RESUMEN
BACKGROUND AND AIM: Cyclophosphamide (CP) chemotherapy is a significant iatrogenic component of premature ovarian failure (POF). The aim of this work was to evaluate the potential protective effects of donepezil, a centrally acting acetylcholinesterase (AChE) inhibitor, on CP-induced POF in mice. METHODS: 40 female Swiss albino mice were split into 5 equal groups: group 1 (control), group 2 (CP-POF); induced by intraperitoneal injection of CP on 8th day of the experiment, and group (3-5); mice received oral donepezil daily (1, 2, or 4 mg/kg, respectively) 8 days before CP injection. Mice were euthanized after 24 h of CP injection, and blood samples were collected to assay serum anti-Mullerian hormone (AMH) levels. Ovarian tissues were dissected, and the right ovary was processed for further assays of nitric oxide (NO), tumor necrosis factor-α (TNF-α), interlukin-6 (IL-6), nucleotide-binding domain-like receptor family, the Pyrin domain-containing 3 (NLRP3) inflammasome, and Toll-like receptor 4 (TLR-4), while the left one was processed for histopathological and immunohistochemical examination of nuclear factor-Kappa beta (NF-κB) and caspase-3. RESULTS: Donepezil, in a dose-dependent manner particularly (4 mg/kg), has an inhibitory action on NO (40 ± 2.85 vs. 28.20 ± 2.23, P < 0.001), proinflammatory cytokines (P < 0.001), the TLR-4/ NF-κB / NLRP3 inflammasome pathway (P < 0.001), and apoptosis (P < 0.001), with a significant elevation in the AMH levels (4.57 ± 1.08 vs. 8.57 ± 0.97, P < 0.001) versus CP-POF group. CONCLUSION: Donepezil may be a potential protective agent against CP-induced POF in mice, but further research is needed to fully understand its therapeutic function experimentally and clinically.
Asunto(s)
Inhibidores de la Colinesterasa , Ciclofosfamida , Citocinas , Donepezilo , FN-kappa B , Proteína con Dominio Pirina 3 de la Familia NLR , Insuficiencia Ovárica Primaria , Receptor Toll-Like 4 , Animales , Femenino , Donepezilo/farmacología , Ratones , Receptor Toll-Like 4/metabolismo , Ciclofosfamida/toxicidad , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Citocinas/metabolismo , Insuficiencia Ovárica Primaria/inducido químicamente , Insuficiencia Ovárica Primaria/prevención & control , Insuficiencia Ovárica Primaria/patología , Inhibidores de la Colinesterasa/farmacología , Ovario/efectos de los fármacos , Ovario/metabolismo , Ovario/patología , Transducción de Señal/efectos de los fármacosRESUMEN
AIM: The aim of this study was to investigate the potential cardioprotective and anti-cancer effects of carvedilol (CAR) either free or as loaded nano-formulated with or without doxorubicin (DOX) in solid Ehrlich carcinoma (SEC)-bearing mice. It focused on assessment of cardiac damage, drug resistance, apoptosis, oxidative stress status, angiogenesis and proliferation. METHODS: CAR was loaded into poly-D,L lactic-co-glycolic acid)PLGA(or Niosomes. SEC was induced in female albino mice as an experimental model of breast cancer. Seventy-two mice were randomly divided into 9 equal groups (Normal control, Untreated-SEC, SEC + DOX, SEC + CAR-free, SEC + CAR-PLGA, SEC + CAR-Niosomes, SEC + DOX + CAR-free, SEC + DOX + CAR-PLGA and SEC + DOX + CAR-Niosomes). Tumor volume and survival rate were recorded. On day 28 from tumor inoculation, mice were sacrificed, and blood samples were collected for determination of serum lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB). One part from tumor tissues was prepared for assessment of multidrug resistance protein-1 (MDR-1), caspase-3, reduced glutathione (GSH) and malondialdehyde (MDA), while the other part was processed for histopathological examination and immunohistochemical expression of vascular endothelial growth factor (VEGF) and Ki-67. RESULTS: There was non-significant difference between CAR-free, CAR-PLGA and CAR-Niosomes as anticancer either alone or when combined with DOX. However, CAR-free demonstrated potential cardioprotective effects against cardiac damage mediated by cancer or DOX that have been enhanced using CAR-PLGA or CAR-Niosomes, but that of Niosomes outperformed them both. CONCLUSION: CAR could be used as an adjuvant therapy with DOX, especially when nanoformualted with PLGA and even better with Niosomes, without compromising its cytotoxicity against cancer cells and preventing its cardiotoxic impacts.
Asunto(s)
Carcinoma , Nanopartículas , Ratones , Femenino , Animales , Carvedilol/farmacología , Liposomas , Factor A de Crecimiento Endotelial Vascular , Doxorrubicina/farmacología , Carcinoma/tratamiento farmacológico , Ácido LácticoRESUMEN
OBJECTIVE: Previous experimental studies have provided evidence of notable changes in thyroid hormone signaling that corresponds to alterations in myocardial function in animal models of heart failure (HF). The present study further explores whether oral thyroid hormone treatment can change left ventricular (LV) mechanics and functional status in patients with idiopathic dilated cardiomyopathy (IDCM) or not. METHODS: Sixty IDCM patients who were receiving conventional HF treatment were randomized to oral L-thyroxine (n = 40) or placebo (n = 20) for 3 months. Fifty-two (86.7%) of all IDCM patients were symptomatic, their mean age was 41 ± 12 years, and their ejection fraction was 32% ± 7%. At baseline, the two groups were comparable in clinical and echocardiographic variables. Vector velocity imaging was utilized to assess LV mechanics. Myocardial longitudinal peak systolic strain, systolic strain rate, early and late diastolic strain rate, circumferential strain, LV dyssynchrony, plasma tri-iodothyronine, thyroxine, and thyroid stimulating hormone levels were measured at baseline and 3 months after treatment. RESULTS: All patients receiving L-thyroxine significantly improved in functional status (New York Heart Association class; P < .001) and echocardiographic parameters including end-diastolic diameter (P < .001), end-systolic diameter (P < .001), mitral regurgitation severity reduction (P < .001), and increased ejection fraction (P < .001). Left ventricular mechanics showed marked improvement at segmental and global levels of both longitudinal and circumferential myocardial strain (P < .005) when compared with placebo group. CONCLUSIONS: Short-term L-thyroxine therapy is well tolerated in IDCM patients. It improves cardiac mechanics and functional status, which might support the potential role of synthetic thyroid hormones in HF treatment.
