RESUMEN

INTRODUCTION: HIV-1 eradication is hindered by the presence of inducible long-lived reservoirs of latently infected cells which rapidly disseminate viral particles upon treatment interruption. Eliminating these reservoirs by the so-called shock and kill strategy represents a crucial concept toward an HIV-1 cure. Several molecules called latency-reversing agents (LRAs) are under intensive investigations to reactivate virus gene expression. These studies are mainly conducted on CD4+ T cells where LRAs are well tolerated and did not induce global cellular activation. However, despite their broad spectrum, the putative impact of LRAs on other cellular reservoirs such as macrophages is still ill-defined. METHODS: We investigated the impact of the protein kinase C (PKC) activator bryostatin-1, bromodomain inhibitor JQ1 and histone deacetylase inhibitor romidepsin used either alone or in combination on human primary monocyte-derived macrophages (MDMs). RESULTS: We demonstrate that bryostatin-1, JQ1, and romidepsin or their combinations are not toxic at nanomolar concentrations but induce metabolic and morphologic alterations of MDMs. Bryostatin-1 triggered the secretion of pro-inflammatory cytokines, while JQ-1 decreased it. Phagocytosis and endocytosis were modestly impaired upon bryostatin-1 treatment whereas efferocytosis was markedly downregulated by romidepsin. Despite its pro-inflammatory profile, bryostatin-1 did not induce classically activated macrophage markers. Finally, we reveal that conditioned medium from bryostatin-1-treated macrophages did not potentiate its reactivation feature. CONCLUSIONS: Our study reveals that LRAs can diversely impact basic physiologic features of human primary macrophages and could potentially decrease reactivation of nearby CD4+ T cells latently infected with HIV-1. Our observations further stress the need to include different cell populations when assessing HIV-1 cure strategies.

Asunto(s)

Infecciones por VIH , Seropositividad para VIH , Humanos , Activación Viral , Latencia del Virus , Brioestatinas/farmacología , Brioestatinas/uso terapéutico , Linfocitos T CD4-Positivos , Infecciones por VIH/tratamiento farmacológico , Macrófagos

RESUMEN

PURPOSE: DNMT3A mutations confer a poor prognosis in acute myeloid leukemia (AML), but the molecular mechanisms downstream of DNMT3A mutations in disease pathogenesis are not completely understood, limiting targeted therapeutic options. The role of miRNA in DNMT3A-mutant AML pathogenesis is understudied. EXPERIMENTAL DESIGN: DNA methylation and miRNA expression was evaluated in human AML patient samples and in Dnmt3a/Flt3-mutant AML mice. The treatment efficacy and molecular mechanisms of TLR7/8-directed therapies on DNMT3A-mutant AML were evaluated in vitro on human AML patient samples and in Dnmt3a/Flt3-mutant AML mice. RESULTS: miR-196b is hypomethylated and overexpressed in DNMT3A-mutant AML and is associated with poor patient outcome. miR-196b overexpression in DNMT3A-mutant AML is important to maintain an immature state and leukemic cell survival through repression of TLR signaling. The TLR7/8 agonist resiquimod induces dendritic cell-like differentiation with costimulatory molecule expression in DNMT3A-mutant AML cells and provides a survival benefit to Dnmt3a/Flt3-mutant AML mice. The small molecule bryostatin-1 augments resiquimod-mediated AML growth inhibition and differentiation. CONCLUSIONS: DNMT3A loss-of-function mutations cause miRNA locus-specific hypomethylation and overexpression important for mutant DNMT3A-mediated pathogenesis and clinical outcomes. Specifically, the overexpression of miR-196b in DNMT3A-mutant AML creates a novel therapeutic vulnerability by controlling sensitivity to TLR7/8-directed therapies.

