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1.
Mol Pain ; 18: 17448069221087033, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35255745

RESUMO

Fabry disease (FD) is a X-linked lysosomal storage disorder caused by deficient function of the alpha-galactosidase A (α-GalA) enzyme. α-GalA deficiency leads to multisystemic clinical manifestations caused by the preferential accumulation of globotriaosylceramide (Gb3). A hallmark symptom of FD patients is neuropathic pain that appears in the early stage of the disease as a result of peripheral small fiber damage. Previous studies have shown that Acetyl-L-carnitine (ALC) has neuroprotective, neurotrophic, and analgesic activity in animal models of neuropathic pain. To study the action of ALC on neuropathic pain associated with FD, we treated α-GalA gene null mice (α-GalA(-/0)) with ALC for 30 days. In α-Gal KO mice, ALC treatment induced acute and long-lasting analgesia, which persisted 1 month after drug withdrawal. This effect was antagonized by single administration of LY341495, an orthosteric antagonist of mGlu2/3 metabotropic glutamate receptors. We also found an up-regulation of mGlu2 receptors in cultured DRG neurons isolated from 30-day ALC-treated α-GalA KO mice. However, the up-regulation of mGlu2 receptors was no longer present in DRG neurons isolated 30 days after the end of treatment. Taken together, these findings suggest that ALC induces analgesia in an animal model of FD by up-regulating mGlu2 receptors, and that analgesia is maintained by additional mechanisms after ALC withdrawal. ALC might represent a valuable pharmacological strategy to reduce pain in FD patients.


Assuntos
Analgesia , Doença de Fabry , Neuralgia , Receptores de Glutamato Metabotrópico , Acetilcarnitina/farmacologia , Animais , Doença de Fabry/tratamento farmacológico , Doença de Fabry/genética , Doença de Fabry/metabolismo , Humanos , Camundongos , Camundongos Knockout , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Manejo da Dor , Receptores de Glutamato Metabotrópico/metabolismo , alfa-Galactosidase/metabolismo
2.
Commun Biol ; 4(1): 783, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34168265

RESUMO

Intergenerational trauma increases lifetime susceptibility to depression and other psychiatric disorders. Whether intergenerational trauma transmission is a consequence of in-utero neurodevelopmental disruptions versus early-life mother-infant interaction is unknown. Here, we demonstrate that trauma exposure during pregnancy induces in mouse offspring social deficits and depressive-like behavior. Normal pups raised by traumatized mothers exhibited similar behavioral deficits to those induced in pups raised by their biological traumatized mothers. Good caregiving by normal mothers did not reverse prenatal trauma-induced behaviors, indicating a two-hit stress mechanism comprising both in-utero abnormalities and early-life poor parenting. The behavioral deficits were associated with profound changes in the brain metabotranscriptome. Striking increases in the mitochondrial hypoxia marker and epigenetic modifier 2-hydroxyglutaric acid in the brains of neonates and adults exposed prenatally to trauma indicated mitochondrial dysfunction and epigenetic mechanisms. Bioinformatic analyses revealed stress- and hypoxia-response metabolic pathways in the neonates, which produced long-lasting alterations in mitochondrial energy metabolism and epigenetic processes (DNA and chromatin modifications). Most strikingly, early pharmacological interventions with acetyl-L-carnitine (ALCAR) supplementation produced long-lasting protection against intergenerational trauma-induced depression.


Assuntos
Encéfalo/metabolismo , Depressão/etiologia , Trauma Histórico/complicações , Metabolômica , Mitocôndrias/metabolismo , Transcriptoma , Acetilcarnitina/farmacologia , Animais , Biologia Computacional , Feminino , Humanos , Masculino , Comportamento Materno , Camundongos , Atividade Motora , Gravidez
3.
Arch Toxicol ; 95(8): 2769-2784, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34164711

RESUMO

Mitochondrial deregulation has emerged as one of the earliest pathological events in Alzheimer's disease (AD), the most common age-related neurodegenerative disorder. Improvement of mitochondrial function in AD has been considered a relevant therapeutic approach. L-carnitine (LC), an amino acid derivative involved in the transport of long-chain fatty acids into mitochondria, was previously demonstrated to improve mitochondrial function, having beneficial effects in neurological disorders; moreover, acetyl-L-carnitine (ALC) is currently under phase 4 clinical trial for AD (ClinicalTrials.gov NCT01320527). Thus, in the present study, we investigated the impact of different forms of carnitines, namely LC, ALC and propionyl-L-carnitine (PLC) on mitochondrial toxicity induced by amyloid-beta peptide 1-42 oligomers (AßO; 1 µM) in mature rat hippocampal neurons. Our results indicate that 5 mM LC, ALC and PLC totally rescued the mitochondrial membrane potential and alleviated both the decrease in oxygen consumption rates and the increase in mitochondrial fragmentation induced by AßO. These could contribute to the prevention of neuronal death by apoptosis. Moreover, only ALC ameliorated AßO-evoked changes in mitochondrial movement by reducing the number of stationary mitochondria and promoting reversal mitochondrial movement. Data suggest that carnitines (LC, ALC and PLC) may act differentially to counteract changes in mitochondrial function and movement in neurons subjected to AßO, thus counteracting AD-related pathological phenotypes.


