The antibiotic doxycycline mimics the NGF signaling in PC12 cells: A relevant mechanism for neuroprotection.

Doxycycline has been used as antibiotic since the 1960s. Recently, studies have shown that doxycycline is neuroprotective in models of neurodegenerative diseases and brain injuries, mainly due to anti-inflammatory and anti-apoptotic effects. However, it is not known if doxycycline has neurotrophic potential, which is relevant, considering the role of axonal degeneration at the early stages of neurodegeneration in Alzheimer's disease, Amyotrophic Lateral Sclerosis and Parkinson's disease as well as in normal aging. Axons are preceded by the formation of neurites, the hallmark of the neuronal differentiation induced by neurotrophins like NGF. Therefore, the modulation of neurotrophin receptors aimed at formation and regeneration of axons has been proposed as a strategy to delay the progression of neurodegeneration and has gained relevance as new techniques for early diagnosis arise. Based on these premises, we investigated the potential of doxycycline to mimic the effects of Nerve Growth Factor (NGF) with focus on the signaling pathways and neuronal modulators of neurite initiation, growth and branching. We used PC12 cells, a neuronal model widely employed to study the neurotrophic pathways and mechanisms induced by NGF. Results showed that doxycycline induced neurite outgrowth via activation of the trkA receptor and the downstream signaling pathways, PI3K/Akt and MAPK/ERK, without inducing the expression of NGF. Doxycycline also increased the expression of GAP-43, synapsin I and NF200, proteins involved in axonal and synaptic plasticity. Altogether, these data demonstrate, for the first time, the neurotrophic potential of doxycycline, which might be useful to restore the neuronal connectivity lost at the initial phase of neurodegeneration.

Overview of cisplatin-induced neurotoxicity and ototoxicity, and the protective agents.

Cisplatin has dramatically improved the survival rate of cancer patients, but it has also increased the prevalence of hearing and neurological deficits in this population. Cisplatin induces ototoxicity, peripheral (most prevalent) and central (rare) neurotoxicity. This review addresses the ototoxicity and the neurotoxicity associated with cisplatin-based chemotherapy, providing an integrated view of the potential protective agents that have been evaluated in vitro, in vivo and in clinical trials, their targets and mechanisms of protection and their effects on the antitumor activity of cisplatin. So far, the findings are insufficient to support the use of any oto- or neuroprotective agent before, during or after cisplatin chemotherapy. Despite their promising effects in vitro and in animal studies, many agents have not been evaluated in clinical trials. Additionally, the clinical trials have limitations concerning the sample size, controls, measurement, heterogeneous groups, several arms of treatment, short follow-up or no blinding. Besides that, for most agents, the effects on the antitumor activity of cisplatin have not been evaluated in tumor-bearing animals, which discourages clinical trials. Further well-designed randomized controlled clinical trials are necessary to definitely demonstrate the effectiveness of the oto- or neuroprotective agents proposed by animal and in vitro studies.

L- and T-type calcium channel blockers protect against the inhibitory effects of mipafox on neurite outgrowth and plasticity-related proteins in SH-SY5Y cells.

Some organophosphorus compounds (OP), including the pesticide mipafox, produce late onset distal axonal degeneration, known as organophosphorus-induced delayed neuropathy (OPIDN). The underlying mechanism involves irreversible inhibition of neuropathy target esterase (NTE) activity, elevated intracellular calcium levels, increased activity of calcium-activated proteases and impaired neuritogenesis. Voltage-gated calcium channels (VGCC) appear to play a role in several neurologic disorders, including OPIDN. Therefore, this study aimed to examine and compare the neuroprotective effects of T-type (amiloride) and L-type (nimodipine) VGCC blockers induced by the inhibitory actions of mipafox on neurite outgrowth and axonal proteins of retinoic-acid-stimulated SH-SY5Y human neuroblastoma cells, a neuronal model widely employed to determine the neurotoxicity attributed to OP. Both nimodipine and amiloride significantly blocked augmentation of intracellular calcium levels and activity of calpains, as well as decreased neurite length, number of differentiated cells, and lowered concentrations of growth-associated protein 43 (GAP-43) and synapsin induced by mipafox. Only nimodipine inhibited reduction of synaptophysin levels produced by mipafox. These findings demonstrate a role for calcium and VGCC in the impairment of neuronal plasticity mediated by mipafox. Data also demonstrated the neuroprotective potential of T-type and L-type VGCC blockers to inhibit OP-mediated actions, which may be beneficial to counteract cases of pesticide poisoning.

High concentration of trichlorfon (1mM) disrupts axonal cytoskeleton and decreases the expression of plasticity-related proteins in SH-SY5Y cells.

