On the chaotic and hyper-chaotic dynamics of nanobeams with low shear stiffness.

We construct a mathematical model of non-linear vibration of a beam nanostructure with low shear stiffness subjected to uniformly distributed harmonic transversal load. The following hypotheses are employed: the nanobeams made from transversal isotropic and elastic material obey the Hooke law and are governed by the kinematic third-order approximation (Sheremetev-Pelekh-Reddy model). The von Kármán geometric non-linear relation between deformations and displacements is taken into account. In order to describe the size-dependent coefficients, the modified couple stress theory is employed. The Hamilton functional yields the governing partial differential equations, as well as the initial and boundary conditions. A solution to the dynamical problem is found via the finite difference method of the second order of accuracy, and next via the Runge-Kutta method of orders from two to eight, as well as the Newmark method. Investigations of the non-linear nanobeam vibrations are carried out with a help of signals (time histories), phase portraits, as well as through the Fourier and wavelet-based analyses. The strength of the nanobeam chaotic vibrations is quantified through the Lyapunov exponents computed based on the Sano-Sawada, Kantz, Wolf, and Rosenstein methods. The application of a few numerical methods on each stage of the modeling procedure allowed us to achieve reliable results. In particular, we have detected chaotic and hyper-chaotic vibrations of the studied nanobeam, and our results are authentic, reliable, and accurate.

Pharmacological effects of fibroblast growth factor 21 are sex-specific in mice with the lethal yellow (Ay) mutation.

Hypothalamic melanocortin 4 receptors (MC4R) regulate energy balance. Mutations in the MC4R gene are the most common cause of monogenic obesity in humans. Fibroblast growth factor 21 (FGF21) is a promising antiobesity agent, but its effects on melanocortin obesity are unknown. Sex is an important biological variable that must be considered when conducting preclinical studies; however, in laboratory animal models, the pharmacological effects of FGF21 are well documented only for male mice. We aimed at investigating whether FGF21 affects metabolism in male and female mice with the lethal yellow (Ay) mutation, which results in MC4R blockage and obesity development. Obese C57Bl-Ay male and female mice were administered subcutaneously for 10 days with vehicle or FGF21 (1 mg per 1 kg). Food intake (FI), body weight (BW), blood parameters, and gene expression in the liver, muscles, brown adipose tissue, subcutaneous and visceral white adipose tissues, and hypothalamus were measured. FGF21 action strongly depended on the sex of the animals. In the males, FGF21 decreased BW and insulin blood levels without affecting FI. In the females, FGF21 increased FI and liver weight, but did not affect BW. In control Ay-mice, expression of genes involved in lipid and glucose metabolism (Ppargc1a, Cpt1, Pck1, G6p, Slc2a2) in the liver and genes involved in lipogenesis (Pparg, Lpl, Slc2a4) in visceral adipose tissue was higher in females than in males, and FGF21 administration inhibited the expression of these genes in females. FGF21 administration decreased hypothalamic POMC mRNA only in males. Thus, the pharmacological effect of FGF21 were significantly different in male and female Ay-mice; unlike males, females were resistant to catabolic effects of FGF21.

Germ Line Deletion Reveals a Nonessential Role of Atypical Mitogen-Activated Protein Kinase 6/Extracellular Signal-Regulated Kinase 3.

Mitogen-activated protein kinase 6/extracellular signal-regulated kinase 3 (MAPK6/ERK3) is an atypical member of the MAPKs. An essential role has been suggested by the perinatal lethal phenotype of ERK3 knockout mice carrying a lacZ insertion in exon 2 due to pulmonary dysfunction and by defects in function, activation, and positive selection of T cells. To study the role of ERK3 in vivo, we generated mice carrying a conditional Erk3 allele with exon 3 flanked by loxP sites. Loss of ERK3 protein was validated after deletion of Erk3 in the female germ line using zona pellucida 3 (Zp3)-cre and a clear reduction of the protein kinase MK5 is detected, providing the first evidence for the existence of the ERK3/MK5 signaling complex in vivo In contrast to the previously reported Erk3 knockout phenotype, these mice are viable and fertile and do not display pulmonary hypoplasia, acute respiratory failure, abnormal T-cell development, reduction of thymocyte numbers, or altered T-cell selection. Hence, ERK3 is dispensable for pulmonary and T-cell functions. The perinatal lethality and lung and T-cell defects of the previous ERK3 knockout mice are likely due to ERK3-unrelated effects of the inserted lacZ-neomycin resistance cassette. The knockout mouse of the closely related atypical MAPK ERK4/MAPK4 is also normal, suggesting redundant functions of both protein kinases.