Assuntos
Acetilcarnitina/farmacologia , Doença de Alzheimer/tratamento farmacológico , Carnitina/análogos & derivados , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/fisiopatologia , Animais , Apoptose/efeitos dos fármacos , Carnitina/farmacologia , Células Cultivadas , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/parasitologia , Fármacos Neuroprotetores/química , Consumo de Oxigênio/efeitos dos fármacos , Ratos , Ratos Wistar
4.
Int J Mol Sci ; 22(4)2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33671213

RESUMO

Palmitoylethanolamide (PEA), a fatty acid amide, has been widely investigated for its analgesic and anti-inflammatory properties. The ultra-micronized formulation of PEA (um-PEA), that has an enhanced rate of dissolution, is extensively used. Acetyl-l-carnitine (LAC), employed for the treatment of neuropathic pain in humans, is able to cause analgesia by up-regulating type-2 metabotropic glutamate (mGlu2) receptors. In the present study, we tested different associations of um-PEA, LAC and non-micronized PEA (non-m-PEA) in a rat model of carrageenan (CAR)-induced paw edema. Intraplantar injection of CAR into the hind paw of animals caused edema, thermal hyperalgesia, accumulation of infiltrating inflammatory cells and augmented myeloperoxidase (MPO) activity. All these parameters were decreased in a significantly manner by oral administration of a compound constituted by a mixture of um-PEA and LAC in relation 1:1 (5 mg/kg), but not with the association of single compounds administered one after the other. These findings showed the superior anti-inflammatory and anti-nociceptive action displayed by oral administration of um-PEA and LAC versus LAC plus, separate but consecutive, um-PEA in the rat paw CAR model of inflammatory pain.


Assuntos
Acetilcarnitina/uso terapêutico , Amidas/uso terapêutico , Etanolaminas/uso terapêutico , Inflamação/tratamento farmacológico , Dor/tratamento farmacológico , Ácidos Palmíticos/uso terapêutico , Acetilcarnitina/farmacologia , Amidas/farmacologia , Animais , Carragenina , Contagem de Células , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Edema/complicações , Edema/tratamento farmacológico , Edema/patologia , Etanolaminas/farmacologia , Hiperalgesia/complicações , Hiperalgesia/tratamento farmacológico , Inflamação/complicações , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-1beta/metabolismo , Masculino , Mastócitos/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/metabolismo , Dor/complicações , Dor/patologia , Ácidos Palmíticos/farmacologia , Peroxidase/metabolismo , Ratos Sprague-Dawley , Fatores de Tempo , Fator de Necrose Tumoral alfa/metabolismo
5.
Metab Brain Dis ; 36(6): 1391-1401, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33710529

RESUMO

Acetyl-L-carnitine has been shown to exert neuroprotection against neurodegenerative diseases. The present study was performed to evaluate neuroprotection effects of acetyl-L-carnitine against lipopolysaccharide (LPS) -induced neuroinflammation and clarify possible mechanisms. A single dose (500 µg/kg) of LPS was intraperitoneally injected to rats to induce model. The animals were intraperitoneally treated with different doses of acetyl-L-carnitine (30, 60, and 100) for 6 days. Y-maze task, single-trial passive avoidance and novel object recognition tests were used to evaluate memory impairments. ELISA assay was used to evaluate the expression of TLR4/NFκB, autophagic and oxidative stress markers. Our result showed that intraperitoneal injection of LPS resulted in initiation of neuroinflammation by activation of TLR4/NFκB, suppression of autophagic markers such as LC3 II/ LC3 I ratio and becline-1, and excessive production of ROS and MDA. Intraperitoneal administration of acetyl-L-carnitine contributed to neuroprotection against LPS -induced neuroinflammation by suppression of TLR4/NFκB pathway, restoring activity of autophagy and inhibition of oxidative stress. Collectively, our findings show that acetyl-L-carnitine attenuated LPS-induced neuroinflammation by targeting TLR4/NFκB pathway, autophagy and oxidative stress.