Asunto(s)

Leucemia Mieloide Aguda , MicroARNs , Animales , Brioestatinas/uso terapéutico , ADN (Citosina-5-)-Metiltransferasas/genética , ADN Metiltransferasa 3A , Metilasas de Modificación del ADN/genética , Humanos , Inmunidad Innata , Leucemia Mieloide Aguda/tratamiento farmacológico , Ratones , MicroARNs/genética , MicroARNs/uso terapéutico , Mutación , Receptor Toll-Like 7/genética , Receptor Toll-Like 7/uso terapéutico

RESUMEN

BACKGROUND: In pre-clinical studies of Alzheimer's disease (AD) transgenic mice, bryostatin restored synaptic connections, prevented neuronal death, reduced amyloid plaques, and reduced neurofibrillary tangles. OBJECTIVE: Within pre-specified cohorts of advanced AD patients in two double-blind placebo-controlled bryostatin Phase II trials, to conduct exploratory statistical analyses of patients with identical conditions of enrollment and treatment. METHODS: Severe Impairment Battery (SIB) scores above baseline at 5, 9, and 13 weeks were analyzed initially in the complete cases, with multiple imputation methods based on an iterative Markov chain Monte Carlo algorithm used for missing SIB scores. To mitigate confounding by a chance imbalance of 4.9 SIB baseline scores (Study #203), each patient was used as their own control with differences in 13-week SIB from baseline in single trial and pooled analyses to measure benefit at 13 weeks using general estimating equations (GEE) modeling. RESULTS: Patients treated with bryostatin pre-specified at Mini-Mental State Examination scores 10-14, without memantine, showed baseline balance, complete safety, and SIB improvements at 13 weeks with multiple imputation analysis: Study #203 = 4.1 SIB points above baseline (p = 0.005), and Study #202 = 4.2 SIB points above baseline (p = 0.016). An increased power (N = 95) "pooled analysis" showed an increased SIB over time and a higher mean SIB at 13 weeks in the bryostatin treatment group (p < 0.001) but not significant (NS) for the placebo patients. CONCLUSION: Pre-specified exploratory analyses for the individual trials and the pooled trials confirmed significant bryostatin-induced improvement over baseline (treatment p < 0.001, placebo NS).

Asunto(s)

Enfermedad de Alzheimer , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/psicología , Animales , Brioestatinas/farmacología , Brioestatinas/uso terapéutico , Ensayos Clínicos Fase II como Asunto , Cognición , Ensayos Clínicos Controlados como Asunto , Método Doble Ciego , Humanos , Memantina/uso terapéutico , Pruebas de Estado Mental y Demencia , Ratones , Resultado del Tratamiento

RESUMEN

AIDS is a pandemic disease caused by HIV that affects 37 million people worldwide. Current antiretroviral therapy slows disease progression but does not eliminate latently infected cells, which resupply active virus, thus necessitating lifelong treatment with associated compliance, cost, and chemoexposure issues. Latency-reversing agents (LRAs) activate these cells, allowing for their potential clearance, thus presenting a strategy to eradicate the infection. Protein kinase C (PKC) modulators-including prostratin, ingenol esters, bryostatin, and their analogs-are potent LRAs in various stages of development for several clinical indications. While LRAs are promising, a major challenge associated with their clinical use is sustaining therapeutically meaningful levels of the active agent while minimizing side effects. Here we describe a strategy to address this problem based on LRA prodrugs, designed for controllable release of the active LRA after a single injection. As intended, these prodrugs exhibit comparable or superior in vitro activity relative to the parent compounds. Selected compounds induced higher in vivo expression of CD69, an activation biomarker, and, by releasing free agent over time, significantly improved tolerability when compared to the parent LRAs. More generally, selected prodrugs of PKC modulators avoid the bolus toxicities of the parent drug and exhibit greater efficacy and expanded tolerability, thereby addressing a longstanding objective for many clinical applications.

Asunto(s)

Fármacos Anti-VIH/farmacología , Brioestatinas/farmacología , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , Profármacos/farmacología , Proteína Quinasa C/metabolismo , Latencia del Virus/efectos de los fármacos , Animales , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/uso terapéutico , Brioestatinas/síntesis química , Brioestatinas/uso terapéutico , Línea Celular Tumoral , Células Cultivadas , Diterpenos/química , Infecciones por VIH/tratamiento farmacológico , VIH-1/fisiología , Humanos , Ratones , Ratones Endogámicos C57BL , Ésteres del Forbol/química , Profármacos/síntesis química , Profármacos/uso terapéutico , Proteína Quinasa C/efectos de los fármacos

RESUMEN

Bryostatins are a class of naturally occurring macrocyclic lactones with a unique fast developing portfolio of clinical applications, including treatment of AIDS, Alzheimer's disease, and cancer. This comprehensive account summarizes the recent progress (2014-present) in the development of bryostatins, including their total synthesis and biomedical applications. An emphasis is placed on the discussion of bryostatin 1, the most-studied analogue to date. This review highlights the synthetic and biological challenges of bryostatins and provides an outlook on their future development.