A Mass Burial of Fossil Lions (Carnivora, Felidae, Panthera (Leo) ex gr. fossilis-spelaea) from Eurasia.

The vertebrate fauna from the cave deposits in Imanai Cave in the Southern Urals (53°02' N, 56°26'E) has been studied. It contains 715 bones that belonged to at least 11 individuals of fossil lion (Panthera (Leo) ex gr. fossilis-spelaea). It has been established that this is one of the largest Eurasian burial sites of fossil lions. The bones were accumulated due to the natural death of animals inside the cave. The age and sex estimations have shown that at least six adult males and five adult females died there. According to the accompanying fauna, radiocarbon, geochemical, and mineralogical analyses and archaeological finds, the interval of the lion bone accumulation is determined as the first half to middle of Late Pleistocene (OIS 5-3).

Nonlinear dynamics of contact interaction of a size-dependent plate supported by a size-dependent beam.

A mathematical model of complex vibrations exhibited by contact dynamics of size-dependent beam-plate constructions was derived by taking the account of constraints between these structural members. The governing equations were yielded by variational principles based on the moment theory of elasticity. The centre of the investigated plate was supported by a beam. The plate and the beam satisfied the Kirchhoff/Euler-Bernoulli hypotheses. The derived partial differential equations (PDEs) were reduced to the Cauchy problems by the Faedo-Galerkin method in higher approximations, whereas the Cauchy problem was solved using a few Runge-Kutta methods. Reliability of results was validated by comparing the solutions obtained by qualitatively different methods. Complex vibrations were investigated with the help of methods of nonlinear dynamics such as vibration signals, phase portraits, Fourier power spectra, wavelet analysis, and estimation of the largest Lyapunov exponents based on the Rosenstein, Kantz, and Wolf methods. The effect of size-dependent parameters of the beam and plate on their contact interaction was investigated. It was detected and illustrated that the first contact between the size-dependent structural members implies chaotic vibrations. In addition, problems of chaotic synchronization between a nanoplate and a nanobeam were addressed.

[The Morbidity of Students Conditioned by Diet Character in Modern Condition of Education].

The article considers characteristics of nervous psychic adaptation, morbidity and character of diet of students of the Russian state social university. The main incentives of combination of university studies and work are analyzed. The impact of combining of studies and work, regimen and diet quality on health are investigated. The psychological studies were implemented using computerized techniques of psychological testing and data collection with blank technique. The morbidity of students was discovered using questionnaire. It is established that students combining studies and work, have optimal indices of nervous psychic adaptation. however, level of their morbidity is twice higher than morbidity of students not combining studies and work. The analysis of regimen and diet character of students established deviations in regimen and structure of diet. The ration of proteins, fats and carbohydrates in day ration of students was imbalanced (1.0:1.4:6.1) at the expense of surplus of content of fat and especially carbohydrates that afterwards can results in development of diseases related to irregular diet.

[COMPARATIVE CHARACTERISTICS OF EPIDEMIC SEASONS OF INFLUENZA 2015-2016AND 2009 -2010].

AIM: Analyze epidemiologic and- clinical features of influenza epidemic seasons 2009 - 2010 and 2015 - 2016. Materials and methods Forms of federal state statistic observation No.4 , 2, 5, and 6; information from the official web-site of the Research Institute of Influenza of the Ministry of Health of Russian Federation; materials of various conferences and congresses on problems of influenza; information-analytical certificates of the Ministry of Health .of Russian Federation. RESULTS: Epidemic morbidity increases in the season 2009 - 2010. and 2015 - 2016 started at various time and had different duration. Children younger than 14 years of age predominated in the structure of patients in the 2009 - 2010 epidemic season, the main mass of patients were presented by individuals aged 45 - 59 years in the 2015 - 2016 season. The number of lethal outcomes with laboratory confirmed influenza diagnosis in 2009 - 2010 was 687-cases, and in 2015 - 2016 - 663 cases. Almost all the deceased from influenza were not vaccinated against this infection. Cardiovascular system diseases were noted in 484 individuals of the total number of deceased. Most of the deceased were late to seek medical aid. CONCLUSION: Influenza epidemic season 2015 - 2016 differs from 2009 - 2010 season by dynamics of morbidity development and a lower amount of severe forms of the disease and lethal outcomes. This may be-due to an increase of population immunity against pandemic strain A(H1N1)pdm09 via pro-epidemizing in the recent years as well as an increase of influenza vaccination coverage.