Assuntos
Acetilcarnitina/farmacologia , Anti-Inflamatórios/farmacologia , Autofagia/efeitos dos fármacos , Lipopolissacarídeos , NF-kappa B/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Receptor 4 Toll-Like/efeitos dos fármacos , Animais , Proteína Beclina-1/antagonistas & inibidores , Injeções Intraperitoneais , Masculino , Proteínas Associadas aos Microtúbulos/antagonistas & inibidores , /psicologia , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Ratos Wistar
6.
Biomed Res Int ; 2021: 8871328, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33532499

RESUMO

Acetyl-L-carnitine (ALC) is an effective substrate for mitochondrial energy metabolism and is known to prevent neurodegeneration and attenuate heavy metal-induced injury. In this study, we investigated the function of ALC in the recovery of mouse spermatogonia cells (GC-1 cells) after heat stress (HS). The cells were randomly divided into three groups: control group, HS group (incubated at 42°C for 90 min), and HS + ALC group (treatment of 150 µM ALC after incubated at 42°C for 90 min). After heat stress, all of the cells were recovered at 37°C for 6 h. In this study, the content of intracellular lactate dehydrogenase (LDH) in the cell supernatant and the malondialdehyde (MDA) levels, catalase (CAT) levels, and total antioxidant capacity (T-AOC) were significantly increased in the HS group compared to the CON group. In addition, the mitochondrial membrane potential (MMP) was markedly decreased, while the apoptosis rate and the expression of apoptosis-related genes (Bcl-2, Bax, and caspase3) were significantly increased in the HS group compared to the CON group. Furthermore, the number of autophagosomes and the expression of autophagy-related genes (Atg5, Beclin1, and LC3II) and protein levels of p62 were increased, but the expression of LAMP1 was decreased in the HS group compared to the CON group. However, treatment with ALC remarkably improved cell survival and decreased cell oxidative stress. It was unexpected that levels of autophagy were markedly increased in the HS + ALC group compared to the HS group. Taken together, our present study evidenced that ALC could alleviate oxidative stress and improve the level of autophagy to accelerate the recovery of GC-1 cells after heat stress.


Assuntos
Acetilcarnitina/farmacologia , Autofagia/efeitos dos fármacos , Resposta ao Choque Térmico/efeitos dos fármacos , Espermatogônias/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Masculino , Malondialdeído/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Espermatogônias/citologia
7.
Sci Rep ; 10(1): 20987, 2020 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-33268815

RESUMO

Homeostatic control of neuronal excitability by modulation of synaptic inhibition (I) and excitation (E) of the principal neurons is important during brain maturation. The fundamental features of in-utero brain development, including local synaptic E-I ratio and bioenergetics, can be modeled by cerebral organoids (CO) that have exhibited highly regular nested oscillatory network events. Therefore, we evaluated a 'Phase Zero' clinical study platform combining broadband Vis/near-infrared(NIR) spectroscopy and electrophysiology with studying E-I ratio based on the spectral exponent of local field potentials and bioenergetics based on the activity of mitochondrial Cytochrome-C Oxidase (CCO). We found a significant effect of the age of the healthy controls iPSC CO from 23 days to 3 months on the CCO activity (chi-square (2, N = 10) = 20, p = 4.5400e-05), and spectral exponent between 30-50 Hz (chi-square (2, N = 16) = 13.88, p = 0.001). Also, a significant effect of drugs, choline (CHO), idebenone (IDB), R-alpha-lipoic acid plus acetyl-L-carnitine (LCLA), was found on the CCO activity (chi-square (3, N = 10) = 25.44, p = 1.2492e-05), spectral exponent between 1 and 20 Hz (chi-square (3, N = 16) = 43.5, p = 1.9273e-09) and 30-50 Hz (chi-square (3, N = 16) = 23.47, p = 3.2148e-05) in 34 days old CO from schizophrenia (SCZ) patients iPSC. We present the feasibility of a multimodal approach, combining electrophysiology and broadband Vis-NIR spectroscopy, to monitor neurodevelopment in brain organoid models that can complement traditional drug design approaches to test clinically meaningful hypotheses.


Assuntos
Encéfalo/crescimento & desenvolvimento , Organoides/crescimento & desenvolvimento , Acetilcarnitina/farmacologia , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Estudos de Casos e Controles , Linhagem Celular , Colina/farmacologia , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Eletrofisiologia , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Masculino , Mitocôndrias/metabolismo , Organoides/efeitos dos fármacos , Organoides/fisiologia , Estudo de Prova de Conceito , Esquizofrenia/metabolismo , Espectroscopia de Luz Próxima ao Infravermelho , Ácido Tióctico/farmacologia , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia
8.
Nutrients ; 12(9)2020 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-32878326

RESUMO

Fibromyalgia syndrome (FMS) is characterised by chronic widespread pain alongside fatigue, poor sleep quality and numerous comorbidities. It is estimated to have a worldwide prevalence of 1.78%, with a predominance in females. Treatment interventions for fibromyalgia have limited success, leading to many patients seeking alternative forms of treatment, including modifications to their diet and lifestyle. The effectiveness of dietary changes in fibromyalgia has not been widely researched or evaluated. This systematic review identified twenty-two studies, including 18 randomised control trials (RCTs) and four cohort studies which were eligible for inclusion. In total these studies investigated 17 different nutritional interventions. Significant improvements in reported pain were observed for those following a vegan diet, as well as with the low fermentable oligo di-mono-saccharides and polyols (FODMAP) diets. Supplementation with Chlorella green algae, coenzyme Q10, acetyl-l-carnitine or a combination of vitamin C and E significantly improved measures of pain. Interpretation of these studies was limited due to the frequent poor quality of the study design, the wide heterogeneity between studies, the small sample size and a high degree of bias. Therefore, there is insufficient evidence to recommend any one particular nutritional intervention for the management of fibromyalgia and further research is needed.


