Studies to Assess the Utility of Serum Neurofilament Light Chain as a Biomarker in Chemotherapy-Induced Peripheral Neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common and disabling dose-limiting toxicities of chemotherapy. We report here the results of two separate non-interventional studies (49 patients), which evaluated blood neurofilament light chain (NfL) as a biomarker of CIPN in breast cancer patients treated with paclitaxel. All patients underwent a standard treatment protocol that was established independently of the present studies. NfL was measured in serum using an ultrasensitive single-molecule array and compared with the self-administered European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-CIPN twenty-item scale (CIPN20) and Total Neuropathy Score clinical version (TNSc), a clinician-reported measure of neuropathy progression. The TNSc increased with cumulative dose compared with baseline, and the NfL concentrations were also strongly associated with the cumulative dose of chemotherapy. The analysis showed a correlation between TNSc and NfL. Both TNSc and NfL showed weak to moderate associations with CIPN20 subscores, with a better association for the CIPN20 sensory compared with motor and autonomic subscores. Data from the two studies provide evidence that serum NfL has the potential to be used as a biomarker to monitor and mitigate CIPN. However, studies with additional patients planned in the ongoing clinical trial will determine the universal application of NfL as a biomarker in CIPN

Small molecule SARM1 inhibitors recapitulate the SARM1 -/- phenotype and allow recovery of a metastable pool of axons fated to degenerate

Axonal degeneration is responsible for disease progression and accumulation of disability in many neurodegenerative conditions. The axonal degenerative process can generate a metastable pool of damaged axons that remain structurally and functionally viable but fated to degenerate in the absence of external intervention. SARM1, an NADase that depletes axonal energy stores upon activation, is the central driver of an evolutionarily conserved program of axonal degeneration. We identify a potent and selective small molecule isoquinoline inhibitor of SARM1 NADase that recapitulates the SARM

Methamphetamine Preconditioning Alters Midbrain Transcriptional Responses to Methamphetamine-Induced Injury in the Rat Striatum

Methamphetamine (METH) is an illicit drug which is neurotoxic to the mammalian brain. Numerous studies have revealed significant decreases in dopamine and serotonin levels in the brains of animals exposed to moderate-to-large METH doses given within short intervals of time. In contrast, repeated injections of small nontoxic doses of the drug followed by a challenge with toxic METH doses afford significant protection against monoamine depletion. The present study was undertaken to test the possibility that repeated injections of the drug might be accompanied by transcriptional changes involved in rendering the nigrostriatal dopaminergic system refractory to METH toxicity. Our results confirm that METH preconditioning can provide significant protection against METH-induced striatal dopamine depletion. In addition, the presence and absence of METH preconditioning were associated with substantial differences in the identity of the genes whose expression was affected by a toxic METH challenge. Quantitative PCR confirmed METH-induced changes in genes of interest and identified additional genes that were differentially impacted by the toxic METH challenge in the presence of METH preconditioning. These genes include small heat shock 27 kD 27 protein 2 (HspB2), thyrotropin-releasing hormone (TRH), brain derived neurotrophic factor (BDNF), c-fos, and some encoding antioxidant proteins including CuZn superoxide dismutase (CuZnSOD), glutathione peroxidase (GPx)-1, and heme oxygenase-1 (Hmox-1). These observations are consistent, in part, with the transcriptional alterations reported in models of lethal ischemic injuries which are preceded by ischemic or pharmacological preconditioning. Our findings suggest that multiple molecular pathways might work in tandem to protect the nigrostriatal dopaminergic pathway against the deleterious effects of the toxic psychostimulant. Further analysis of the molecular and cellular pathways regulated by these genes should help to provide some insight into the neuroadaptive potentials of the brain when repeatedly exposed to drugs of abuse

Studies to Assess the Utility of Serum Neurofilament Light Chain as a Biomarker in Chemotherapy-Induced Peripheral Neuropathy

: Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common and disabling dose-limiting toxicities of chemotherapy. We report here the results of two separate non-interventional studies (49 patients), which evaluated blood neurofilament light chain (NfL) as a biomarker of CIPN in breast cancer patients treated with paclitaxel. All patients underwent a standard treatment protocol that was established independently of the present studies. NfL was measured in serum using an ultrasensitive single-molecule array and compared with the self-administered European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-CIPN twenty-item scale (CIPN20) and Total Neuropathy Score clinical version (TNSc), a clinician-reported measure of neuropathy progression. The TNSc increased with cumulative dose compared with baseline, and the NfL concentrations were also strongly associated with the cumulative dose of chemotherapy. The analysis showed a correlation between TNSc and NfL. Both TNSc and NfL showed weak to moderate associations with CIPN20 subscores, with a better association for the CIPN20 sensory compared with motor and autonomic subscores. Data from the two studies provide evidence that serum NfL has the potential to be used as a biomarker to monitor and mitigate CIPN. However, studies with additional patients planned in the ongoing clinical trial will determine the universal application of NfL as a biomarker in CIPN

Therapeutic efficacy of sonic hedgehog protein in experimental diabetic neuropathy