Some organophosphorus compounds (OPs) induce a neurodegenerative disorder known as organophosphate-induced delayed neuropathy (OPIDN), which is related to irreversible inhibition of neuropathy target esterase (NTE) and impairment of neurite outgrowth. The present study addresses the effects of trichlorfon, mipafox (neuropathic model) and paraoxon (non-neuropathic model) on neurite outgrowth and neuroplasticity-related proteins in retinoic-acid-stimulated SH-SY5Y cells, a cellular model widely used to study the neurotoxicity of OPs. Mipafox (20µM) decreased cellular differentiation and the expression of neurofilament 200 (NF-200), growth associated- (GAP-43) and synaptic proteins (synapsin I and synaptophysin); whereas paraoxon (300µM) induced no effect on cellular differentiation, but significant decrease of NF-200, GAP-43, synapsin I and synaptophysin as compared to controls. However, the effects of paraoxon on these proteins were significantly lower than the effects of mipafox. In conclusion, axonal cytoskeletal proteins, as well as axonal plasticity-related proteins are more effectively affected by neuropathic (mipafox) than by non-neuropathic (paraoxon) OPs, suggesting that they might play a role in the mechanism of OPIDN. At high concentration (1mM), trichlorfon induced effects similar to those of the neuropathic OP, mipafox (20µM), but also caused high inhibition of AChE. Therefore, these effects are unlikely to occur in humans at non-lethal doses of trichlorfon.

Effect of diabetes on biodistribution, nephrotoxicity and antitumor activity of cisplatin in mice.

Both types of diabetes are associated with higher incidence of some types of cancer. Treating cancer in diabetic patients without aggravating diabetes-related complications is a challenge for clinicians. Additionally, little is known about how diabetes affects the treatment of cancer. One of the most effective chemotherapeutic drugs is cisplatin, which is nephrotoxic. Studies suggest that diabetes acts as a protective factor against the nephrotoxicity of cisplatin, but the mechanisms involved have not been elucidated yet. This renal protection has been attributed to decreased accumulation of cisplatin in the kidneys, which could be associated with deficient active transport of proximal tubular cells or to pharmacokinetic alterations caused by diabetes. However, it is uncertain if diabetes also compromises the antitumor activity of cisplatin. To address this issue, we developed a mouse model bearing cisplatin-induced nephrotoxicity, Sarcoma 180 and streptozotocin-induced diabetes. Four groups of treatment were defined: (i) control, (ii) diabetic, (iii) cisplatin and (iv) diabetic treated with cisplatin. The following parameters were evaluated: renal function, oxidative stress, apoptosis, renal histopathology, tumor remission, survival rate, genotoxicity and platinum concentration in tumor and several organs. Results indicate that diabetes protects against the renal damage induced by cisplatin, while also compromises its antitumor effectiveness. This is the first study to demonstrate this effect.

Coenzyme Q10 and its effects in the treatment of neurodegenerative diseases: [review] / A coenzima Q10 e seus efeitos no tratamento de doenças neurodegenerativas: [revisão]

According to clinical and pre-clinical studies, oxidative stress and its consequences may be the cause or, at least, a contributing factor, to a large number of neurodegenerative diseases. These diseases include common and debilitating disorders, characterized by progressive and irreversible loss of neurons in specific regions of the brain. The most common neurodegenerative diseases are Parkinson's disease, Huntington's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Coenzyme Q10 (CoQ10) has been extensively studied since its discovery in 1957. It is a component of the electron transportation chain and participates in aerobic cellular respiration, generating energy in the form of adenosine triphosphate (ATP). The property of CoQ10 to act as an antioxidant or a pro-oxidant, suggests that it also plays an important role in the modulation of redox cellular status under physiological and pathological conditions, also performing a role in the ageing process. In several animal models of neurodegenerative diseases, CoQ10 has shown beneficial effects in reducing disease progression. However, further studies are needed to assess the outcome and effectiveness of CoQ10 before exposing patients to unnecessary health risks at significant costs.

De acordo com estudos clínicos e pré-clínicos, o estresse oxidativo e suas conseqüências podem ser a causa, ou, no mínimo, o fator que contribui para grande número de doenças degenerativas. Estas doenças incluem problemas comuns e debilitantes, caracterizados por perda progressiva e irreversível de neurônios em regiões específicas do cérebro. As doenças degenerativas mais comuns são doença de Parkinson, de Hutington, de Alzheimer e esclerose amiotrófica lateral. A Coenzima Q10 (CoQ10) tem sido intensamente estudada desde sua descoberta, em 1957. É um componente da cadeia de transporte eletrônico e participa da respiração aeróbica celular, gerando energia na forma de trifosfato de adenosina (ATP). A propriedade da CoQ10 de atuar como antioxidante ou pró-oxidante sugere papel importante na modulação do estado redox celular sob condições fisiológicas e patológicas, desempenhando, também, papel no processo de envelhecimento. Em vários modelos animais de doenças neurodegenerativas, a CoQ10 mostrou efeitos benéficos na redução do curso da doença. Entretanto, há necessidade de estudos adicionais para avaliar o efeito e a eficácia da CoQ10 antes de expor os pacientes a riscos de saúde desnecessários e de alto custo.

