of the anti-apoptotic protein Bcl-2. Neuronal numbers in the CA1 area were much reduced by pilocarpine treatment, and DA3-CH protected neurons from neurotoxicity. CONCLUSION: These results demonstrated that DA3-CH could mitigate pilocarpine-induced neuro-inflammation, mitochondrial apoptosis and neuronal loss. The findings encourage the development of dual agonists as novel therapeutic interventions for epilepsy.
Assuntos
Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Fármacos Neuroprotetores/uso terapêutico , Pilocarpina/toxicidade , Receptores dos Hormônios Gastrointestinais/agonistas , Animais , Modelos Animais de Doenças , Epilepsia/fisiopatologia , Receptor do Peptídeo Semelhante ao Glucagon 1/fisiologia , Masculino , Fármacos Neuroprotetores/farmacologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Receptores dos Hormônios Gastrointestinais/fisiologiaRESUMO
Glucagon-like peptide-1(GLP-1) is a growth factor that has neuroprotective and anti-inflammatory properties. The protease resistant GLP-1 analogue liraglutide has been shown to be neuroprotective in previous studies in animal models of Alzheimer's disease or Parkinson's disease. Status epilepticus (SE) is a complex disorder, involving many underlying pathological processes, including excitotoxic and chronic inflammatory events. The present pilot study aims to investigate whether liraglutide alleviates the chronic inflammation response and mitochondrial stress induced by SE in the lithium-pilocarpine animal model. We found that treatment with 25nmol/kg. i.p. once-daily after the induction of SE for 7â¯days reduced chronic inflammation as shown by reduced numbers of activated microglia and astrocytes, and reduced levels of TNF-α and IL-1ß in the hippocampus. The mitochondrial stress marker BAX was reduced and the survival factor Bcl-2 was enhanced by liraglutide. Blood glucose levels were not affected by liraglutide. We show for the first time that liraglutide can reduce the chronic inflammation and mitochondrial stress induced by SE, and the results suggest that GLP-1 receptor agonists such as liraglutide have restorative and protective effects in the brain after SE and could serve as a potential treatment.
Assuntos
Anti-Inflamatórios/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/etiologia , Inflamação/prevenção & controle , Liraglutida/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Animais , Glicemia/efeitos dos fármacos , Convulsivantes/toxicidade , Citocinas/metabolismo , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Lítio/toxicidade , Masculino , Mitocôndrias/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Pilocarpina/toxicidade , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/complicações , Estado Epiléptico/patologia , Fatores de Tempo , Proteína X Associada a bcl-2RESUMO
Type 2 diabetes mellitus (T2DM) is a risk factors for developing Parkinson's disease (PD). Insulin desensitization is observed in the brains of PD patients, which may be an underlying mechanism that promotes neurodegeneration. Incretin hormones are growth factors that can re-sensitize insulin signalling. We have previously shown that analogues of the incretins GLP-1 or GIP have neuroprotective effects in the MPTP mouse model of PD. Novel dual GLP-1/GIP receptor agonists have been developed as treatments for T2DM. We have tested 3 novel dual receptor agonists DA-JC1, DA-JC4 and DA-CH5 in comparison with the GLP-1 analogue liraglutide (all drugs at 25â¯nmol/kg ip once-daily for 6 days) in the MPTP mouse model of PD (4â¯×â¯25â¯mg/kg ip). In the Rotarod and grip strength assessment, DA-CH5 performed best in reversing the MPTP-induced motor impairment. Dopamine synthesis as indicated by levels of tyrosine hydroxylase was much reduced by MPTP in the substantia nigra and striatum, and DA-CH5 was the best drug to reverse this. Pro-inflammatory cytokines were best reduced by DA-CH5, while expression levels of the neuroprotective growth factor Glial-Derived Neurotrophic Factor (GDNF) was most increased by DA-JC4. Synapses were protected best by DA-JC4 and DA-CH5. Both DA-JC1 and liraglutide showed inferior effects. These results show that a combination of GLP-1 and GIP receptor activation is more efficient compared to single GLP-1 receptor activation. We conclude that dual agonists are a promising novel treatment for PD. The GLP-1 mimetic exendin-4 has previously shown disease modifying effects in two clinical trials in Parkinson patients.
Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Intoxicação por MPTP/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Peptídeos/uso terapêutico , Receptores dos Hormônios Gastrointestinais/agonistas , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Animais , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/química , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Hipoglicemiantes/uso terapêutico , Liraglutida/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Neurotoxinas/toxicidade , Receptores dos Hormônios Gastrointestinais/química , Receptores dos Hormônios Gastrointestinais/metabolismoRESUMO
Type 2 diabetes mellitus (T2DM) is one of the risk factors for Parkinson's disease (PD). Insulin desensitisation has been observed in the brains of patients, which may promote neurodegeneration. Incretins are a family of growth factors that can re-sensitise insulin signalling. We have previously shown that mimetics of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropypridine (MPTP) mouse model of PD. Recently, dual GLP-1/GIP receptor agonists have been developed. We therefore tested the novel dual agonist DA3-CH in comparison with the best GLP-1 analogue currently on the market, liraglutide (both drugs 25nmol/kg ip once-daily for 7 days) in the MPTP mouse model of PD (25mg/kg ip once-daily for 7 days). In the Rotarod and grip strength assessment, DA3-CH was superior to liraglutide in reversing the MPTP-induced motor impairment. Dopamine synthesis as indicated by levels of tyrosine hydroxylase was much reduced by MPTP in the substantia nigra and striatum, and DA3-CH reversed this while liragutide only partially reversed this. The chronic inflammation response as shown in increased levels of activated microglia and astrocytes was reduced by both drugs. Importantly, expression levels of the neuroprotective growth factor Glial Derived Neurotrophic Factor (GDNF) was much enhanced by both DA3-CH and liragutide. The results demonstrate that the combination of GLP-1 and GIP receptor activation is superior to single GLP-1 receptor activation alone. Therefore, new dual agonists may be a promising treatment for PD. The GLP-1 receptor agonist exendin-4 has already shown disease modifying effects in clinical trials in PD patients.
Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Liraglutida/farmacologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Receptores dos Hormônios Gastrointestinais/agonistas , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Dopamina/biossíntese , Força da Mão , Inflamação/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/metabolismo , Atividade Motora/efeitos dos fármacos , Doença de Parkinson/etiologia , Doença de Parkinson/fisiopatologia , Teste de Desempenho do Rota-RodRESUMO
The incretins glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are growth factors. GLP-1 mimetics are on the market as treatments for type 2 diabetes. Both GLP-1 and GIP mimetics have shown neuroprotective properties in previous studies. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in a clinical trial in Parkinson's disease (PD) patients. Novel GLP-1/GIP dual-agonist peptides have been developed to treat diabetes. Here, we report the neuroprotective effects of a novel dual agonist (DA-JC1) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP was injected once daily (20 mg/kg intraperitoneally) for 7 days and the dual agonist was coinjected once daily (50 nmol/kg intraperitoneally). We found that the drug reduced most of the MPTP-induced motor impairments in the rotarod, open-field locomotion, and muscle strength test. The number of tyrosine hydroxylase-positive neurons in the substantia nigra and striatum was reduced by MPTP and increased by DA-JC1. Synapse numbers (synaptophysin expression) were reduced in the substantia nigra and the striatum by MPTP and DA-JC1 reversed this effect. The activation of a chronic inflammation response by MPTP was considerably reduced by the dual agonist (DA) (astroglia and microglia activation). Therefore, dual agonists show promise as a novel treatment of PD.
