RESUMEN
The endogenous cannabinoid system (ECS) of the brain plays an important role in the molecular pathogenesis of Parkinson's disease (PD). It is involved in the formation of numerous clinical manifestations of the disease by regulating the level of endogenous cannabinoids and changing the activation of cannabinoid receptors (CBRs). Therefore, ECS modulation with new drugs specifically designed for this purpose may be a promising strategy in the treatment of PD. However, fine regulation of the ECS is quite a complex task due to the functional diversity of CBRs in the basal ganglia and other parts of the central nervous system. In this review, the effects of ECS modulators in various experimental models of PD in vivo and in vitro, as well as in patients with PD, are analyzed. Prospects for the development of new cannabinoid drugs for the treatment of motor and non-motor symptoms in PD are presented.
Asunto(s)
Enfermedad de Parkinson , Receptores de Cannabinoides , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Humanos , Animales , Receptores de Cannabinoides/metabolismo , Endocannabinoides/metabolismo , Cannabinoides/uso terapéutico , Cannabinoides/farmacología , Cannabinoides/metabolismoRESUMEN
Astrocytes perform a wide range of important functions in the brain. As structural and functional components of synapses, astrocytes secrete various factors (proteins, lipids, small molecules, etc.) that bind to neuronal receptor and contribute to synaptogenesis and regulation of synaptic contacts. Astrocytic factors play a key role in the formation of neural networks undergoing short- and long-term synaptic morphological and functional rearrangements essential in the memory formation and behavior. The review summarizes the data on the molecular mechanisms mediating the involvement of astrocyte-secreted factors in synaptogenesis in the brain and provides up-to-date information on the role of astrocytes and astrocytic synaptogenic factors in the long-term plastic rearrangements of synaptic contacts.
Asunto(s)
Astrocitos , Plasticidad Neuronal , Astrocitos/metabolismo , Plasticidad Neuronal/fisiología , Sinapsis/metabolismo , Encéfalo/fisiología , NeurogénesisRESUMEN
The review summarizes the results of studies on the cellular and molecular mechanisms mediating the impact of stress on the pathogenesis of neurodegenerative brain pathologies (Alzheimer's disease, Parkinson's disease, etc.) and presents current information on the role of stress in the hyperphosphorylation of tau protein, aggregation of beta-amyloid, and hyperactivation of the hypothalamic-pituitary-adrenal axis involved in the hyperproduction of factors that contribute to the pathogenetic role of stress in neurodegeneration. The data on the participation of microglia in the effects of stress on the pathogenesis of neurodegenerative diseases are presented.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Estrés Psicológico , Proteínas tau/metabolismo , Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Animales , Demencia/etiología , Demencia/metabolismo , Demencia/fisiopatología , Humanos , Enfermedades Neurodegenerativas/etiología , Enfermedades Neurodegenerativas/fisiopatología , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/fisiopatología , Fosforilación , Agregación Patológica de Proteínas , Procesamiento Proteico-PostraduccionalRESUMEN
Copper (Cu2+) is an essential metal presented in the mammalian brain and released from synaptic vesicles following neuronal depolarization. However, the disturbance of Cu2+ homeostasis results in neurotoxicity. In our study we performed for the first time a combined functional investigation of cultured hippocampal neurons under Cu2+ exposure, its effect on spontaneous spike activity of hippocampal neuronal network cultured on multielectrode array (MEA), and development of long-term potentiation (LTP) in acute hippocampal slices in the presence of Cu2+. Application of 0.2mM CuCl2 for 24h reduced viability of cultured neurons to 40±6%, whereas 0.01mM CuCl2 did not influence significantly on the neuronal survival. However, exposure to the action of 0.01mM Cu2+ resulted in pronounced reduction of network spike activity and abolished LTP induced by high-frequency stimulation of Schaffer's collaterals in CA1 pyramidal neurons of hippocampal slices. Antioxidant Trolox, the hydrosoluble vitamin E analogue, prevented neurotoxic effect and alterations of network activity under Cu2+ exposure, but didn't change the impairment of LTP in Cu2+-exposured hippocampal slices. We hypothesized that spontaneous network neuronal activity probably is one of the potential targets of Cu2+-induced neurotoxicity, in which free radicals can be involved. At the same time, it may be suggested that Cu2+-induced alterations of long-lasting trace processes (like LTP) are not mediated by oxidative damage.
Asunto(s)
Cobre/toxicidad , Neuronas/efectos de los fármacos , Animales , Supervivencia Celular/efectos de los fármacos , Hipocampo/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Ratones , Transmisión Sináptica/efectos de los fármacosRESUMEN
A protective behavioral effect of a nerve growth factor dipeptide mimetic GK-2 in the model of open focal trauma of rat brain sensorimotor cortex and its antioxidative and regenerative properties in cultures of rat cerebellar granule cells and mouse embryonal spinal ganglion, respectively, were studied. Intraperitoneal injections of GK-2 (1 mg/kg) for 5 days daily after traumatic brain injury improved significantly motor function of limbs. Moreover, supplementation the incubation medium with GK-2 (0.5-1.5 mg/l) decreased neuronal death induced by H2O2 in cerebellar granule cell cultures and stimulated neurite outgrowth from cultured mouse embryonal spinal ganglia. Our results suggest that GK-2 exhibits pronounced positive behavioral effect in vivo as well as neuroprotective and regenerative effects in vitro, and that these neuroprotective properties probably associated with cell survival but not with cell differentiation pathway.