Asunto(s)
Cardiomiopatía Dilatada , Insuficiencia Cardíaca , Disfunción Ventricular Izquierda , Cardiomiopatía Dilatada/complicaciones , Cardiomiopatía Dilatada/diagnóstico por imagen , Cardiomiopatía Dilatada/tratamiento farmacológico , Ecocardiografía , Insuficiencia Cardíaca/tratamiento farmacológico , Ventrículos Cardíacos/diagnóstico por imagen , Humanos , Recién Nacido , Tiroxina , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/tratamiento farmacológico , Función Ventricular IzquierdaRESUMEN
Multiple sclerosis (MS) is a progressive inflammatory autoimmune demyelinating disease of the brain and spinal cord. Glucocorticoids (GCs) are the standard treatment of MS, however they have several drawbacks like oxidative stress and apoptosis. This study was designed to evaluate some possible antioxidant, anti-apoptotic and immune modulatory effects of Acetyl-l-carnitine (ALCAR) when used either alone or as an add-on therapy with dexamethasone for treatment of a relapsing-remitting (RR) experimental autoimmune encephalomyelitis (EAE) as a model of MS. This experiment was performed on 50 female Sprague Dawley rats divided into; normal control group, untreated EAE group, EAE group treated by dexamethasone, EAE group treated by ALCAR, and EAE group treated by both dexamethasone and ALCAR. The clinical score of the motor deficit of EAE was recorded daily. At the end of experiment, rats were sacrificed and the brain and spinal cord were processed for assessment of reduced glutathione (GSH), malondialdehyde (MDA) and caspase-3 activity. Histopathological changes and immunohistochemical expression of Bcl-2 and CD4+ T cell were carried out. Combination of both dexamethasone and ALCAR provided marked antioxidant and anti-apoptotic effects represented by significant decrease in MDA, caspase-3 and significant increase in GSH, Bcl-2 expression, and it also exhibited marked immunosuppressive effect represented by significant decrease in CD4+ T cells expression with significant improvement in clinical outcome when compared to untreated EAE group or to dexamethasone treated group. These findings pave the way for using ALCAR as an adjuvant therapy during long-term use of dexamethasone in MS.
Asunto(s)
Acetilcarnitina/uso terapéutico , Antioxidantes/uso terapéutico , Apoptosis , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Acetilcarnitina/farmacología , Animales , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Biomarcadores/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Linfocitos T CD4-Positivos/inmunología , Caspasa 3/metabolismo , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Femenino , Glutatión/metabolismo , Malondialdehído/metabolismo , Estrés Oxidativo/efectos de los fármacos , Parálisis/complicaciones , Parálisis/patología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas Sprague-Dawley , Médula Espinal/metabolismo , Médula Espinal/patologíaRESUMEN
BACKGROUND: Morphine sulfate has long been used for analgesia, but clinical applications can be limited by side effects, tolerance, and potential for addiction at therapeutic doses. An agent that produces therapeutic analgesia when coadministered with low-dose morphine could have important clinical uses. The anticonvulsant agent gabapentin has been identified as having antihyperalgesic properties acting on the alpha2delta1 subunit of N-type voltage-activated calcium channels on dorsal root ganglia neurons. In this study, intrathecal gabapentin, which by itself is ineffective when administered spinally, was combined with low-dose morphine and tested in an acute bradykinin-induced pancreatitis model in rats. METHODS: An intrathecal catheter was surgically inserted into the subarachnoid space of male Sprague-Dawley rats. A laparotomy was performed for ligation and cannulation of the bile-pancreatic duct. Rats were pretreated intrathecally with artificial cerebrospinal fluid, gabapentin, morphine, or combined gabapentin and morphine 30 min before bradykinin injection into the bile-pancreatic duct. Spontaneous behavioral activity (cage crossing, rearing, and hind limb extension) was monitored before drug injection (baseline) and after bradykinin injection into the bile-pancreatic duct to assess visceral pain. RESULTS: Spinal pretreatment with up to 300 microg gabapentin alone was not effective in reducing hind limb extension in this model, but did restore some cage crossing and rearing behaviors. Spinal treatment with low-dose morphine reduced hind limb extension only. Spinal pretreatment with combined gabapentin and subtherapeutic doses of morphine sulfate resulted in restoration of all spontaneous behaviors to surgical baseline levels including elimination of hind limb extension. CONCLUSION: Combined spinal administration of gabapentin and low doses of morphine significantly reduces pain-related behaviors in this acute rat pancreatitis model, whereas these agents were ineffective when used alone in this dose range. These data suggest that the alpha2delta1 subunit of the N-type voltage-activated Ca2+ channels is involved in transmission of this visceral pain, likely through effects on primary afferent endings in the spinal cord. Thus, gabapentin may be an effective adjuvant to initial low dose spinal opioid therapy for clinical management of visceral pain.