Effects of H(2)-receptor antagonists on dapsone-induced methaemoglobinaemia in rats.

Dapsone (DDS) (4,4'diaminodiphenylsulfone), the drug of choice for the treatment of leprosy, frequently induces haemolytic anaemia and methaemoglobinaemia. N-hydroxylation, one of the major pathways of biotransformation, has been constantly related to the methaemoglobinaemia observed with the use of the drug. In order to determine the reversible inhibition of this toxicologic bioactivation pathway without changing the detoxification pathways of the drug or cytosolic acetylation, cimetidine (CIM), ranitidine and famotidine were administered in combination with DDS to male Wistar rats weighing 200-220 g. The animals were divided into nine groups of eight: group 1 received a single dose of 40 mg kg (-1) DDS in dimethylsulfoxide (DMSO) and groups 2-4 received the same treatment as group 1 but after the administration of a single dose of 100, 150 and 200 mg kg (-1) CIM, respectively, injected 2 h prior DDS administration. Groups 5-9 received the same treatment as group 2 but after the treatment of ranitidine (50 and 100 mg kg (-1) intraperitoneally (i.p.) in 200 microl DMSO) and famotidine (10, 50 and 100 mg kg (-1) i.p. in 200 microl DMSO), respectively. The animals were then anaesthetized with ether and blood was collected from the aorta for the determination of plasma DDS and monoacetyldapsone concentrations by HPLC and later for the determination of methaemoglobinaemia by spectrophotometry. CIM showed a higher affinity for cytochrome P-450 than famotidine and ranitidine. The results obtained showed the potentiality of the pharmacological effects of DDS with a low risk of adverse reactions, especially methaemoglobinaemia, which is dose dependent.

Efeito hemoprotetor da cimetidina na metemoglobinemia induzida pela dapsona em regime de dose única em ratos / Hemoprotective effect of cimetidine single dosis schedule on dapsone induced methemoglobinemia in rats

A dapsona (4,4-diaminodifenilsulfona), quimioterápico bacteriostático utilizado no tratamento da hanseníase, vem sendo associada a intercorrências clínicas, principalmente devido à sua hemotoxicidade caracterizada por metemoglobinemia e anemia hemolítica. A N-hidroxilação, uma das principais vias de biotransformação da dapsona, vem sendo associada constantemente a quadros de metemoglobinemia decorrentes de sua utilização. Com o objetivo de verificar-se a inibição reversível da via de bioativação toxicológica, sem alterar as vias de destoxificação do composto, a acetilação citosólica, a cimetidina foi administrada concomitantemente à dapsona em ratos machos Wistar, com peso variando entre 200 e 220 g, divididos em 8 grupos (n=6 por grupo), em estudo de dose única...

Efeitos renais crônicas em trabalhadores expostos ao chumbo e suas relaçöes com a pressäo arterial / The chronic renal effects in workers occupationally exposed to lead and its correlation with arterial pressure

Determinaram-se as atividades de duas enzimas de membrana: alanina-aminopeptidase (AAP), -glutamil-transpeptidase e da enzima lisossomal N-acetil-B-D-glucosaminidase, os níveis de proteína total, albumina e ácido delta-aminolevulínico em urinas de indivíduos expostos ocupacionalmente ao chumbo e de indivíduos näo expostos. Todos os indivíduos apresentavam creatinina sérica inferior a 1,5 mg/dl. Foram determinados os níveis sangüíneos de chumbo e aferidas pressäo arterial diastólica e pressäo arterial sistólica. Objetivou-se investigar a toxicidade renal crônica do chumbo e sua possível correlaçäo com a pressäo arterial em indivíduos com funçäo renal normal. A pressäo arterial diastóeca foi maior no grupo exposto. Observaram-se correlaçöes das pressöes com tempo de exposiçäo e com chumbo no sangue

Quantificacao da carbamazepina e carbamazepina-10,11-epoxoxido em plasma por cromatografia liquida de alta eficiencia com finalidade de controle terapeutico / Quantification of carbamazepine and carbamazepine-10,11-epoxide by high performance liquid chromatography for therapeutic control

Foi desenvolvido um metodo empregando a cromatografia liquida de alta eficiencia para a quantificacao de carbamazepina e carbamazepina-10,11-epoxido em plasma com finalidade de controle terapeutico. Os farmacos foram extraidos com diclorometano, em meio alcalino,e cromatografados em coluna de fase reversa (C-18), usando acetonitrila: agua (1:1) como fase movel e deteccao em 220 nm. O metodo mostrou-se preciso com coeficientes de variacao para analise intra-ensaio de 2,8 e 3,8%, para a carbamazepina e seu epoxido, respectivamente. A precisao inter-ensaios foi de 4,4 e 4,7%. O metodo mostrou-se adequado para a analise da carbamazepina em plasma de pacientes sob mono ou politerapia