Asunto(s)

Antineoplásicos/química , Brioestatinas/síntesis química , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Brioestatinas/farmacología , Brioestatinas/uso terapéutico , Senescencia Celular/efectos de los fármacos , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Infecciones por VIH/tratamiento farmacológico , Humanos , Proteína Quinasa C/antagonistas & inhibidores , Proteína Quinasa C/metabolismo

RESUMEN

BACKGROUND: Alzheimer's disease (AD) animal models have revealed neuroprotective actions of Bryostatin-1 mediated by activation of novel PKC isoforms, suppression of beta-amyloid and downregulation of inflammatory and angiogenic events, making Bryostatin-1 an attractive candidate for attenuating AD-associated neural, vascular, and cognitive disturbances. OBJECTIVE: To further enhance Bryostatin-1 efficacy, nanoparticle-encapsulated Bryostatin-1 formulations were prepared. METHODS: We compared nano-encapsulated and unmodified Bryostatin-1 in in vitro models of neuronal PKC-d, PKC-e isoforms, α-secretase and studied nano-encapsulated Bryostatin-1 in an AD mouse model of spatial memory (BC3-Tg (APPswe, PSEN1 dE9) 85Dbo/J mice). RESULTS: We found that nanoencapsulated Bryostatin-1 formulations displayed activity greater or equal to that of unmodified Bryostatin-1 in PKC-δ and -ε and α-secretase activation assays. We next evaluated how treatment with a nanoencapsulated Bryostatin-1 formulation facilitated spatial learning in the Morris water maze. AD transgenic mice (6.5 to 8 months of age) were treated with nanoparticle encapsulated Bryostatin-1 formulation (1, 2.5, or 5 µg/mouse) three times the week before testing and then daily for each of the 5 days of testing. Across the acquisition phase, mice treated with nanoencapsulated Bryostatin-1 had shorter latencies, increased % time in the target zone and decreased % time in the opposite quadrant. The mice were given retention testing after a 2-week period without drug treatment. Mice treated with nanoencapsulated Bryostatin-1 had shorter latencies to find the escape platform, indicating retention of spatial memory. CONCLUSION: These data suggest that cognitive deficits associated with AD could be treated using highly potent nanoparticle-encapsulated formulations of Bryostatin-1.

Asunto(s)

Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide , Brioestatinas/uso terapéutico , Ratones Transgénicos , Proteína Quinasa C , Aprendizaje Espacial , Péptidos beta-Amiloides , Animales , Modelos Animales de Enfermedad , Humanos , Técnicas In Vitro , Ratones , Nanopartículas , Isoformas de Proteínas

RESUMEN

Recent advances in sampling and novel techniques in drug synthesis and isolation have promoted the discovery of anticancer agents from marine organisms to combat this major threat to public health worldwide. Bryozoans, which are filter-feeding, aquatic invertebrates often characterized by a calcified skeleton, are an excellent source of pharmacologically interesting compounds including well-known chemical classes such as alkaloids and polyketides. This review covers the literature for secondary metabolites isolated from marine cheilostome and ctenostome bryozoans that have shown potential as cancer drugs. Moreover, we highlight examples such as bryostatins, the most known class of marine-derived compounds from this animal phylum, which are advancing through anticancer clinical trials due to their low toxicity and antineoplastic activity. The bryozoan antitumor compounds discovered until now show a wide range of chemical diversity and biological activities. Therefore, more research focusing on the isolation of secondary metabolites with potential anticancer properties from bryozoans and other overlooked taxa covering wider geographic areas is needed for an efficient bioprospecting of natural products.