DERIVATION AND CHARACTERISTICS OF THE NEW SUBLINE OF HUMAN EMBRYONIC STEM CELLS SC6-FF IN ALLOGENIC FEEDER-FREE CULTURE SYSTEM.

A new human embryonic stem cell subline SC6-FF has been derived from SC6 cells in allogenic feeder-free culture system. Extracellular matrix proteins and conditioned medium from mesenchymal stem cell line SC6-MSC were the key components of the feeder-free culture system that therefore was allogenic for SC6-FF cells. SC6-FF subline has underwent more than 100 cell population doublings and retained normal diploid human karyotype: 46, XX. The average doubling time of the cell population was 23.7 ± 0.8 h that does not differ from that for the parent SC6 line. The presence of undifferentiated hESCs markers, alkaline phosphatase activity, Oct-4, SSEA-4 and TRA-1-60, has been verified by histochemical and immunofluorescence analysis. Non-directional differentiation of SC6-FF subline has led to development of cells that differ in size and morphology from the cells in the parent population. These cells demonstrate the ability of differentiation in the derivates of three germ layers by expressing the characteristic markers of the ectoderm (alpha-fetoprotein), mesoderm (a-actinin) and endoderm (a-fetoprotein) cells. We can conclude that the obtained characteristics of the new feeder-free SC6-FF sub-line correspond to the status of the human embryonic stem cells.

[CHARACTERISTICS OF NEW MESENCHYMAL STEM CELL LINE DERIVED FROM HUMAN EMBRYONIC STEM CELLS].

New nonimmortalized fibroblast-like cell line SC6-MSC has been obtained from a line of human embryonic stem cells (ESC)--SC6. Numerical and structural karyotypic analysis has shown hypodiploidy karyotypic: 45, X0 in this line. The average cell population doublings time, for SC6-MSC is 26.0 ± 0.4 h at the 8th passage and 82.0 ± 9.2 h at the 18th passage. The growth curves showed active proliferation for 8-10 passages with a consequent gradual decrease of proliferative activity, which ended to 20th passage. To determine the line's status, the analysis of the surface markers by flow cytometry was carried out. We have revealed the expression of surface antigens CD44, CD73, CD90, CD105 and HLA-ABC characteristic for human MSC, and the absence of CD34 and HLA-DR expression. However, the level of expression of surface markers CD90 and CD105 was significantly lower in comparison with other MSC lines including the line SC5-MSC derived from the line human ESC-SC5. Immunofluorescence analysis of the expression of the surface markers and transcription factor Oct-4 characteristic for human embryonic stem cells showed the absence of Oct-4 expression and the presence of SSEA-4 and TRA-1-60 expression, which is characteristic for a number of MSC lines with normal karyotype. Immunofluorescence analysis has shown the presence of the markers of early differentiation in the derivates of three germ layers, characteristic for human ESC, which in corresponding microenvironments may allow MSC to be useful for reparation of tissue injures. The directed osteogenic and chondrogenic differentiation of line SC6-MSC has shown. However, no directed adipogenic differentiation of this line has been found. The obtained results with high probability may indicate what alteration of chromosomal and, accordingly, gene balance, in line SC6-MSC with karyotype 45, X0 resulted in decrease in differential potential, in expression CD90, associated in particular with the processes of differentiation and aging of cells.

[STUDYING THE ROLE OF BRAIN MELANOCORTIN RECEPTORS IN THE SUPPRESSING OF FOOD INTAKE UNDER ETHER STRESS IN MICE].

Melanocortin (MC) system regulates food intake under the rest conditions. Stress inhibits food intake. It is not clear whether brain MC system is involved in stress-induced anorexia in mice. The aim of the work was to investigate the effect of pharmacological blockade and activation of brain MC receptors on food intake under stress. C57B1/6J male mice were subjected to ether stress (0.5 minute ether anesthesia) before the administration of saline solution or synthetic non-selective blocker (SHU9119) or agonist (Melanotan II) of MC receptors into the lateral brain ventricle. Food intake was pre-stimulated with 17 hours of fasting in all mice. Ether stress decreased food intake, increased the plasma corticosterone level and hypothalamic mRNA AgRP (natural MC receptor antagonist) level at 1 hour after the stress. Pharmacological blockade of the MC receptors weakened stress-induced anorexia and decreased mRNA AgRP level in the hypothalamus. Pharmacological stimulation of the MC receptors enhanced ether stress-induced anorexia and hypercortisolism. Thus, our data demonstrated that the central MC system was involved in the development of stress-induced anorexia in mice.