Assuntos
Dieta Vegana , Suplementos Nutricionais , Fibromialgia/dietoterapia , Fibromialgia/tratamento farmacológico , Nigella sativa/química , Fitoterapia , Acetilcarnitina/farmacologia , Ácido Ascórbico/farmacologia , Chlorella/metabolismo , Humanos , Dor/dietoterapia , Dor/tratamento farmacológico , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Sementes/química , Resultado do Tratamento , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia , Vitamina E/farmacologia
9.
J Int Med Res ; 48(8): 300060520951393, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32865065

RESUMO

OBJECTIVE: Cisplatin (CDDP) toxicity is a dose-limiting clinical problem in clinical practice, mainly because of nephrotoxicity or ototoxicity. However, the mechanism of CDDP-induced cardiotoxicity is poorly understood. Acetyl-l-carnitine (ALCAR) is an antioxidant agent with protective effects against the side effects of various chemotherapeutics. CDDP-induced cardiotoxicity and the protective role of ALCAR were evaluated in this study. METHODS: Morphological changes were evaluated in hematoxylin and eosin-stained sections, and immunohistochemistry for caspase-3, superoxide dismutase-2 (SOD-2), inducible nitrite oxide synthase (iNOS), cyclooxygenase-2, and Bcl-2 was performed using the hearts of athymic nude mice carrying xenograft neuroblastoma tumors. Mice were randomized (six/group) to the control, CDDP (16 mg/kg), and ALCAR (200 mg/kg)+CDDP (16 mg/kg) groups. Results were analyzed using nonparametric tests. RESULTS: No difference was observed in the rates of cardiac necrosis, dilated/congested blood vessels, hemorrhage, polymorphonuclear leukocyte infiltration, edema, and pyknotic nuclei among the groups. SOD-2 expression was increased in the CDDP group but not in the ALCAR+CDDP group. iNOS, Bcl-2, and caspase-3 levels were not significantly different among the groups. CONCLUSIONS: ALCAR might be a candidate protective agent for CDDP-induced cardiotoxicity. SOD-2, as a member of the oxidant system, should be evaluated in further studies as a biomarker of cardiotoxicity.


Assuntos
Antineoplásicos , Cisplatino , Acetilcarnitina/farmacologia , Animais , Antioxidantes , Cardiotoxicidade , Cisplatino/toxicidade , Camundongos , Camundongos Nus
10.
Cell Tissue Bank ; 21(4): 655-666, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32564258

RESUMO

Low survival rate of grafted mesenchymal stem cells (MSC) in injured tissue is one of the major limitations of stem cell therapy. One of the most important factors that limits the MSCs survival rate and retention is ischemic stress, which can lead to damage to all components of the cell. In particular, it can damage mitochondria, that play an important role in apoptosis with releasing apoptotic factors. Therefore, we investigated the protective effects of Acetyl-L-carnitine (ALCAR) against serum and glucose deprivation (SGD) in adipose-derived mesenchymal stem cells (AD-MSCs). We measured cell viability, proliferation, and apoptosis in cells experiencing SGD stress for 8 h with exposure to varying concentrations of ALCAR. Results showed that ALCAR protects cells against SGD stress by reducing apoptosis. Its protective effects are associated with reductions in cleaved caspase-3 and attenuation of apoptosis. Result showed that ALCAR exhibits protective effects against SGD-induced damage to AD-MSCs by enhancing the expression of survival signals and by decreasing the expression of death signals.