Asunto(s)

Antineoplásicos/química , Briozoos/química , Alcaloides/química , Alcaloides/farmacología , Alcaloides/uso terapéutico , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Organismos Acuáticos/química , Productos Biológicos/química , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Brioestatinas/química , Brioestatinas/farmacología , Brioestatinas/uso terapéutico , Humanos , Invertebrados/química

RESUMEN

Bryostatin-1 (Bry-1) has been proven to be effective and safe in clinical trials of a variety of immune-related diseases. However, little is known about its effect on Crohn's disease (CD). We aimed to investigate the impact of Bry-1 on CD-like colitis and determine the mechanism underlying this effect. In the present study, 15-week-old male Il-10-/- mice with spontaneous colitis were divided into positive control and Bry-1-treated (Bry-1, 30 µg/kg every other day, injected intraperitoneally for 4 weeks) groups. Age-matched, male wild-type (WT) mice were used as a negative control. The effects of Bry-1 on colitis, intestinal barrier function and T cell responses as well as the potential regulatory mechanisms were evaluated. We found that the systemic delivery of Bry-1 significantly ameliorated colitis in Il-10-/- mice, as demonstrated by decreases in the disease activity index (DAI), inflammatory score and proinflammatory mediator levels. The protective effects of Bry-1 on CD-like colitis included the maintenance of intestinal barrier integrity and the helper T cell (Th)/regulatory T cell (Treg) balance. These effects of Bry-1 may act in part through nuclear factor erythroid 2-related factor 2 (Nrf2) signalling activation and STAT3/4 signalling inhibition. The protective effect of Bry-1 on CD-like colitis suggests Bry-1 has therapeutic potential in human CD, particularly given the established clinical safety of Bry-1.

Asunto(s)

Brioestatinas/uso terapéutico , Colitis/tratamiento farmacológico , Colitis/inmunología , Interleucina-10/deficiencia , Intestinos/inmunología , Intestinos/patología , Animales , Apoptosis/efectos de los fármacos , Brioestatinas/farmacología , Colitis/patología , Regulación hacia Abajo/efectos de los fármacos , Células Epiteliales/metabolismo , Interleucina-10/metabolismo , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/metabolismo , Permeabilidad , Transducción de Señal/efectos de los fármacos , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células Th17/efectos de los fármacos , Células Th17/inmunología , Proteínas de Uniones Estrechas/metabolismo , Uniones Estrechas/efectos de los fármacos , Uniones Estrechas/metabolismo , Uniones Estrechas/ultraestructura

RESUMEN

Bryostatin-1, a macrolide lactone derived from marine organism Bugula neritina, has been shown to inhibit carcinogenesis in several prospective clinical trials. In the current study, the therapeutic potential of bryostatin-1 in inhibiting proliferation of hepatocarcinoma was evaluated by in vitro and in vivo studies. The mechanisms of action of bryostatin-1 were predicted by in silico assay and further validated by surface plasmon resonance and western blot assay. Our results show that bryostatin-1 (100, 200 nM) treatment can suppress cell proliferation and induce G1 cell cycle arrest in PLC/PRF/5 and SMCC7721 cell. We also found a significant inhibitory action of bryostatin-1 (100, 200 nM) on CyclinD1 activity in PLC/PRF/5 cells, and bryostatin-1 can promote ubiquitination-dependent protein degradation of CyclinD1 in PLC/PRF/5 cells. Western blot results confirmed that the active form phospho-GSK3ß Tyr216 expression was increased significantly after bryostatin-1 treatment. Activation of GSK3ß might be responsible for bryostatin-1 induced cyclinD1 degradation and cell cycle arrest. Taken together, bryostatin-1 may inhibit HCC cells proliferation by promoting cyclinD1 proteolysis and inducing cell cycle arrest.

Asunto(s)

Antineoplásicos/uso terapéutico , Brioestatinas/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Brioestatinas/farmacología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Femenino , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Ratones Endogámicos BALB C , Ratones Desnudos