Orientadora : Drª Lucélia DonattiTese (doutorado) - Universidade Federal do Paraná, Setor de Ciências Biológicas, Programa de Pós-Graduação em Biologia Celular e Molecular. Defesa: Curitiba, 31/07/2014Inclui referências : f. 71-83Resumo: Os peixes que habitam o Oceano Antártico são extremamente adaptados ao frio, sendo seu metabolismo, bioquímico e fisiológico, eficiente em baixas temperaturas. Oscilações sazonais de luminosidade e do suprimento alimentar são também apontados como fatores determinantes da biodiversidade e limitantes da biomassa e da produtividade primária do Oceano Antártico. A tolerância a temperaturas mais altas dos organismos marinhos antárticos tem sido estudada devido à preocupação dos pesquisadores frente ao aquecimento global e da Península Antártica. Os poucos resultados existentes têm demonstrado que esses organismos são extremamente estenotérmicos e que alterações de temperatura podem ser letais. O sistema antioxidante representa um importante marcador de resposta dos organismos submetidos a situações de estresse e alterações de temperatura podem promover a geração de espécies reativas de oxigênio ocasionando danos celulares. Atualmente, a extrema estenotermia dos organismos marinhos antárticos também tem sido estudada através da expressão das proteínas do choque térmico (HSPs). Dentre a família das HSPs, a HSP70 apresenta síntese rápida e significativa diante de diferentes estressores, por isso é uma ferramenta útil para quantificar e prever níveis de estresse em organismos. As coletas e os bioensaios deste trabalho, foram realizados na Baía do Almirantado, Ilha Rei George, no Arquipélago das Shetlands do Sul, Península Antártica, onde se localiza a Estação Antártica Comandante Ferraz (EACF). O presente trabalho tem como objetivo investigar variações nos níveis de HSP70, nos níveis de atividade de várias enzimas antioxidantes (SOD, CAT, GPx, GR e GST) e nos níveis dos marcadores não enzimáticos (GSH, PC e LPO) do estresse oxidativo nos peixes antárticos, Notothenia rossii e Nottohenia coriiceps em condições naturais e de estresse térmico. Para tanto, três capítulos compõem este trabalho, onde o primeiro analisa o efeito da temperatura no metabolismo oxidativo de N. rossii e N. coriiceps; o segundo avalia os níveis de expressão de HSP70 no fígado de N. rossii e N. coriiceps submetidos a estresse térmico e o terceiro analisa ao longo do ano os níveis de atividades dos marcadores de estresse oxidativo em diferentes órgãos de N. rossii e N. coriiceps da Baia do Almirantado, Ilha Rei George, Península Antártica. Palavras-chaves: temperatura, sazonalidade, estresse oxidativo, peixes antárticos, proteína do choque térmico.Abstract: The fish that inhabit the Southern Ocean are highly adapted to the cold, and its metabolism, biochemical and physiological, efficient at low temperatures. Seasonal fluctuations of light and food supply are determinants of biodiversity and limiting biomass and primary productivity of the Southern Ocean. The tolerance to higher temperatures of Antarctic marine organisms have studied due to the concern of researchers against global warming and the Antarctic Peninsula. The few results have demonstrated that these organisms are extremely stenothermal and rapid temperature change can be lethal. The antioxidant system is an important response marker of organisms subjected to stress and temperature changes situations can promote the generation of reactive oxygen species causing cell damage. Currently, the extreme stenothermal of Antarctic marine organisms has studied through the expression of heat shock proteins (HSPs). Among the family of HSPs, the HSP70 has significant and rapid synthesis on different stressors, so it is a useful tool to quantify and predict stress levels in organisms. The experiments of were performed in Admiralty Bay, King George Island, in the Archipelago of the South Shetlands, Antarctic Peninsula, where is the Comandante Ferraz Antarctic Station (EACF). This study aims to investigate variations in the levels of HSP70 in the activity levels of several antioxidant enzymes (SOD, CAT, GPx, GR and GST) and the levels of non-enzymatic markers (GSH, PC and LPO) oxidative stress in Antarctic fish, Notothenia rossii and Nottohenia coriiceps in natural and heat stress conditions. Therefore, three chapters make this work, where the first examines the effect of temperature on the oxidative metabolism of N. rossii and N. coriiceps; the second evaluates the HSP70 expression levels in liver N. rossii and N. coriiceps submited to thermal stress and the third analyzes throughout the year, the activity levels of oxidative stress markers in different tissues of N. rossii and N. coriiceps of Admiralty Bay, King George Island, Antarctic Peninsula. Keywords: temperature, seasonality, oxidative stress, Antarctic fish, heat shock proteins

Therapeutic efficacy of sonic hedgehog protein in experimental diabetic neuropathy

Hedgehog proteins modulate development and patterning of the embryonic nervous system. As expression of desert hedgehog and the hedgehog receptor, patched-1, persist in the postnatal and adult peripheral nerves, the hedgehog pathway may have a role in maturation and maintenance of the peripheral nervous system in normal and disease states. We measured desert hedgehog expression in the peripheral nerve of maturing diabetic rats and found that diabetes caused a significant reduction in desert hedgehog mRNA. Treating diabetic rats with a sonic hedgehog–IgG fusion protein fully restored motor- and sensory-nerve conduction velocities and maintained the axonal caliber of large myelinated fibers. Diabetes-induced deficits in retrograde transport of nerve growth factor and sciatic-nerve levels of calcitonin gene–related product and neuropeptide Y were also ameliorated by treatment with the sonic hedgehog–IgG fusion protein, as was thermal hypoalgesia in the paw. These studies implicate disruption of normal hedgehog function in the etiology of diabetes-induced peripheral-nerve dysfunction and indicate that delivery of exogenous hedgehog proteins may have therapeutic potential for the treatment of diabetic neuropathy