Assuntos
Acetilcarnitina/farmacologia , Apoptose/efeitos dos fármacos , Glucose/deficiência , Células-Tronco Mesenquimais/citologia , Substâncias Protetoras/farmacologia , Animais , Caspase 3/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Meios de Cultura Livres de Soro , Fragmentação do DNA/efeitos dos fármacos , Masculino , Células-Tronco Multipotentes/citologia , Células-Tronco Multipotentes/efeitos dos fármacos , Ratos Wistar
11.
Nutrients ; 12(5)2020 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-32408706

RESUMO

Several studies explored the effects of acetyl-L-carnitine (ALC) in dementia, suggesting a role in slowing down cognitive decline. Nevertheless, in 2003 a systematic review concluded there was insufficient evidence to recommend a clinical use, although a meta-analysis in the same year showed a significant advantage for ALC for clinical scales and psychometric tests. Since then, other studies have been published; however, a critical review is still lacking. We provide an update of the studies on ALC in primary and secondary dementia, highlighting the current limitations and translational implications. Overall, the role of ALC in dementia is still under debate. The underlying mechanisms may include restoring of cell membranes and synaptic functioning, enhancing cholinergic activity, promoting mitochondrial energy metabolism, protecting against toxins, and exerting neurotrophic effects. The effects of ALC on the gut-liver-brain axis seem to identify the category of patients in which the new insights contribute most to the mechanisms of action of ALC, likely being the liver metabolism and the improvement of hepatic detoxifying mechanisms the primary targets. In this framework, our research group has dealt with this topic, focusing on the ALC-related cross-talk mechanisms. Further studies with homogeneous sample and longitudinal assessment are needed before a systematic clinical application.


Assuntos
Acetilcarnitina/farmacologia , Transtornos Cognitivos/tratamento farmacológico , Demência/tratamento farmacológico , /tendências , Encéfalo/metabolismo , Cognição/efeitos dos fármacos , Transtornos Cognitivos/prevenção & controle , Demência/prevenção & controle , Humanos , Fígado/metabolismo , Nootrópicos/metabolismo
12.
Neurotoxicol Teratol ; 80: 106891, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32376384

RESUMO

Many studies have shown that prolonged or repeated use of general anesthesia early in life can cause an increase in neurodegeneration and lasting changes in behavior. While short periods of general anesthesia appear to be safe, there is a concern about the neurotoxic potential of prolonged or repeated general anesthesia in young children. Unfortunately, the use of general anesthesia in children cannot be avoided. It would be a great benefit to develop a strategy to reduce or reverse anesthesia mitigated neurotoxicity. The mechanisms behind anesthesia related neurotoxicity are unknown, but evidence suggests that mitochondrial dysfunction and abnormal energy utilization are involved. Recent research suggests that a class of compounds known as carnitines may be effective at preventing anesthesia related neurotoxicity by influencing fatty acid metabolism in the mitochondria. However, it is unknown if carnitines can provide protection against changes in behavior associated with early life exposure to anesthesia. Accordingly, we evaluated the neuroprotective potential of acetyl-l-carnitine in 7-day old rats. Rat pups were exposed to 6 h of general anesthesia with sevoflurane or a control condition, with and without acetyl-l-carnitine. The oxygenation level of animals was continuously monitored during sevoflurane exposure, and any animal showing signs of hypoxia was removed from the study. Animals exposed to sevoflurane showed clear signs of neurodegeneration 2 h after sevoflurane exposure. The hippocampus, cortex, thalamus, and caudate putamen all had elevated levels of Fluoro-Jade C staining. Despite the elevated levels of Fluoro-Jade C, few behavioral changes were observed in an independent cohort of animals treated with sevoflurane. Furthermore, acetyl-l-carnitine had little impact on levels of Fluoro-Jade C staining in animals treated with sevoflurane. These data suggest that acetyl-l-carnitine may offer little protection again anesthesia related neurotoxicity in fully oxygenated animals.


Assuntos
Acetilcarnitina/farmacologia , Anestesia Geral/efeitos adversos , Anestésicos Inalatórios/efeitos adversos , Sevoflurano/farmacologia , Anestésicos Inalatórios/toxicidade , Animais , Animais Recém-Nascidos , Encéfalo/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Éteres Metílicos/farmacologia , Éteres Metílicos/toxicidade , Neurônios/efeitos dos fármacos , Síndromes Neurotóxicas/metabolismo , Ratos Sprague-Dawley , Sevoflurano/metabolismo
13.
Curr Pharm Des ; 26(12): 1277-1285, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32048954

RESUMO

BACKGROUND: Current therapy of neurological disorders has several limitations. Although a high number of drugs are clinically available, several subjects do not achieve full symptomatic remission. In recent years, there has been an increasing interest in the therapeutic potential of L-carnitine (LCAR) and acetyl-L-carnitine (ALCAR) because of the multiplicity of actions they exert in energy metabolism, as antioxidants, neuromodulators and neuroprotectors. They also show excellent safety and tolerability profile. OBJECTIVE: To assess the role of LCAR and ALCAR in neurological disorders. METHODS: A meticulous review of the literature was conducted in order to establish the linkage between LCAR and ALCAR and neurological diseases. RESULTS: LCAR and ALCAR mechanisms and effects were studied for Alzheimer's disease, depression, neuropathic pain, bipolar disorder, Parkinson's disease and epilepsy in the elderly. Both substances exert their actions mainly on primary metabolism, enhancing energy production, through ß-oxidation, and the ammonia elimination via urea cycle promotion. These systemic actions impact positively on the Central Nervous System state, as Ammonia and energy depletion seem to underlie most of the neurotoxic events, such as inflammation, oxidative stress, membrane degeneration, and neurotransmitters disbalances, present in neurological disorders, mainly in the elderly. The impact on bipolar disorder is controversial. LCAR absorption seems to be impaired in the elderly due to the decrease of active transportation; therefore, ALCAR seems to be the more effective option to administer. CONCLUSION: ALCAR emerges as a simple, economical and safe adjuvant option in order to impair the progression of most neurological disorders.