Assuntos
Antiparkinsonianos/uso terapêutico , Encéfalo/metabolismo , Intoxicação por MPTP/patologia , Intoxicação por MPTP/prevenção & controle , Peptídeos/uso terapêutico , Análise de Variância , Animais , Encéfalo/efeitos dos fármacos , Proteínas de Ligação ao Cálcio , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Locomoção/efeitos dos fármacos , Intoxicação por MPTP/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos , Receptores dos Hormônios Gastrointestinais/agonistas , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
The incretins glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) are growth factors with neuroprotective properties. GLP-1 mimetics are on the market as treatments for type 2 diabetes and are well tolerated. Both GLP-1 and GIP mimetics have shown neuroprotective properties in animal models of Parkinson's and Alzheimer's disease. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in a clinical trial in Parkinson's disease (PD) patients. Novel GLP-1/GIP dual-agonist peptides have been developed and are tested in diabetic patients. Here we demonstrate the neuroprotective effects of a novel dual agonist (DA-JC1) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP was injected once-daily (20 mg/kg i.p.) for 7 days, and the dual agonist was injected 30 min later i.p. (50 nmol/kg bw). The PI3k inhibitor LY294002 (0.6 mg/kg i.v.) was co-injected in one group. DA-JC1 reduced or reversed most of the MPTP induced motor impairments in the rotarod and in a muscle strength test. The number of tyrosine hydroxylase (TH) positive neurons in the substantia nigra (SN) was reduced by MPTP and increased by DA-JC1. The ratio of anti-inflammatory Bcl-2 to pro-inflammatory BAX as well as the activation of the growth factor kinase Akt was reduced by MPTP and reversed by DA-JC1. The PI3k inhibitor had only limited effect on the DA-JC1 drug effect. Importantly, levels of the neuroprotective brain derived neurotropic factor (BDNF) were reduced by MPTP and enhanced by DA-JC1. The results demonstrate that DA-JC1 shows promise as a novel treatment for PD.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Fármacos Neuroprotetores/administração & dosagem , Transtornos Parkinsonianos/metabolismo , Receptores dos Hormônios Gastrointestinais/agonistas , Animais , Apoptose/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Força Muscular/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Transtornos Parkinsonianos/prevenção & controle , Proteínas Proto-Oncogênicas c-akt/metabolismo , Teste de Desempenho do Rota-Rod , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Glucose-dependent insulinotropic polypeptide (GIP) is a member of the incretin hormones and growth factors. Neurons express the GIP receptor, and GIP and its agonists can pass through the blood brain barrier and show remarkable neuroprotective effects by protecting synapse function and numbers, promoting neuronal proliferation, reducing amyloid plaques in the cortex and reducing the chronic inflammation response of the nervous system. Long-acting analogues of GIP that are protease resistant had been developed as a treatment for type 2 diabetes. It has been found that such GIP analogues show good protective effects in animal models of Alzheimer's disease. Novel dual agonist peptides that activate the GIP receptor and another incretin receptor, glucagon-like peptide -1 (GLP-1), are under development that show superior effects in diabetic patients compared to single GLP-1 agonists. The dual agonists also show great promise in treating neurodegenerative disorders, and there are currently several clinical trials ongoing, testing GLP-1 mimetics in people with Alzheimer's or Parkinson's disease.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Polipeptídeo Inibidor Gástrico/análogos & derivados , Fármacos Neuroprotetores/uso terapêutico , Doença de Alzheimer/prevenção & controle , Animais , Polipeptídeo Inibidor Gástrico/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Fármacos Neuroprotetores/farmacologia , Receptores dos Hormônios Gastrointestinais/agonistas , Transdução de Sinais , Sinapses/efeitos dos fármacosRESUMO
Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have been shown to be neuroprotective in previous studies in animal models of Alzheimer's or Parkinson's disease. Recently, novel dual-GLP-1/GIP receptor agonists that activate both receptors (DA) were developed to treat diabetes. We tested the protective effects of a novel potent DA against middle cerebral artery occlusion injury in rats and compared it with a potent GLP-1 analog, Val(8)-GLP-1(glu-PAL). Animals were evaluated for neurologic deficit score, infarct volume, and immunohistochemical analyses of the brain at several time points after ischemia. The Val(8)-GLP-1(glu-PAL)-treated and DA-treated groups showed significantly reduced scores of neurological dysfunction, cerebral infarction size, and percentage of TUNEL-positive apoptotic neurons. Furthermore, the expression of the apoptosis marker Bax, the inflammation marker iNOS, and the survival marker Bcl-2 was significantly increased. The DA-treated group was better protected against neurodegeneration than the Val(8)-GLP-1(glu-PAL) group, and the scores of neurological dysfunction, cerebral infarction size, and expression of Bcl-2 were higher, whereas the percentage of TUNEL-positive neurons and the levels of Bax and iNOS were lower in the DA group. DA treatment reduced the infarct volume and improved the functional deficit. It also suppressed the inflammatory response and cell apoptosis after reperfusion. In conclusion, the novel GIP and GLP-1 dual-receptor agonist is more neuroprotective than a GLP-1 receptor agonist in key biomarkers of neuronal degeneration.