RESUMEN

BACKGROUND: Bryostatin-activated PKC epsilon pre-clinically induces synaptogenesis, anti-apoptosis, anti-amyloid-ß oligomers, and anti-hyperphosphorylated tau. OBJECTIVES: To investigate bryostatin safety, tolerability, and efficacy to improve cognition in advanced Alzheimer's disease (AD) patients. METHODS: A double-blind, randomized, placebo-controlled Phase II, 12-week trial of i.v. bryostatin for 150 advanced AD patients (55-85) with MMSE-2 of 4-15, randomized 1:1:1 into 20 µg and 40 µg bryostatin, and placebo arms. The Full Analysis Set (FAS) and the Completer Analysis Set (CAS) were pre-specified alternative assessments (1-sided, p < 0.1 for primary efficacy, and 2-sided, p < 0.05 for pre-specified and post hoc exploratory analyses). RESULTS: The safety profile was similar for 20 µg treatment and placebo patients. The 40 µg patients showed safety and drop-out issues, but no efficacy. Primary improvement of Severe Impairment Battery (SIB) scores at 13 weeks was not significant (p = 0.134) in the FAS, although in the CAS, the SIB comparison favored 20 µg bryostatin compared to placebo patients (p < 0.07). Secondary analyses at weeks 5 and 15 (i.e., 30 days post-final dosing) also favored 20 µg bryostatin compared to placebo patients. A pre-specified ANCOVA for baseline memantine blocking bryostatin and positive post-hoc trend analyses were statistically significant (2-sided, p < 0.05). CONCLUSION: Although the primary endpoint was not significant in the FAS, primary and secondary analyses in the CAS, and pre-specified and post-hoc exploratory analyses did favor bryostatin 20 µg compared to the placebo cohort. These promising Phase II results support further trials of 20 µg bryostatin- without memantine- to treat AD.

Asunto(s)

Enfermedad de Alzheimer/tratamiento farmacológico , Brioestatinas/efectos adversos , Brioestatinas/uso terapéutico , Actividades Cotidianas , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/psicología , Brioestatinas/administración & dosificación , Cognición , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Infusiones Intravenosas , Masculino , Pruebas de Estado Mental y Demencia , Persona de Mediana Edad , Resultados Negativos , Pacientes Desistentes del Tratamiento , Resultado del Tratamiento

RESUMEN

Multiple sclerosis (MS) is an inflammatory disorder targeting the central nervous system (CNS). The relapsing-remitting phase of MS is largely driven by peripheral activation of autoreactive T-helper (Th) 1 and Th17 lymphocytes. In contrast, compartmentalized inflammation within the CNS, including diffuse activation of innate myeloid cells, characterizes the progressive phase of MS, the most debilitating phase that currently lacks satisfactory treatments. Recently, bryostatin-1 (bryo-1), a naturally occurring, CNS-permeable compound with a favorable safety profile in humans, has been shown to act on antigen-presenting cells to promote differentiation of lymphocytes into Th2 cells, an action that might benefit Th1-driven inflammatory conditions such as MS. In the present study, we show that bryo-1 provides marked benefit in mice with experimental autoimmune encephalomyelitis (EAE), an experimental MS animal model. Preventive treatment with bryo-1 abolishes the onset of neurologic deficits in EAE. More strikingly, bryo-1 reverses neurologic deficits after EAE onset, even when treatment is initiated at a late stage of disease when peak adaptive immunity has subsided. Treatment with bryo-1 in vitro promotes an anti-inflammatory phenotype in antigen-presenting dendritic cells, macrophages, and to a lesser extent, lymphocytes. These findings suggest the potential for bryo-1 as a therapeutic agent in MS, particularly given its established clinical safety. Furthermore, the benefit of bryo-1, even in late treatment of EAE, combined with its targeting of innate myeloid cells suggests therapeutic potential in progressive forms of MS.

Asunto(s)

Brioestatinas/uso terapéutico , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Animales , Anticuerpos , Linfocitos T CD4-Positivos , Sistema Nervioso Central/inmunología , Femenino , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple

RESUMEN

Despite the success of antiretroviral therapy (ART), there is currently no HIV cure and treatment is life long. HIV persists during ART due to long-lived and proliferating latently infected CD4+ T cells. One strategy to eliminate latency is to activate virus production using latency reversing agents (LRAs) with the goal of triggering cell death through virus-induced cytolysis or immune-mediated clearance. However, multiple studies have demonstrated that activation of viral transcription alone is insufficient to induce cell death and some LRAs may counteract cell death by promoting cell survival. Here, we review new approaches to induce death of latently infected cells through apoptosis and inhibition of pathways critical for cell survival, which are often hijacked by HIV proteins. Given advances in the commercial development of compounds that induce apoptosis in cancer chemotherapy, these agents could move rapidly into clinical trials, either alone or in combination with LRAs, to eliminate latent HIV infection.

