ABSTRACT
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.
Subject(s)
Astrocytes , Neuronal Plasticity , Astrocytes/metabolism , Neuronal Plasticity/physiology , Synapses/metabolism , Brain/physiology , NeurogenesisABSTRACT
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.
Subject(s)
Amyloid beta-Peptides/metabolism , Neurodegenerative Diseases/metabolism , Stress, Psychological , tau Proteins/metabolism , Alzheimer Disease/etiology , Alzheimer Disease/metabolism , Alzheimer Disease/physiopathology , Animals , Dementia/etiology , Dementia/metabolism , Dementia/physiopathology , Humans , Neurodegenerative Diseases/etiology , Neurodegenerative Diseases/physiopathology , Parkinson Disease/etiology , Parkinson Disease/metabolism , Parkinson Disease/physiopathology , Phosphorylation , Protein Aggregation, Pathological , Protein Processing, Post-TranslationalABSTRACT
The prominent protective effects in diverse neuron injury paradigms exerted by cannabinoids and in particular their endogenously produced species render the endocannabinoid system a promising molecular target in the treatment of neurodegenerative diseases. However, the effects of individual endocannabinoids in human cells remain poorly investigated. Neural derivatives of human induced pluripotent stem cells (iPSC) offer unique opportunities for studying the neuroprotective compounds and development of patient-specific treatment. For the first time the cytotoxic and neuroprotective effects endocannabinoids N-arachidonoyl dopamine (N-ADA) and N-docosahexaenoyl dopamine (N-DDA) were assessed in human neural progenitors and dopamine neurons derived from iPSCs of healthy donors and patients with Parkinson's disease. While the short-term treatment with the investigated compounds in 0.1-10 µM concentration range exerted no toxicity in these cell types, the long-term exposure to 0.1-5 µM N-ADA or N-DDA reduced the survival of human neural progenitors. At the same time, both N-ADA and N-DDA protected neural progenitors and terminally differentiated neurons both from healthy donors and patients with Parkinson's disease against oxidative stress induced by hydrogen peroxide. The observed dramatic difference in the mode of action of N-acyl dopamines points on the possible existence of novel pathogenic mechanism of neurodegeneration induced by prolonged uncompensated production of these substances within neuronal tissue and should also be considered as a precaution in the future development of N-acyl dopamine-based therapeutic drugs.
Subject(s)
Arachidonic Acids/pharmacology , Dopamine/analogs & derivatives , Endocannabinoids/pharmacology , Induced Pluripotent Stem Cells/drug effects , Neuroprotective Agents/pharmacology , Parkinson Disease/metabolism , Arachidonic Acids/toxicity , Cell Death/drug effects , Cell Line , Dopamine/pharmacology , Dopamine/toxicity , Endocannabinoids/toxicity , Fluorescent Antibody Technique , Humans , Neurons/drug effects , Oxidative Stress/drug effectsABSTRACT
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.
Subject(s)
Copper/toxicity , Neurons/drug effects , Animals , Cell Survival/drug effects , Hippocampus/drug effects , Long-Term Potentiation/drug effects , Mice , Synaptic Transmission/drug effectsABSTRACT
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.
Subject(s)
Brain Injuries/drug therapy , Dipeptides/therapeutic use , Motor Activity/drug effects , Nervous System Diseases/drug therapy , Neuroprotective Agents/therapeutic use , Analysis of Variance , Animals , Animals, Newborn , Brain Injuries/complications , Cell Count , Cells, Cultured , Cerebellum/cytology , Disease Models, Animal , Dose-Response Relationship, Drug , Ganglia, Spinal/drug effects , Male , Mice , Nerve Growth Factor/pharmacology , Nervous System Diseases/etiology , Neurons/drug effects , Rats , Rats, WistarABSTRACT
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.
Subject(s)
Antioxidants/pharmacology , Arachidonic Acids/pharmacology , Brain/drug effects , Cytoprotection/drug effects , Dopamine/analogs & derivatives , Neuroprotective Agents/pharmacology , Animals , Animals, Newborn , Antioxidants/chemistry , Antioxidants/metabolism , Arachidonic Acids/chemistry , Arachidonic Acids/metabolism , Biological Assay , Brain/metabolism , Cell Survival/drug effects , Cell Survival/physiology , Cells, Cultured , Culture Media, Serum-Free/pharmacology , Cytoprotection/physiology , Dopamine/chemistry , Dopamine/metabolism , Dopamine/pharmacology , Dose-Response Relationship, Drug , Excitatory Amino Acid Antagonists/pharmacology , Glutamic Acid/toxicity , Molecular Structure , Neurons/drug effects , Neurons/metabolism , Neuroprotective Agents/chemistry , Neuroprotective Agents/metabolism , Peroxides/metabolism , Rats , Rats, WistarABSTRACT
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.
