RESUMO
The present manuscript stems from evidence, which indicates that specific wavelength produce an activation of the autophagy pathway in the retina. These effects were recently reported to synergize with the autophagy-inducing properties of specific phytochemicals. The combined administration of photo-modulation and phytochemicals was recently shown to have a strong potential in eliciting the recovery in the course of retinal degeneration and it was suggested as a non-invasive approach named "Lugano protocol" to treat age-related macular degeneration (AMD). Recent translational findings indicate that the protective role of autophagy may extend also to acute neuronal injuries including traumatic neuronal damage. At the same time, very recent investigations indicate that autophagy activation and retinal anatomical recovery may benefit from sound exposure. Therefore, in the present study, the anatomical rescue of a traumatic neuronal loss at macular level was investigated in a patient with idiopathic macular hole by using a combined approach of physical and chemical non-invasive treatments. In detail, light exposure was administered in combination with sound pulses to the affected retina. This treatment was supplemented by phytochemicals known to act as autophagy inducers, which were administered orally for 6 months. This combined administration of light and sound with nutraceuticals reported here as Advanced Lugano's Protocol (ALP) produced a remarkable effect in the anatomical architecture of the retina affected by the macular hole. The anatomical recovery was almost complete at roughly one year after diagnosis and beginning of treatment. The structural healing of the macular hole was concomitant with a strong improvement of visual acuity and the disappearance of metamorphopsia. The present findings are discussed in the light of a synergism shown at neuronal level between light and sound in the presence of phytochemicals to stimulate autophagy and promote proliferation and neuronal differentiation of retinal stem cells.
Assuntos
Perfurações Retinianas , Suplementos Nutricionais , Humanos , Retina , Perfurações Retinianas/cirurgia , Acuidade Visual , Vitrectomia/métodosRESUMO
The present article presents a case report and discusses the neurobiology underlying the potential neuro-repair induced by combined administration of phytochemicals in a patient undergoing photo-bio-modulation (PBM), which improves anatomical and clinical abnormalities in the course of age-related macular degeneration (AMD). After combined treatments the patient with nutraceuticals and PBM had noticeable improvement of retinal tissue with excellent vision for her age and no worsening of corneal guttae, which was present at the time of diagnosis. The present treatment was tailored, based on translational evidence, to improve the autophagy pathway, which is a key determinant in the onset and progression of AMD. In fact, treatment with specific patterns of light exposure combined with specific phytochemicals, may synergize in improving the microanatomy of the retina by restoring its neurobiology. The combination of light exposure, at selective wavelengths, with the effects produced by the intake of specific phytochemicals to treat AMD is reported here as "Lugano Protocol". Such a clinical protocol represents an "in progress" development backed up by translational research. In fact, recent evidence indicates that, specific phytochemicals, when administered in combination may promote anatomical and functional integrity within the retina. These in turn synergize with analogous effects produced by specific wavelengths, when administered at specific time intervals. The synergism between specific light and combined phytochemicals is discussed at molecular level, where recent data indicate how these treatments, when delivered according to specific patterns, may enhance autophagy in the retina. The improvement of retinal morphology and visual acuity, observed in this case report is thoroughly discussed in the light of the key role of autophagy in regulating the integrity of the retinal epithelium. Despite exciting, and consistent with translational evidence, the clinical report of a disease modifying effect during AMD owns the inherent limit of a case report, which requires wide validation in large number of patients. The potential effectiveness of "Lugano protocol" may apply to other types of retinal degenerations, where common alterations in the autophagy pathway do occur. Thus, such a therapeutic approach may extend to a common late stage of retinal trans-synaptic degeneration, where maladaptive plasticity during several types of retinal degenerative disorders eventually converge.
Assuntos
Degeneração Macular , Degeneração Retiniana , Suplementos Nutricionais , Feminino , Humanos , Degeneração Macular/terapia , Retina , Degeneração Retiniana/terapia , Acuidade VisualRESUMO
Age-related macular degeneration represents the main retinal disorder leading to irreversible blindness in people over the age of 50 in the Western World. Here we describe a case report, which suggest that specific nutraceutical compounds may exert beneficial effects on the progression of dry age-related macular degeneration (AMD), an eye disease with no approved treatment or cure. Specific antioxidants, such as lutein, resveratrol and Vaccinium Myrtillus, which are known to reduce the risk of developing AMD, when co-administered alone, were supplemented to diet of an informed patient suffering from dry AMD. The case report indicates an improvement of visual acuity and a long lasting decrease in druse volume and number. The concomitant intake of lutein, resveratrol and Vaccinium Myrtillus when administered for six months produced a marked decrease in the drusen observed at OCT at the 6-month follow-up. At this time interval, the patient experienced a noticeable improvement in visual acuity, a decrease in eye strain, more color contrast, higher visual definition. The case report indicates the potential benefit for a non-invasive treatment with improved quality of vision in dry AMD. A larger population followed over a long-term period is warranted. The support of nutraceuticals could therefore offer a new non-invasive, adverse effect-free which may restore the pathology affecting the cross talk between choroid and retinal cells. The results of this case report are discussed within the frame of molecular mechanisms synergizing site-specifically at the anatomical border between the outer retina and inner choroid.