Asunto(s)

Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Activación Viral/efectos de los fármacos , Latencia del Virus/efectos de los fármacos , Brioestatinas/uso terapéutico , Linfocitos T CD4-Positivos/virología , Depsipéptidos/uso terapéutico , Infecciones por VIH/virología , Humanos , Ácidos Hidroxámicos/uso terapéutico , Indoles/uso terapéutico , Panobinostat , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Vorinostat

RESUMEN

Bryostatin 1 is an exceedingly scarce marine-derived natural product that is in clinical development directed at HIV/AIDS eradication, cancer immunotherapy, and the treatment of Alzheimer's disease. Despite this unique portfolio of indications, its availability has been limited and variable, thus impeding research and clinical studies. Here, we report a total synthesis of bryostatin 1 that proceeds in 29 total steps (19 in the longest linear sequence, >80% average yield per step), collectively produces grams of material, and can be scaled to meet clinical needs (~20 grams per year). This practical solution to the bryostatin supply problem also opens broad, facile, and efficient access to derivatives and potentially superior analogs.

Asunto(s)

Adyuvantes Inmunológicos/síntesis química , Fármacos Anti-VIH/síntesis química , Brioestatinas/síntesis química , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Latencia del Virus/efectos de los fármacos , Adyuvantes Inmunológicos/química , Adyuvantes Inmunológicos/farmacología , Adyuvantes Inmunológicos/uso terapéutico , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Brioestatinas/química , Brioestatinas/farmacología , Brioestatinas/uso terapéutico , Erradicación de la Enfermedad , Humanos

RESUMEN

Despite over a half-century's intensive research worldwide, the currently available antidepressants remain sub-optimal. Therapeutic options for treatment-resistant depression, for instance, are rather limited. Here, we found that rats exhibited a lasting treatment-resistant depressive immobility in response to open space swim test at a high intensity of induction. The induced depressive behavior is associated with a dramatic impairment in spatial learning and memory. Both the depressive immobility and impairment in spatial learning and memory are sensitive to a period of chronic treatment with bryopstatin-1, a relatively selective activator of protein kinase Cε. Bryostatin-1-like analogues therefore might have therapeutic values for the treatment of treatment-resistant depression.

Asunto(s)

Brioestatinas/farmacología , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Animales , Conducta Animal/efectos de los fármacos , Brioestatinas/uso terapéutico , Trastorno Depresivo Resistente al Tratamiento/fisiopatología , Masculino , Ratas , Ratas Wistar , Aprendizaje Espacial/efectos de los fármacos , Factores de Tiempo

RESUMEN

Bryostatin 1, a potent activator of protein kinase C epsilon (PKCɛ), has been shown to reverse synaptic loss and facilitate synaptic maturation in animal models of Alzheimer's disease (AD), Fragile X, stroke, and other neurological disorders. In a single-dose (25 µg/m2) randomized double-blind Phase IIa clinical trial, bryostatin levels reached a maximum at 1-2 h after the start of infusion. In close parallel with peak blood levels of bryostatin, an increase of PBMC PKCɛ was measured (p = 0.0185) within 1 h from the onset of infusion. Of 9 patients with a clinical diagnosis of AD, of which 6 received drug and 3 received vehicle within a double-blind protocol, bryostatin increased the Mini-Mental State Examination (MMSE) score by +1.83±0.70 unit at 3 h versus -1.00±1.53 unit for placebo. Bryostatin was well tolerated in these AD patients and no drug-related adverse events were reported. The 25 µg/m2 administered dose was based on prior clinical experience with three Expanded Access advanced AD patients treated with bryostatin, in which return of major functions such as swallowing, vocalization, and word recognition were noted. In one Expanded Access patient trial, elevated PKCɛ levels closely tracked cognitive benefits in the first 24 weeks as measured by MMSE and ADCS-ADL psychometrics. Pre-clinical mouse studies showed effective activation of PKCɛ and increased levels of BDNF and PSD-95. Together, these Phase IIa, Expanded Access, and pre-clinical results provide initial encouragement for bryostatin 1 as a potential treatment for AD.