Assuntos
Acetilcarnitina/farmacologia , Doença de Alzheimer , Carnitina , Idoso , Metabolismo Energético , Humanos , Estresse Oxidativo
14.
J Biochem Mol Toxicol ; 34(4): e22449, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31967697

RESUMO

Propionic acid (PRA) is used as a food preservative. This study was aimed to investigate the neuroprotective effect of acetyl-l-carnitine (ALC) and nano-Coenzyme Q (N-CoQ) on brain intoxication induced by PRA in rats. Rats were divided into five groups: group I: control; group II: received PRA; group III: received ALC; group IV: received N-CoQ; and group V: received ALC and N-CoQ for 5 days. The antioxidants in question markedly ameliorated serum interleukin-1ß and tumor necrosis factor-α, and brain NO, lipid peroxide, glutathione, and superoxide dismutase levels as well as protein expression of brain-derived neurotrophic factor (BDNF) and P-cyclic-AMP response element-binding protein (CREB) that were altered by a toxic dose of PRA, as well as histopathological alterations, including improvement of the cerebellum architecture. Interestingly, the combination therapy of ALC and N-CoQ achieved the most neuroprotective effect compared with monotherapies. The current study established that N-CoQ is considered as a useful tool to prevent brain injury induced by PRA. BDNF and CREB proteins are involved in both PRA neurotoxicity and treatment.


Assuntos
Acetilcarnitina/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Conservantes de Alimentos/toxicidade , Fármacos Neuroprotetores/farmacologia , Propionatos/toxicidade , Ubiquinona/análogos & derivados , Animais , Antioxidantes/farmacologia , Biomarcadores/sangue , Biomarcadores/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Masculino , Nanopartículas/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos , Ubiquinona/farmacologia
15.
Med Sci Monit ; 26: e920250, 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31945029

RESUMO

BACKGROUND The purpose of the present study was to evaluate the regulatory effects of acetyl-L-carnitine (ALCAR) on atherosclerosis in Wister rats and to explore its anti-atherosclerotic mechanism. MATERIAL AND METHODS We randomly divided 32 Wister rats into 4 groups: a normal diet group (control group, n=8), a normal diet+ALCAR group (ALCAR group, n=8), an atherosclerosis group (AS group, n=8), and an atherosclerosis+ALCAR group (AS+ALCAR group, n=8). The serum lipid distribution, oxidative stress, inflammatory factors and adiponectin (APN) in the blood, and heart and aortic tissues were determined using the standard assay kits, xanthine oxidase method, and ELISA, respectively. HE staining was performed to observe aortic pathology structure change, and the level of angiotensin II (AngII) in the aorta was assessed using radioimmunoassay. In addition, real-time quantitative PCR and Western blot analysis were applied to detect the expression of iNOS, IL-1ß, TNF-alpha, and CRP in the aortic and heart tissues. RESULTS Compared with the AS group, the levels of serum TC, TG, LDL, and VLDL in rats decreased significantly, while HDL level significantly increased in the AS+ALCAR group. ALCAR administration enhanced the SOD and GSH-Px activities and decreased MDA activity. APN level was significantly elevated in the AS group, but ALCAR had no significant effect on APN. Further, ALCAR reduced the expressions of inflammation factors TNF-alpha, IL-1ß, iNOS, and CRP, and the concentration of AngII in serum, aortic, and heart tissues. CONCLUSIONS ALCAR can inhibit the expressions of inflammatory factors and antioxidation to suppress the development of atherosclerosis by adjusting blood lipid in the myocardium of AS rats.