[The season of birth and mortality (Based on workers mortality epidemiological study materials)].

The article presents a comparative assessment of the death absolute risk for the humans born in different seasons and months of the year based on the epidemiological studies found on the retrospective cohort for the 40 years period (the end of the 20th-beginning 21st century). It is shown that mortality of people born in January-February differ from similar parameters of persons born in March-April.

Zyklophin, a short-acting kappa opioid antagonist, induces scratching in mice.

It has been shown previously that norbinaltorphimine (norBNI) and 5'-guanidinonaltrindole (5'-GNTI), long-acting kappa opioid receptor (KOPR) antagonists, cause frenzied scratching in mice [1,2]. In the current study, we examined if zyklophin, a short-acting cyclic peptide KOPR antagonist, also elicited scratching behavior. When injected s.c. in the nape of the neck of male Swiss-Webster mice, zyklophin at doses of 0.1, 0.3 and 1mg/kg induced dose-related hindleg scratching of the neck between 3 and 15 min after injection. Pretreating mice with norBNI (20mg/kg, i.p.) at 18-20 h before challenge with zyklophin (0.3mg/kg) did not markedly affect scratching. Additionally, KOPR-/- mice given 0.3mg/kg of zyklophin displayed similar levels of scratching as wild-type animals. The absence of KOPR in KOPR-/- mice was confirmed with ex vivo radioligand binding using [(3)H]U69,593. Taken together, our data suggest that the presence of kappa receptors is not required for the excessive scratching caused by zyklophin. Thus, zyklophin, similar to the structurally different KOPR antagonist 5'-GNTI, appears to act at other targets to elicit scratching and potentially the sensation of itch.

Exaggerated anorexigenic response to restraint stress in A(y) mice is associated with elevated CRFR2 mRNA expression in the hypothalamus.

The "lethal yellow" mutation at the mouse agouti locus (A(y)) results in hyperphagia, obesity, and type 2 diabetes at rest, but helps to reduce food intake under stress. The aim of this work was to investigate mechanisms of exaggerated anorectic response to stress in A(y) mice. All parameters were measured in C57BL/6J male mice of a/a (control) and A(y)/a genotypes before, 0, 1, and 3h after a 1-h restraint. Baseline food intake and plasma insulin concentrations were higher in A(y)/a mice compared to a/a mice. Restraint reduced food intake and plasma insulin concentrations only in A(y)/a mice. Stress-induced anorexia in A(y)/a mice was independent of pathways involving hypothalamic-pituitary-adrenal axis activity and hypothalamic orexigenic neuropeptide (agouti-related peptide and neuropeptide Y) gene expressions and corticotrophin-releasing factor type 1 receptor (CRFR1). Gene expression of CRFR2 was elevated in A(y)/a mice with genotype differences particularly manifested immediately after the restraint. Hypothalamic CRFR2 is known to mediate anorectic signals from CRF-related peptides. Thus, our data suggest that stress-induced anorexia in A(y)/a mice may be associated with increased anorectic signals mediated by CRFR2 in the hypothalamus.

[Atorvastatin and oxidative stress in coronary heart disease with obesity].

The aim of the work was to study the role of atorvastatin in the correction of oxidative stress manifestations in patients with coronary heart disease and dyslipidemnia (DLP). It included 122 patients with stable forms of CHD and 20 practically healthy subjects. Plasma lipids and products of lipid peroxidation (dienic conjugates and compounds reacting with 2-thiobarbituric acid), eryhrocyte antioxidative enzymes glutathione peroxidase and superoxide dismutase were determined by standard methods; activity of the ceruloplasmin/transferrin antioxidant system) was measured by electron paramagnetic resonance. The patients underwent 24 hr ECG Holter monitoring. Atorvastatin at a dose of 20 mg/d given during 6 months exerted antioxidative and antiperoxidative effects in 90% of the patients. It normalized parameters of lipid peroxidation and antioxidant protection thereby improving the clinical course of CHD.

Pregnancy and lactation have anti-obesity and anti-diabetic effects in A(y)/a mice.