Assuntos
Encéfalo/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Ataque Isquêmico Transitório/tratamento farmacológico , Lipopeptídeos/farmacologia , Receptores dos Hormônios Gastrointestinais/agonistas , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Infarto da Artéria Cerebral Média , Ataque Isquêmico Transitório/complicações , Ataque Isquêmico Transitório/metabolismo , Ataque Isquêmico Transitório/patologia , Masculino , Atividade Motora/efeitos dos fármacos , Degeneração Neural/tratamento farmacológico , Degeneração Neural/etiologia , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico Sintase Tipo II/metabolismo , Distribuição Aleatória , Ratos Sprague-Dawley , Receptores dos Hormônios Gastrointestinais/metabolismo , Proteína X Associada a bcl-2/metabolismoRESUMO
Human umbilical cord-derived mesenchymal stem cell (UC-MSC) transplantation has shown promise for the treatment of various diseases. For clinical applications, UC-MSCs have been stored in 0.9% saline, 5% dextrose, dextrose and sodium chloride injection, Plasma-Lyte A, 1% human serum albumin (1% HSA), or 5% HSA before administration, but the effect of storage conditions on the viability and biological function of the cells remains unknown. Freshly harvested UC-MSCs were resuspended and incubated in these solutions for 2, 4, or 6 h at 4°C or room temperature (24°C). Cell viability, apoptotic/necrotic fraction, poststorage growth potential, immunophenotype, immunosuppressive capacity, and differentiation capacity were analyzed. When stored in parenteral solutions, UC-MSCs showed progressive deterioration in survival viability and adhesion ability. After 6-h storage, the best viability and attachment rate of UC-MSCs decreased to 83.0 ± 1.6% and 71.8 ± 3.2%, respectively. Our results suggested that UC-MSCs in these conditions lose their viability in a short time. However, it seems that the other biological functions of the surviving UC-MSCs were little affected. Since UC-MSCs suspended in these mediums lose their survival viability in a short time to levels significantly below the permissible limits (70%) by FDA, precautions need to be taken on using these solutions as suspension medium and further studies on the optimal methods for preservation are urgent.
Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Soluções para Preservação de Órgãos/farmacologia , Cordão Umbilical/citologia , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Humanos , Imunomodulação/efeitos dos fármacos , Imunofenotipagem , Terapia de Imunossupressão , Células-Tronco Mesenquimais/metabolismo , FenótipoRESUMO
Nonunion and nerve injury are the most severe and common complications of bone fracture treatments. There is still no ideal therapy for these two complications. In this report, we first applied umbilical cord mesenchymal stem cell (UC-MSC) therapy to one patient with both nonunion and nerve injury, and observed the therapeutic effects. UC-MSCs were produced and expanded according to a clinical-grade technique using serum-free medium enriched in human platelet lysate. Flow cytometry was performed to evaluate the purity of UC-MSCs, which were then intravenously injected. At 60 days postinjection, clinical examinations were performed to evaluate the therapeutic effects. Compared with before treatment, the patient's nerve reflex was present, and their muscle tone and strength increased, and x-ray and electromyography analysis further showed that the fracture gap disappeared and the nerve conduction velocity increased with shorter latency and higher amplitude. Furthermore, the clinical evolution was favorable and no side effects were observed during the 1-year follow-up. Overall, this novel treatment might open up a new strategy for the treatment of bone fracture complications.