Assuntos
Acetilcarnitina/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Acetilcarnitina/farmacologia , Adiponectina/sangue , Angiotensina II , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Aorta/metabolismo , Aterosclerose/sangue , Aterosclerose/patologia , Biomarcadores/metabolismo , Proteína C-Reativa/metabolismo , Mediadores da Inflamação/sangue , Interleucina-1beta/metabolismo , Lipídeos/sangue , Masculino , Miocárdio/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
16.
Elife ; 92020 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-31922486

RESUMO

Emerging evidence suggests that hierarchical status provides vulnerability to develop stress-induced depression. Energy metabolic changes in the nucleus accumbens (NAc) were recently related to hierarchical status and vulnerability to develop depression-like behavior. Acetyl-L-carnitine (LAC), a mitochondria-boosting supplement, has shown promising antidepressant-like effects opening therapeutic opportunities for restoring energy balance in depressed patients. We investigated the metabolic impact in the NAc of antidepressant LAC treatment in chronically-stressed mice using 1H-magnetic resonance spectroscopy (1H-MRS). High rank, but not low rank, mice, as assessed with the tube test, showed behavioral vulnerability to stress, supporting a higher susceptibility of high social rank mice to develop depressive-like behaviors. High rank mice also showed reduced levels of several energy-related metabolites in the NAc that were counteracted by LAC treatment. Therefore, we reveal a metabolic signature in the NAc for antidepressant-like effects of LAC in vulnerable mice characterized by restoration of stress-induced neuroenergetics alterations and lipid function.


Assuntos
Acetilcarnitina/farmacologia , Antidepressivos/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Animais , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Núcleo Accumbens/metabolismo , Comportamento Social
17.
J Exp Clin Cancer Res ; 38(1): 464, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31718684

RESUMO

BACKGROUND: Prostate cancer (PCa) is a leading cause of cancer-related death in males worldwide. Exacerbated inflammation and angiogenesis have been largely demonstrated to contribute to PCa progression. Diverse naturally occurring compounds and dietary supplements are endowed with anti-oxidant, anti-inflammatory and anti-angiogenic activities, representing valid compounds to target the aberrant cytokine/chemokine production governing PCa progression and angiogenesis, in a chemopreventive setting. Using mass spectrometry analysis on serum samples of prostate cancer patients, we have previously found higher levels of carnitines in non-cancer individuals, suggesting a protective role. Here we investigated the ability of Acetyl-L-carnitine (ALCAR) to interfere with key functional properties of prostate cancer progression and angiogenesis in vitro and in vivo and identified target molecules modulated by ALCAR. METHODS: The chemopreventive/angiopreventive activities ALCAR were investigated in vitro on four different prostate cancer (PCa) cell lines (PC-3, DU-145, LNCaP, 22Rv1) and a benign prostatic hyperplasia (BPH) cell line. The effects of ALCAR on the induction of apoptosis and cell cycle arrest were investigated by flow cytometry (FC). Functional analysis of cell adhesion, migration and invasion (Boyden chambers) were performed. ALCAR modulation of surface antigen receptor (chemokines) and intracellular cytokine production was assessed by FC. The release of pro-angiogenic factors was detected by a multiplex immunoassay. The effects of ALCAR on PCa cell growth in vivo was investigated using tumour xenografts. RESULTS: We found that ALCAR reduces cell proliferation, induces apoptosis, hinders the production of pro inflammatory cytokines (TNF-α and IFN-γ) and of chemokines CCL2, CXCL12 and receptor CXCR4 involved in the chemotactic axis and impairs the adhesion, migration and invasion capabilities of PCa and BPH cells in vitro. ALCAR exerts angiopreventive activities on PCa by reducing production/release of pro angiogenic factors (VEGF, CXCL8, CCL2, angiogenin) and metalloprotease MMP-9. Exposure of endothelial cells to conditioned media from PCa cells, pre-treated with ALCAR, inhibited the expression of CXCR4, CXCR1, CXCR2 and CCR2 compared to those from untreated cells. Oral administration (drinking water) of ALCAR to mice xenografted with two different PCa cell lines, resulted in reduced tumour cell growth in vivo. CONCLUSIONS: Our results highlight the capability of ALCAR to down-modulate growth, adhesion, migration and invasion of prostate cancer cells, by reducing the production of several crucial chemokines, cytokines and MMP9. ALCAR is a widely diffused dietary supplements and our findings provide a rational for studying ALCAR as a possible molecule for chemoprevention approaches in subjects at high risk to develop prostate cancer. We propose ALCAR as a new possible "repurposed agent' for cancer prevention and interception, similar to aspirin, metformin or beta-blockers.


Assuntos
Acetilcarnitina/farmacologia , Indutores da Angiogênese/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Regulação para Baixo , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Camundongos Nus , Células PC-3 , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Neurochem Res ; 44(10): 2405-2412, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31041669