Subject(s)
Adenosine Triphosphatases/physiology , Protein Serine-Threonine Kinases/physiology , Transcriptional Activation , Adenosine Triphosphatases/metabolism , Animals , Cell Line , Cerebellum/cytology , DNA Helicases , Drug Synergism , Hippocampus/cytology , Humans , Mice , Neurons/chemistry , Neurons/ultrastructure , Nuclear Proteins/metabolism , Nuclear Proteins/physiology , Protein Binding , Protein Serine-Threonine Kinases/metabolism , Protein-Tyrosine Kinases , RNA, Small Interfering/pharmacology , Steroids/pharmacology , Dyrk KinasesABSTRACT
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.
Subject(s)
Brain-Derived Neurotrophic Factor/metabolism , Cell Death/drug effects , Neuroprotective Agents/metabolism , Receptors, Cannabinoid/metabolism , Animals , Animals, Newborn , Brain-Derived Neurotrophic Factor/pharmacology , Cannabinoid Receptor Antagonists , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Interactions , Excitatory Amino Acid Agonists/toxicity , Hippocampus/cytology , Hippocampus/drug effects , Hippocampus/injuries , Hippocampus/pathology , Kainic Acid/toxicity , Mice , Mice, Inbred C57BL , Mice, Knockout , Neurons/drug effects , Neurons/metabolism , Neuroprotective Agents/pharmacology , Organ Culture Techniques , Piperidines/pharmacology , Propidium/metabolism , Pyrazoles/pharmacology , Receptors, Cannabinoid/genetics , Rimonabant , Time FactorsABSTRACT
El estudio de la organización estructural de diferentes áreas en la corteza cerebral de los animales recién nacidos, maduros antes del nacimiento, y sus diferencias estructurales durante los primeros días de la vida post-natal, contribuye a la revelación de los mecanismos específicos del desarrollo que se realizan bajo la influencia de los factores neurogenéticos y del medio externo. Según nuestras observaciones, las áreas corticales motora y senso-motora en los cobayos tienen igual estratificación al momento de nacer (cuatro estratos). Durante la primera semana siguiente, esta estratificación sufre cambios que reflejan en cada edad un nivel superior al desarrollo estructural. Al término de la semana, el área senso-motora presenta la organización de seis capas, mientras que el área motora continúa con cuatro capas, pero más diferenciada. Paralelamente ocurre la evolución de las fibras nerviosas en ambas áreas(AU)
Subject(s)
Motor Cortex/growth & development , Somatosensory Cortex/growth & development , Guinea Pigs , Infant, NewbornABSTRACT
Pretendemos esclarecer las diferencias en la estratificación de la corteza motora de ratas y cobayos con cero y siete días de nacidos. Según nuestras observaciones comprobamos que tanto en las ratas como en los cobayos, el grosor de la corteza motora y de su capa molecular aumenta a los siete días de nacidos. La estratificación de la cortaza motora en los cobayos no varía durante la primera semana de vida postnatal, mientras que en las ratas ocurren intensos cambios en la organización y maduración, aunque el grado que logra aún no alcanza el de los cobayos recien nacidos. El alto grado de organización que presenta la corteza motora de los cobayos en comparación con el de las ratas, al momento de nacer y durante la primera semana de vida postnatal, concuerda con los actos motores complejos que realizan los cobayos después del nacimiento y no así las ratas(AU)
Subject(s)
Animals , Infant, Newborn , Guinea Pigs , Rats , Motor Cortex/growth & development , Rats , Guinea Pigs , Animals, NewbornABSTRACT
Se pretende realizar un estudio comparativo de algunos aspectos del desarrollo postnatal de la formación hipocampal en ratas y cobayos. Entre los resultados obtenidos, resalta que el grado de maduración de la Fascia Dentada y el Cuerno de Ammón varía con el tipo y edad del animal estudiado. Lo anterior expuesto nos indica que la formación hipocampal inmediatamente después del nacimiento es más organizada y desarrollada en cobayos, animales que realizan actividades de conducta complejas desde el momento de nacer. Por otro lado, el desarrollo postnatal del hipocampo es más intenso en las ratas; lo que indica la posible importancia funcional del hipocampo para la realización de actos de conducta después del nacimiento(AU)
Subject(s)
Animals , Infant, Newborn , Guinea Pigs , Rats , Hippocampus/growth & development , Rats , Guinea Pigs , Animals, NewbornABSTRACT
Se analiza evolutivamente el desarrollo de la fibroarquitectura del hipocampo en la primera semana del desarrollo postnatal en ratones. Los hipocampos de recién nacidos (1, 4 y 5 días de nacidos) se impregnaron en plata al 1, 8 por ciento según la técnica de Ramón Cajal modificada por Levi-Montalchini. Se demuestra que en los recién nacidos el tracto perforante fundamentalmente llega a la capa molecular del Cuerno de Ammon, atravesando sólo muy pocas fibras la cisura hipocámpica. A los 4 ó 5 días se observa cómo éstas cursan paralelamente a la superficie de la Fascia Dentada y en el Cuerno de Ammon conforman una gruesa capa molecular. Se concluye que las fibras del tracto perforante en esta etapa de la vida constituyen dos sistemas aferentes principales, uno en el Cuerno de Ammon y el otro en la Gyrus dentate(AU)