Asunto(s)

Enfermedad de Alzheimer , Antipsicóticos/uso terapéutico , Brioestatinas/uso terapéutico , Trastornos del Conocimiento , Proteína Quinasa C-epsilon/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/enzimología , Análisis de Varianza , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/enzimología , Trastornos del Conocimiento/etiología , Homólogo 4 de la Proteína Discs Large/metabolismo , Método Doble Ciego , Femenino , Humanos , Masculino , Escala del Estado Mental , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Pruebas Neuropsicológicas , Fosfopiruvato Hidratasa/metabolismo , Psicometría , Sinaptofisina/metabolismo , Factores de Tiempo

RESUMEN

Although it has been suggested that the combination of exercise and bryostatin-1 administration may induce greater functional recovery than exercise alone, the detailed molecular mechanisms are not well known. Here, we examined the relationship between this combination treatment and monoamine dynamics in the cerebral cortex peri-infarction area to promote our understanding of these molecular mechanisms. Experimental cerebral cortex infarctions were produced by photothrombosis in rats. Voluntary exercise was initiated 2 days after surgery. Motor performance was then measured using the rotarod test. Monoamine concentrations in the perilesional cortex were analyzed by high-performance liquid chromatography. In behavioral evaluations, performance in the rotarod test was significantly increased by exercise. Moreover, performance in the rotarod test after the combination of exercise and bryostatin-1 administration was significantly greater than that after exercise alone. In the analysis of monoamines, serotonin (5-HT) concentrations were significantly higher in the groups treated with exercise and bryostatin-1. In addition, 5-HT turnover was significantly lower in the groups treated with exercise and bryostatin-1. Furthermore, the mean latency in the rotarod test showed a significant positive correlation with 5-HT levels. In immunohistochemical analysis, 5-HT immunoreactivity in the dorsal raphe nucleus was shown to be higher in the groups treated with exercise. In the present study, we detected changes in the levels of monoamines associated with the combined treatment of exercise and bryostatin-1 administration in the perilesional cortex. It has been suggested that this combination of therapies may affect 5-HT turnover and serve to increase local 5-HT concentrations in the perilesional area.

Asunto(s)

Adyuvantes Inmunológicos/uso terapéutico , Brioestatinas/uso terapéutico , Infarto Cerebral/tratamiento farmacológico , Infarto Cerebral/rehabilitación , Terapia por Ejercicio/métodos , Serotonina/metabolismo , Animales , Monoaminas Biogénicas/metabolismo , Corteza Cerebral/metabolismo , Modelos Animales de Enfermedad , Masculino , Actividad Motora/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/fisiología , Prueba de Desempeño de Rotación con Aceleración Constante

RESUMEN

Purpose: This study was conducted to evaluate the pharmacological interventions to target vascular proliferation in the Retinopathy of Prematurity (ROP). Methods: Protein Kinase C modulator (Bryostatin), tubulin polymerization inhibitor (Dolastatin 10), antiVEGF (Bevacizumab) and a non-specific VEGF inhibitor (Thalidomide) were screened in Retinopathy of Prematurity (ROP) model. The retinal vasculature was evaluated by calculating the tortuosity indices of vessels and electroretinography responses in terms of 'b' wave amplitude and was recorded from ROP rats on postnatal Day 17 and Day 25. Results: Retinopathy was seen in the form of tortousity of vessels at the posterior pole with arteries being affected more than veins. Maximum reduction in tortousity of vessels and the highest 'b' wave amplitude noted in bryostatin with a significant correlation between the two. Conclusion: Bryostatin showed a potential anti-angiogenic effect on the progression of ROP and may hold a promising future in the treatment of ROP.

Asunto(s)

Bevacizumab/uso terapéutico , Brioestatinas/uso terapéutico , Depsipéptidos/uso terapéutico , Oxígeno/toxicidad , Retinopatía de la Prematuridad/tratamiento farmacológico , Talidomida/uso terapéutico , Adyuvantes Inmunológicos/uso terapéutico , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Animales Recién Nacidos , Hiperoxia , Ratas , Ratas Wistar , Moduladores de Tubulina/uso terapéutico

RESUMEN

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder. Current approved drugs may only ameliorate symptoms in a restricted number of patients and for a restricted period of time. Currently, there is a translational research challenge into identifying the new effective drugs and their respective new therapeutic targets in AD and other neurodegenerative disorders. In this review, selected examples of marine-derived compounds in neurodegeneration, specifically in AD field are reported. The emphasis has been done on compounds and their possible relevant biological activities. The proposed drug development paradigm and current hypotheses should be accurately investigated in the future of AD therapy directions although taking into account successful examples of such approach represented by Cytarabine, Trabectedin, Eribulin and Ziconotide. We review a complexity of the translational research for such a development of new therapies for AD. Bryostatin is a prominent candidate for the therapy of AD and other types of dementia in humans.