AIM: Dominant 'yellow' mutation at the mouse agouti locus (A(y)) results in obesity. Pregnancy and lactation are characterized by large energy demand. The aim of this study was to investigate whether obesity would develop in pregnant and suckling A(y) mice. METHODS: Body weight and food intake in pregnancy, lactation, and after weaning, plasma leptin, insulin, corticosterone and blood glucose concentrations on days 7, 13 and 18 of pregnancy, days 1, 10, 21 and 80 postpartum, glucose and insulin tolerance on pregnancy days 7 and 18 were measured in C57Bl/6J mice of a/a (normal metabolism) and A(y)/a genotypes. The same parameters were also measured in age-matched virgin females. RESULTS: Virgin A(y)/a females exhibited hyperphagia, enhanced body weight, glucose intolerance and normal blood parameters at the mating age. With age, they developed obesity, hyperleptinaemia, hyperinsulinaemia and hyperglycaemia. Obesity did not develop in mated A(y)/a mice; during suckling, they had equal food intake and body weight as a/a mice. During pregnancy, glucose tolerance was enhanced in A(y)/a mice and became equal in both genotypes. In both genotypes, concentrations of hormones increased, and glucose decreased from pregnancy day 7 to day 18 and returned to normal values after parturition. A(y)/a mice did not differ from a/a in corticosterone, insulin and glucose levels during pregnancy and lactation, in leptin levels during suckling; however, A(y)/a mice had two times higher leptin levels than a/a during pregnancy. After weaning, A(y)/a mice began to eat and weigh more than a/a exhibiting normal metabolic parameters for 50 days. CONCLUSION: Pregnancy and lactation retard obesity and diabetes development in A(y) mice.

Caspase-3 activity is reduced after spinal cord injury in mice lacking dynorphin: differential effects on glia and neurons.

Dynorphins are endogenous opioid peptide products of the prodynorphin gene. An extensive literature suggests that dynorphins have deleterious effects on CNS injury outcome. We thus examined whether a deficiency of dynorphin would protect against tissue damage after spinal cord injury (SCI), and if individual cell types would be specifically affected. Wild-type and prodynorphin(-/-) mice received a moderate contusion injury at 10th thoracic vertebrae (T10). Caspase-3 activity at the injury site was significantly decreased in tissue homogenates from prodynorphin(-/-) mice after 4 h. We examined frozen sections at 4 h post-injury by immunostaining for active caspase-3. At 3-4 mm rostral or caudal to the injury, >90% of all neurons, astrocytes and oligodendrocytes expressed active caspase-3 in both wild-type and knockout mice. At 6-7 mm, there were fewer caspase-3(+) oligodendrocytes and astrocytes than at 3-4 mm. Importantly, caspase-3 activation was significantly lower in prodynorphin(-/-) oligodendrocytes and astrocytes, as compared with wild-type mice. In contrast, while caspase-3 expression in neurons also declined with further distance from the injury, there was no effect of genotype. Radioimmunoassay showed that dynorphin A(1-17) was regionally increased in wild-type injured versus sham-injured tissues, although levels of the prodynorphin processing product Arg(6)-Leu-enkephalin were unchanged. Our results indicate that dynorphin peptides affect the extent of post-injury caspase-3 activation, and that glia are especially sensitive to these effects. By promoting caspase-3 activation, dynorphin peptides likely increase the probability of glial apoptosis after SCI. While normally beneficial, our findings suggest that prodynorphin or its peptide products become maladaptive following SCI and contribute to secondary injury.

Dysregulation of dynorphins in Alzheimer disease.

The opioid peptides dynorphins may be involved in pathogenesis of Alzheimer disease (AD) by inducing neurodegeneration or cognitive impairment. To test this hypothesis, the dynorphin system was analyzed in postmortem samples from AD and control subjects, and subjects with Parkinson or cerebro-vascular diseases for comparison. Dynorphin A, dynorphin B and related neuropeptide nociceptin were determined in the Brodmann area 7 by radioimmunoassay. The precursor protein prodynorphin, processing convertase PC2 and the neuroendocrine pro7B2 and 7B2 proteins required for PC2 maturation were analyzed by Western blot. AD subjects displayed robustly elevated levels of dynorphin A and no differences in dynorphin B and nociceptin compared to controls. Subjects with Parkinson or cerebro-vascular diseases did not differ from controls with respect to any of the three peptides. PC2 levels were also increased, whereas, those of prodynorphin and pro7B2/7B2 were not changed in AD. Dynorphin A levels correlated with the neuritic plaque density. These results along with the known non-opioid ability of dynorphin A to induce neurodegeneration suggest a role for this neuropeptide in AD neuropathology.