RESUMO

Neonatal hypoxia-ischemia (HI) is a common cause of brain injury in infants. Acute kidney injury frequently occurs after birth asphyxia and is associated with adverse outcome. Treatment with acetyl-L-carnitine (ALCAR) after HI protects brain and improves outcome. Rat pups underwent carotid ligation and 75 min hypoxia on postnatal day 7 to determine effects of HI on kidney which is understudied in this model. HI + ALCAR pups were treated at 0, 4 and 24 h after HI. The organic cation/carnitine transporter 2 (OCTN2), transports ALCAR and functions to reabsorb carnitine and acylcarnitines from urine. At 24 h after injury OCTN2 levels were significantly decreased in kidney from HI pups, 0.80 ± 0.04 (mean ± SEM, p < 0.01), compared to sham controls 1.03 ± 0.04, and HI + ALCAR pups 1.11 ± 0.06. The effect of HI on the level of pyruvate dehydrogenase (PDH) was determined since kidney has high energy requirements. At 24 h after HI, kidney PDH/ß-actin ratios were significantly lower in HI pups, 0.98 ± 0.05 (mean ± SEM, p < 0.05), compared to sham controls 1.16 ± 0.06, and HI + ALCAR pups 1.24 ± 0.03, p < 0.01. Treatment of pups with ALCAR after HI prevented the decrease in renal OCTN2 and PDH levels at 24 h after injury. Protection of PDH and OCTN2 after HI would improve energy metabolism in kidney, maintain tissue carnitine levels and overall carnitine homeostasis which is essential for neonatal health.


Assuntos
Acetilcarnitina/farmacologia , Lesões Encefálicas/tratamento farmacológico , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Rim/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Transporte Biológico/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Carnitina/análogos & derivados , Carnitina/farmacologia , Feminino , Hipóxia/tratamento farmacológico , Hipóxia-Isquemia Encefálica/metabolismo , Masculino , Ratos Sprague-Dawley
19.
Neurosci Lett ; 706: 36-42, 2019 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-31078678

RESUMO

Ketamine, an anesthetic, is a non-competitive antagonist of the calcium-permeable N-methyl-d-aspartate (NMDA) receptor. High concentrations of ketamine have been implicated in cardiotoxicity and neurotoxicity. Often, these toxicities are thought to be mediated by reactive oxygen species (ROS). However, findings to the contrary showing ketamine reducing ROS in mammalian cells and neurons in vitro, are emerging. Here, we determined the effects of ketamine on ROS levels in zebrafish larvae in vivo. Based on our earlier studies demonstrating reduction in ATP levels by ketamine, we hypothesized that as a calcium antagonist, ketamine would also prevent ROS generation, which is a by-product of ATP synthesis. To confirm that the detected ROS in a whole organism, such as the zebrafish larva, is specific, we used diphenyleneiodonium (DPI) that blocks ROS production by inhibiting the NADPH Oxidases (NOX). Upon 20 h exposure, DPI (5 and 10 µM) and ketamine at (1 and 2 mM) reduced ROS in the zebrafish larvae in vivo. Using acetyl l-carnitine (ALCAR), a dietary supplement, that induces mitochondrial ATP synthesis, we show elevated ROS generation with increasing ALCAR concentrations. Combined, ketamine and ALCAR counter-balanced ROS generation in the larvae suggesting that ketamine and ALCAR have opposing effects on mitochondrial metabolism, which may be key to maintaining ROS homeostasis in the larvae and affords ALCAR the ability to prevent ketamine toxicity. These results for the first time show ketamine's antioxidative and ALCAR's prooxidative effects in a live vertebrate.


Assuntos
Acetilcarnitina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ketamina/farmacologia , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Animais , Embrião não Mamífero/efeitos dos fármacos , Microscopia de Fluorescência , Neurônios/metabolismo , Oniocompostos/farmacologia , Peixe-Zebra
20.
Neuropharmacology ; 150: 145-152, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30917915

RESUMO

Stress-related psychiatric disorders are mental conditions that affect mood, cognition and behavior and arise because of the impact of prolonged stress on the central nervous system (CNS). Acetyl-L-carnitine (ALC) is an acetyl ester of L-carnitine that easily crosses the blood-brain barrier and was recently found to be decreased in patients with major depressive disorder. ALC plays a role in energy metabolism and is widely consumed as a nutritional supplement to improve physical performance. In this study, our objective was to evaluate the effects of ALC treatment (0.1 mg/L, 10 min) for 7 days on behavior and oxidative stress in zebrafish subjected to unpredictable chronic stress (UCS) protocol. Behavioral outcomes were assessed in the novel tank test, and parameters of oxidative status (lipid peroxidation and antioxidant defenses) were evaluated in the brain using colorimetric methods. According to our previous findings, UCS increased anxiety-like behavior and lipid peroxidation, while it decreased non-protein thiol levels and superoxide dismutase activity. However, ALC reversed the anxiety-like behavior and oxidative damage in stressed animals, while it was devoid of effect in control animals. Although our data reinforce the neuroprotective potential of ALC in the treatment of psychiatric disorders related to stress, further investigations are required to clarify its mechanisms of action and confirm its efficacy.


Assuntos
Acetilcarnitina/farmacologia , Antioxidantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Acetilcarnitina/uso terapêutico , Animais , Antioxidantes/uso terapêutico , Encéfalo/metabolismo , Feminino , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Peixe-Zebra
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