RESUMEN
Huperzia serrata (Thunb.) Trevis is widely used in traditional asiatic medicine to treat many central disorders including, schizophrenia, cognitive dysfunction, and dementia. The major alkaloid, Huperzine A (HA), of H. serrata is a well-known competitive reversible inhibitor of acetylcholinesterase (AChE) with neuroprotective effects. Inspired by the tradition, we developed a green one-step method using microwave assisted extraction to generate an extract of H. serrata, called NSP01. This green extract conserves original neuropharmacological activity and chemical profile of traditional extract. The neuroprotective activity of NSP01 is based on a precise combination of three major constituents: HA and two phenolic acids, caffeic acid (CA) and ferulic acid (FA). We show that CA and FA potentiate HA-mediated neuroprotective activity. Importantly, the combination of HA with CA and FA does not potentiate the AChE inhibitory property of HA which is responsible for its adverse side effects. Collectively, these experimental findings demonstrated that NSP01, is a very promising plant extract for the prevention of Alzheimer's disease and memory deficits.
RESUMEN
Progranulin (PGRN) is a protein with multiple functions including the regulation of neuroinflammation, neuronal survival, neurite and synapsis growth. Although the mechanisms of action of PGRN are currently unknown, its potential therapeutic application in treating neurodegenerative diseases is huge. Thus, strategies to increase PGRN levels in patients could provide an effective treatment. In the present study, we investigated the effects of AZP2006, a lysotropic molecule now in phase 2a clinical trial in Progressive Supranuclear Palsy patients, for its ability to increase PGRN level and promote neuroprotection. We showed for the first time the in vitro and in vivo neuroprotective effects of AZP2006 in neurons injured with Aß1-42 and in two different pathological animal models of Alzheimer's disease (AD) and aging. Thus, the chronic treatment with AZP2006 was shown to reduce the loss of central synapses and neurons but also to dramatically decrease the massive neuroinflammation associated with the animal pathology. A deeper investigation showed that the beneficial effects of AZP2006 were associated with PGRN production. Also, AZP2006 binds to PSAP (the cofactor of PGRN) and inhibits TLR9 receptors normally responsible for proinflammation when activated. Altogether, these results showed the high potential of AZP2006 as a new putative treatment for AD and related diseases.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Piperazinas/uso terapéutico , Envejecimiento/patología , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/toxicidad , Animales , Muerte Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/patología , Modelos Biológicos , Neuronas/efectos de los fármacos , Neuronas/patología , Fármacos Neuroprotectores/farmacología , Piperazinas/farmacología , Progranulinas/metabolismo , Multimerización de Proteína , Ratas , Saposinas/metabolismo , SolubilidadRESUMEN
Pancreatic ductal adenocarcinoma (PDA) is a critical health issue in the field of cancer, with few therapeutic options. Evidence supports an implication of the intratumoral microenvironment (stroma) on PDA progression. However, its contribution to the role of neuroplastic changes within the pathophysiology and clinical course of PDA, through tumor recurrence and neuropathic pain, remains unknown, neglecting a putative, therapeutic window. Here, we report that the intratumoral microenvironment is a mediator of PDA-associated neural remodeling (PANR), and we highlight factors such as 'SLIT2' (an axon guidance molecule), which is expressed by cancer-associated fibroblasts (CAFs), that impact on neuroplastic changes in human PDA. We showed that 'CAF-secreted SLIT2' increases neurite outgrowth from dorsal root ganglia neurons as well as from Schwann cell migration/proliferation by modulating N-cadherin/ß-catenin signaling. Importantly, SLIT2/ROBO signaling inhibition disrupts this stromal/neural connection. Finally, we revealed that SLIT2 expression and CAFs are correlated with neural remodeling within human and mouse PDA. All together, our data demonstrate the implication of CAFs, through the secretion of axon guidance molecule, in PANR. Furthermore, it provides rationale to investigate the disruption of the stromal/neural compartment connection with SLIT2/ROBO inhibitors for the treatment of pancreatic cancer recurrence and pain.
Asunto(s)
Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neuronas/patología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Animales , Axones/efectos de los fármacos , Axones/metabolismo , Cadherinas/metabolismo , Comunicación Celular/efectos de los fármacos , Compartimento Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Medios de Cultivo/farmacología , Fibroblastos/metabolismo , Fibroblastos/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Ratones Desnudos , Modelos Biológicos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neoplasias Pancreáticas/genética , Células de Schwann/efectos de los fármacos , Células de Schwann/metabolismo , Células de Schwann/patología , Transducción de Señal/efectos de los fármacos , Células del Estroma/efectos de los fármacos , Células del Estroma/metabolismo , Células del Estroma/patología , Transcriptoma/genética , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/genética , beta Catenina/metabolismo , Neoplasias PancreáticasRESUMEN
Sensory neuropathies are frequently associated with diabetes or with antimitotic treatments in humans suffering from cancer, and are in this case the most important limitation to the use of antimitotic drugs. For this reason, there is a need to establish and validate animal models of sensory neuropathies that could be routinely used, together with the already known models, for studying and evaluating the effects of putative neuroprotective compounds. In the present study, we prove by behavioral and electromyographical analyses that (a) it is possible to induce a nonlethal, exclusively sensory, reversible neuropathy by intoxicating rats with large amounts of pyridoxine, using a new schedule of intoxication; (b) 4-methylcatechol, a drug known to induce nerve growth factor synthesis, improves the clinical status of pyridoxine-intoxicated animals, shortens the duration of the disease, and restores the morphological integrity of the sensory fibers. Owing to its mode of installation and its clinical features, we propose that this model be used as an additional model for preclinical studies of neuroprotective drugs.
Asunto(s)
Catecoles/farmacología , Fármacos Neuroprotectores/farmacología , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Piridoxina/envenenamiento , Animales , Peso Corporal/efectos de los fármacos , Modelos Animales de Enfermedad , Electromiografía , Femenino , Neuronas Aferentes/patología , Umbral del Dolor/efectos de los fármacos , Enfermedades del Sistema Nervioso Periférico/patología , Equilibrio Postural/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , CaminataRESUMEN
The frissonnant (fri) mutation is an autosomic recessive mutation which spontaneously appeared in the stock of C3H mice. fri mutant mice have locomotor instability and rapid tremor. Since tremor ceases when mutant mice have sleep or are anaesthetized, and because of their obvious stereotyped motor behavior, these mice could represent an inherited Parkinsonian syndrome. We show here that the fri/fri mouse fulfills two out of the three criteria required to validate an experimental model of human disease, that is isomorphism, homology and predictivity. Indeed, fri/fri mice present an important motor deficit accompanying visible tremor and stereotypies. They display some memory deficits as in human Parkinson's desease. l-Dopa and apomorphine (dopaminergic agonists), ropinirole (selective D2 agonist), and selegiline (an monoamino-oxidase B [MAO-B] inhibitor) improve their clinical status. However, neither anatomopathological evidence of nigrostriatal lesion, nor decrease in tyrosine hydroxylase production could be seen.