Function of the hypothalamo-hypophyseal-adrenal system in mice with ectopic hyperproduction of the agouti protein.

The agouti protein is known to compete with the melanocortin hormones (ACTH, melanocyte-stimulating hormone) at melanocortin receptors, which in turn are involved in controlling the central and peripheral components of the hypothalamo-hypophyseal-adrenal system. The aim of the present work was therefore to assess the effects of the dominant mutation Agouti yellow (A(y)/a), which induces ectopic hyperproduction of the agouti protein and yellow coat color, on the function of the hypothalamo-hypophyseal-adrenal system. Experiments were performed on male A(y)/a mice of the C57BI/6J line. Controls consisted of mice of the same line bearing the recessive mutation nonagouti (a/a), which leads to the absence of agouti protein and black coat color. The experimental results showed that mice with different agouti genotypes had identical basal corticosterone levels, though yellow mice, as compared with black mice, had increased corticosterone levels after restriction stress (p < 0.02), along with decreased stress reactivity after treatment with dexamethasone (p < 0.0007), and increased adrenal sensitivity to small doses of activity, both in vitro and in vivo.

Study of molecular events in cells by fluorescence correlation spectroscopy.

To understand processes in a living cell, sophisticated and creative approaches are required that can be used for gathering quantitative information about large number of components interacting across temporal and spatial scales without major disruption of the integral network of processes. A physical method of analysis that can meet these requirements is fluorescence correlation spectroscopy (FCS), which is an ultrasensitive and non-invasive detection method capable of single-molecule and real-time resolution. Since its introduction about 3 decades ago, this until recently emerging technology has reached maturity. As commercially built equipment is now available, FCS is extensively applied for extracting biological information from living cells unattainable by other methods, and new biological concepts are formulated based on findings by FCS. In this review, we focus on examples in the field of molecular cellular biology. The versatility of the technique in this field is illustrated in studies of single-molecule dynamics and conformational flexibility of proteins, and the relevance of conformational flexibility for biological functions regarding the multispecificity of antibodies, modulation of activity of C5a receptors in clathrin-mediated endocytosis and multiplicity of functional responses mediated by the p53 tumor suppressor protein; quantitative characterization of physicochemical properties of the cellular interior; protein trafficking; and ligand-receptor interactions. FCS can also be used to study cell-to-cell communication, here exemplified by clustering of apoptotic cells via bystander killing by hydrogen peroxide.

Dynorphin A (1-17) induces apoptosis in striatal neurons in vitro through alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptor-mediated cytochrome c release and caspase-3 activation.

Dynorphin A (1-17), an endogenous opioid neuropeptide, can have pathophysiological consequences at high concentrations through actions involving glutamate receptors. Despite evidence of excitotoxicity, the basic mechanisms underlying dynorphin-induced cell death have not been explored. To address this question, we examined the role of caspase-dependent apoptotic events in mediating dynorphin A (1-17) toxicity in embryonic mouse striatal neuron cultures. In addition, the role of opioid and/or glutamate receptors were assessed pharmacologically using dizocilpine maleate (MK(+)801), a non-equilibrium N-methyl-D-aspartate (NMDA) antagonist; 6-cyano-7-nitroquinoxaline-2,3-dione, a competitive alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate antagonist; or (-)-naloxone, a general opioid antagonist. The results show that dynorphin A (1-17) (>or=10 nM) caused concentration-dependent increases in caspase-3 activity that were accompanied by mitochondrial release of cytochrome c and the subsequent death of cultured mouse striatal neurons. Moreover, dynorphin A-induced neurotoxicity and caspase-3 activation were significantly attenuated by the cell permeable caspase inhibitor, caspase-3 inhibitor-II (z-DEVD-FMK), further suggesting an apoptotic cascade involving caspase-3. AMPA/kainate receptor blockade significantly attenuated dynorphin A-induced cytochrome c release and/or caspase-3 activity, while NMDA or opioid receptor blockade typically failed to prevent the apoptotic response. Last, dynorphin-induced caspase-3 activation was mimicked by the ampakine CX546 [1-(1,4-benzodioxan-6-ylcarbonyl)piperidine], which suggests that the activation of AMPA receptor subunits may be sufficient to mediate toxicity in striatal neurons. These findings provide novel evidence that dynorphin-induced striatal neurotoxicity is mediated by a caspase-dependent apoptotic mechanism that largely involves AMPA/kainate receptors.