Asunto(s)
Lesiones Encefálicas/tratamiento farmacológico , Dipéptidos/uso terapéutico , Actividad Motora/efectos de los fármacos , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Análisis de Varianza , Animales , Animales Recién Nacidos , Lesiones Encefálicas/complicaciones , Recuento de Células , Células Cultivadas , Cerebelo/citología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ganglios Espinales/efectos de los fármacos , Masculino , Ratones , Factor de Crecimiento Nervioso/farmacología , Enfermedades del Sistema Nervioso/etiología , Neuronas/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
N-Acyldopamines were recently described as putative endogenous substances in the rat brain. Among them, N-arachidonoyldopamine (AADA) was characterized as cannabinoid CB1 and vanilloid TRPV1 receptor ligand. The physiological significance of such compounds is yet poorly understood. In this study, we describe the novel properties of AADA as antioxidant and neuroprotectant. Antioxidant potential of AADA and its analogs were first tested in the galvinoxyl assay. It was found that N-acyldopamines are potent antioxidants and that the number of free hydroxyl groups in the phenolic moiety of dopamine is essential for the activity. AADA dose dependently (0.1-10 microM) protected cultured cerebellar granule neurons (CGN) in the model of oxidative stress induced by hydrogen peroxide. N-Oleoyldopamine, another endogenous substance, was much less potent in these conditions while the natural antioxidant alpha-tocopherol was inactive. In this test, AADA decreased the peroxide level in CGN preparations and its neuroprotection was independent of cannabinoid/vanilloid receptors blockade. AADA (10 microM) also protected CGN from death induced by K(+)/serum deprivation and glutamate exitotoxicity. These data indicate that AADA may act as endogenous antioxidant in different pathological conditions.
Asunto(s)
Antioxidantes/farmacología , Ácidos Araquidónicos/farmacología , Encéfalo/efectos de los fármacos , Citoprotección/efectos de los fármacos , Dopamina/análogos & derivados , Fármacos Neuroprotectores/farmacología , Animales , Animales Recién Nacidos , Antioxidantes/química , Antioxidantes/metabolismo , Ácidos Araquidónicos/química , Ácidos Araquidónicos/metabolismo , Bioensayo , Encéfalo/metabolismo , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Células Cultivadas , Medio de Cultivo Libre de Suero/farmacología , Citoprotección/fisiología , Dopamina/química , Dopamina/metabolismo , Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/farmacología , Ácido Glutámico/toxicidad , Estructura Molecular , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/metabolismo , Peróxidos/metabolismo , Ratas , Ratas WistarRESUMEN
Dyrk1A, a mammalian homolog of the Drosophila minibrain gene, encodes a dual-specificity kinase, involved in neuronal development and in adult brain physiology. In humans, a third copy of DYRK1A is present in Down syndrome (trisomy 21) and has been implicated in the etiology of mental retardation. To further understand this pathology, we searched for Dyrk1A-interacting proteins and identified Arip4 (androgen receptor-interacting protein 4), a SNF2-like steroid hormone receptor cofactor. Mouse hippocampal and cerebellar neurons coexpress Dyrk1A and Arip4. In HEK293 cells and hippocampal neurons, both proteins are colocalized in a speckle-like nuclear subcompartment. The functional interaction of Dyrk1A with Arip4 was analyzed in a series of transactivation assays. Either Dyrk1A or Arip4 alone displays an activating effect on androgen receptor- and glucocorticoid receptor-mediated transactivation, and Dyrk1A and Arip4 together act synergistically. These effects are independent of the kinase activity of Dyrk1A. Inhibition of endogenous Dyrk1A and Arip4 expression by RNA interference showed that both proteins are necessary for the efficient activation of androgen receptor- and glucocorticoid receptor-dependent transcription. As Dyrk1A is an activator of steroid hormone-regulated transcription, the overexpression of DYRK1A in persons with Down syndrome may cause rather broad changes in the homeostasis of steroid hormone-controlled cellular events.
Asunto(s)
Adenosina Trifosfatasas/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Activación Transcripcional , Adenosina Trifosfatasas/metabolismo , Animales , Línea Celular , Cerebelo/citología , ADN Helicasas , Sinergismo Farmacológico , Hipocampo/citología , Humanos , Ratones , Neuronas/química , Neuronas/ultraestructura , Proteínas Nucleares/metabolismo , Proteínas Nucleares/fisiología , Unión Proteica , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Tirosina Quinasas , ARN Interferente Pequeño/farmacología , Esteroides/farmacología , Quinasas DyrKRESUMEN
Cannabinoid type 1 (CB1) receptors play a central role in the protection against excitotoxicity induced by treatment of mice with kainic acid (KA). As inactivation of CB1 receptor function in mice blocks KA-induced increase of brain-derived neurotrophic factor (BDNF) mRNA levels in hippocampus, the notion was put forward that BDNF might be a mediator, at least in part, of CB1 receptor-dependent neuroprotection [Marsicano et al. (2003) Science, 302, 84-88]. To assess this signalling cascade in more detail, organotypic hippocampal slice cultures were used, as this in vitro system conserves morphological and functional properties of the hippocampus. Here, we show that both genetic ablation of CB1 receptors and pharmacological blockade with the specific CB1 receptor antagonist SR141716A increased the susceptibility of the in vitro cultures to KA-induced excitotoxicity, leading to extensive neuronal death. Next, we found that the application of SR141716A to hippocampal cultures from wild-type mice abolished the KA-induced increase in BDNF protein levels. Therefore, we tried to rescue these organotypic cultures from neuronal death by exogenously applied BDNF. Indeed, BDNF was sufficient to prevent KA-induced neuronal death after blockade of CB1 receptor signalling. In conclusion, our results strongly suggest that BDNF is a key mediator in CB1 receptor-dependent protection against excitotoxicity, and further underline the physiological importance of the endogenous cannabinoid system in neuroprotection.