Assuntos
Suplementos Nutricionais , Degeneração Macular , Antioxidantes/uso terapêutico , Dieta , Humanos , Degeneração Macular/terapia , Acuidade VisualRESUMO
The higher and selective cytotoxicity of [Pt(O,O'-acac)(γ-acac)(DMS)] toward cancer cell in both immortalized cell lines and in breast cancer cells in primary cultures, stimulated a pre-clinical study so as to evaluate its therapeutic potential in vivo. The efficacy of [Pt(O,O'-acac)(γ-acac)(DMS)] was assessed using a xenograft model of breast cancer developed by injection of MCF-7 cells in the flank of BALB/c nude mice. Treatment of solid tumor-bearing mice with [Pt(O,O'-acac)(γ-acac)(DMS)] induced up to 50% reduction of tumor mass compared with an average 10% inhibition recorded in cisplatin-treated animals. Thus, chemotherapy with [Pt(O,O'-acac)(γ-acac)(DMS)] was much more effective than cisplatin. We also demonstrated enhanced in vivo pharmacokinetics, biodistribution and tolerability of [Pt(O,O'-acac)(γ-acac)(DMS)] when compared with cisplatin administered in Wistar rats. Pharmacokinetics studies with [Pt(O,O'-acac)(γ-acac)(DMS)] revealed prolonged Pt persistence in systemic blood circulation and decreased nefrotoxicity and hepatotoxicity, major target sites of cisplatin toxicity. Overall, [Pt(O,O'-acac)(γ-acac)(DMS)] turned out to be extremely promising in terms of greater in vivo anticancer activity, reduced nephrotoxicity and acute toxicity compared with cisplatin.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Neoplasias da Mama/tratamento farmacológico , Compostos Organoplatínicos/administração & dosagem , Animais , Antineoplásicos/efeitos adversos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Compostos Organoplatínicos/efeitos adversos , Compostos Organoplatínicos/farmacocinética , Ratos , Ratos Wistar , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Trimethyltin (TMT) is a triorganotin compound which determines neurodegeneration of specific brain areas particularly damaging the limbic system. Earlier ultrastructural studies indicated the formation of autophagic vacuoles in neurons after TMT intoxication. However, no evaluation has been attempted to determine the role of the autophagic pathway in TMT neurotoxicity. To assess the contribution of autophagy to TMT-induced neuronal cell death, we checked the vulnerability of neuronal cultures to TMT after activation or inhibition of autophagy. Our results show that autophagy inhibitors (3-methyladenine and L-asparagine) greatly enhanced TMT neurotoxicity. Conversely, known activators of autophagy, such as lithium and rapamycin, displayed neuroprotection against this toxic compound. Due to its diverse targets, the action of lithium was complex. When lithium was administered according to a chronic treatment protocol (6 days pretreatment) it was able to rescue both hippocampal and cortical neurons from TMT (or from glutamate toxicity used as reference). This effect was accompanied by an increased phosphorylation of glycogen synthase kinase 3 which is a known target for lithium neuroprotection. If the pre-incubation time was reduced to 2 h (acute treatment protocol), lithium was still able to counteract TMT toxicity in hippocampal but not in cortical neurons. The neuroprotective effect of lithium acutely administered against TMT in hippocampal neurons can be completely reverted by an excess of inositol and is possibly related to the inactivation of inositol monophosphatase, a key regulator of autophagy. These data indicate that TMT neurotoxicity can be dramatically modified, at least in vitro, by lithium addition which seems to act through different mechanisms if acutely or chronically administered.
Assuntos
Adenina/análogos & derivados , Asparagina/farmacologia , Autofagia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Compostos de Trimetilestanho/toxicidade , Adenina/farmacologia , Adjuvantes Imunológicos/farmacologia , Aldeídos/metabolismo , Análise de Variância , Animais , Encéfalo/citologia , Contagem de Células , Células Cultivadas , Relação Dose-Resposta a Droga , Embrião de Mamíferos , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , L-Lactato Desidrogenase/metabolismo , Cloreto de Lítio/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Neurônios/ultraestrutura , Fosforilação/efeitos dos fármacos , Serina/metabolismo , Sirolimo/farmacologia , Sais de Tetrazólio , Tiazóis , Vacúolos/efeitos dos fármacos , Vacúolos/metabolismoRESUMO
Eight-month old WAG/Rij rats, which developed spontaneous occurring absence seizures, showed a reduced function of mGlu1 metabotropic glutamate receptors in the thalamus, as assessed by in vivo measurements of DHPG-stimulated polyphosphoinositide hydrolysis, in the presence of the mGlu5 antagonist MPEP as compared to age-matched non-epileptic control rats. These symptomatic 8-month old WAG/Rij rats also showed lower levels of thalamic mGlu1α receptors than age-matched controls and 2-month old (pre-symptomatic) WAG/Rij rats, as detected by immunoblotting. Immunohistochemical and in situ hybridization analysis indicated that the reduced expression of mGlu1 receptors found in symptomatic WAG/Rij rats was confined to an area of the thalamus that excluded the ventroposterolateral nucleus. No mGlu1 receptor mRNA was detected in the reticular thalamic nucleus. Pharmacological manipulation of mGlu1 receptors had a strong impact on absence seizures in WAG/Rij rats. Systemic treatment with the mGlu1 receptor enhancer SYN119, corresponding to compound RO0711401, reduced spontaneous spike and wave discharges spike-wave discharges (SWDs) in epileptic rats. Subcutaneous doses of 10 mg/kg of SYN119 only reduced the incidence of SWDs, whereas higher doses (30 mg/kg) also reduced the mean duration of SWDs. In contrast, treatment with the non-competitive mGlu1 receptor antagonist, JNJ16259685 (2.5 and 5 mg/kg, i.p.) increased the incidence of SWDs. These data suggest that absence epilepsy might be associated with a reduction of mGlu1 receptors in the thalamus, and that compounds that amplify the activity of mGlu1 receptors might be developed as novel anti-absence drugs. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.