Asunto(s)

Enfermedad de Alzheimer/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Organismos Acuáticos/metabolismo , Brioestatinas/química , Brioestatinas/uso terapéutico , Ensayos Clínicos como Asunto , Humanos , Fármacos Neuroprotectores/química , Agua de Mar

RESUMEN

Recent wars in Iraq and Afghanistan have accounted for an estimated 270,000 blast exposures among military personnel. Blast traumatic brain injury (TBI) is the 'signature injury' of modern warfare. Blood brain barrier (BBB) disruption following blast TBI can lead to long-term and diffuse neuroinflammation. In this study, we investigate for the first time the role of bryostatin-1, a specific protein kinase C (PKC) modulator, in ameliorating BBB breakdown. Thirty seven Sprague-Dawley rats were used for this study. We utilized a clinically relevant and validated blast model to expose animals to moderate blast exposure. Groups included: control, single blast exposure, and single blast exposure + bryostatin-1. Bryostatin-1 was administered i.p. 2.5 mg/kg after blast exposure. Evan's blue, immunohistochemistry, and western blot analysis were performed to assess injury. Evan's blue binds to albumin and is a marker for BBB disruption. The single blast exposure caused an increase in permeability compared to control (t = 4.808, p < 0.05), and a reduction back toward control levels when bryostatin-1 was administered (t = 5.113, p < 0.01). Three important PKC isozymes, PKCα, PKCδ, and PKCε, were co-localized primarily with endothelial cells but not astrocytes. Bryostatin-1 administration reduced toxic PKCα levels back toward control levels (t = 4.559, p < 0.01) and increased the neuroprotective isozyme PKCε (t = 6.102, p < 0.01). Bryostatin-1 caused a significant increase in the tight junction proteins VE-cadherin, ZO-1, and occludin through modulation of PKC activity. Bryostatin-1 ultimately decreased BBB breakdown potentially due to modulation of PKC isozymes. Future work will examine the role of bryostatin-1 in preventing chronic neurodegeneration following repetitive neurotrauma.

Asunto(s)

Traumatismos por Explosión/tratamiento farmacológico , Barrera Hematoencefálica/efectos de los fármacos , Lesiones Encefálicas/tratamiento farmacológico , Brioestatinas/uso terapéutico , Animales , Antígenos CD/metabolismo , Astrocitos/enzimología , Traumatismos por Explosión/fisiopatología , Lesiones Encefálicas/fisiopatología , Brioestatinas/farmacología , Cadherinas/metabolismo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/enzimología , Células Endoteliales/fisiología , Masculino , Ocludina/metabolismo , Corteza Prefrontal/irrigación sanguínea , Proteína Quinasa C-alfa/antagonistas & inhibidores , Proteína Quinasa C-alfa/metabolismo , Proteína Quinasa C-delta/metabolismo , Proteína Quinasa C-epsilon/efectos de los fármacos , Proteína Quinasa C-epsilon/metabolismo , Ratas , Ratas Sprague-Dawley , Uniones Estrechas/efectos de los fármacos , Proteína de la Zonula Occludens-1/metabolismo

RESUMEN

Recently, it has become widely known that neuronal reorganization in the perilesional cortex contributes to some improvement of hemiparesis after stroke. Here, the authors examined in vivo the effects of administration of bryostatin-1, an activator of protein kinase C, combined with voluntary exercise on functional recovery and on cortical phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluR1 after infarction.In behavioral evaluation, the mean latency until falling from a rotating rod in the group with exercise and administered agent at 8 days after infarction was significantly longer than that in the other groups. Although there were no significant changes in GluR1 phosphorylation between bryostatin-1 administration alone and the untreated groups, exercise induced an increase in phosphorylated-Ser845-GluR1. Moreover, combining exercise with administration led to increased phosphorylated-Ser831-GluR1.These results suggest that bryostatin-1 facilitated exercise-induced paralysis recovery, which is possibly mediated by synaptic plasticity related to an increase in synaptic transmission efficiency.

Asunto(s)

Brioestatinas/uso terapéutico , Infarto Cerebral/terapia , Condicionamiento Físico Animal , Proteína Quinasa C/metabolismo , Animales , Western Blotting , Terapia Combinada , Activación Enzimática , Masculino , Fosforilación , Ratas Sprague-Dawley , Receptores AMPA/metabolismo