David Mikeladze - Academia.edu (original) (raw)
Papers by David Mikeladze
Journal of Biological Physics and Chemistry, 2008
PubMed, Apr 1, 2023
Objective: Thyroid hormones are involved in the pathogenesis of various neurological disorders. I... more Objective: Thyroid hormones are involved in the pathogenesis of various neurological disorders. Ischemia/hypoxia that induces rigidity of the actin filaments, which initiates neurodegeneration and reduces synaptic plasticity. We hypothesized that thyroid hormones via alpha-v-beta-3 (αvβ3) integrin could regulate the actin filament rearrangement during hypoxia and increase neuronal cell viability. Materials and methods: In this experimental study, we analysed the dynamics of actin cytoskeleton according to the G/F actin ratio, cofilin-1/p-cofilin-1 ratio, and p-Fyn/Fyn ratio in differentiated PC-12 cells with/without T3 hormone (3,5,3'-triiodo-L-thyronine) treatment and blocking αvβ3-integrin-antibody under hypoxic conditions using electrophoresis and western blotting methods. We assessed NADPH oxidase activity under the hypoxic condition by the luminometric method and Rac1 activity using the ELISA-based (G-LISA) activation assay kit. Results: The T3 hormone induces the αvβ3 integrin-dependent dephosphorylation of the Fyn kinase (P=0.0010), modulates the G/F actin ratio (P=0.0010) and activates the Rac1/NADPH oxidase/cofilin-1 (P=0.0069, P=0.0010, P=0.0045) pathway. T3 increases PC-12 cell viability (P=0.0050) during hypoxia via αvβ3 integrin-dependent downstream regulation systems. Conclusion: The T3 thyroid hormone may modulate the G/F actin ratio via the Rac1 GTPase/NADPH oxidase/ cofilin1signaling pathway and αvβ3-integrin-dependent suppression of Fyn kinase phosphorylation.
Neurophysiology, Oct 1, 2018
At present, several studies have highlighted the relation between changes in the gut microbiota/ ... more At present, several studies have highlighted the relation between changes in the gut microbiota/ microbiome and a few pathologies of the CNS, including autism and other disorders of social behavior. We have checked out a hypothesis that gut microbiome-produced neurotoxins might participate in the development of these disorders. As was found, intraperitoneal injections of a gut toxin, p-cresol, induced changes in social behavior of rats, which could be interpreted as autism-like ones. Intranasal administration of oxytocin rescued the behavioral impairments in p-cresol-treated rats in the threechambered social approach test and neutralized the respective modifications of locomotor activity, research activity, and emotion-related indices in the open-field test. The effects of oxytocin were eliminated by administration of an opioid antagonist, naltrexone. These data suggest that there are functional interactions between the oxytocinergic and opioidergic systems in p-cresol-induced changes of social behavior under condtions of the animal model used.
PubMed, Jul 23, 2019
Previously we reported that amyloid-β (Aβ) leads to endoplasmic reticulum (ER) stress in cultured... more Previously we reported that amyloid-β (Aβ) leads to endoplasmic reticulum (ER) stress in cultured cortical neurons and that ER-mitochondria Ca 2+ transfer is involved in Aβ-induced apoptotic neuronal cell death. In cybrid cells which recreate the defect in mitochondrial cytochrome c oxidase (COX) activity observed in platelets from Alzheimer's disease (AD) patients, we have shown that mitochondrial dysfunction affects the ER stress response triggered by Aβ. Here, we further investigated the impact of COX inhibition on Aβ-induced ER dysfunction using a neuronal model. Primary cultures of cortical neurons were challenged with toxic concentrations of Aβ upon chemical inhibition of COX with potassium cyanide (KCN). ER Ca 2+ homeostasis was evaluated under these conditions, together with the levels of ER stress markers, namely the chaperone GRP78 and XBP-1, a mediator of the ER unfolded protein response (UPR). We demonstrated that COX inhibition potentiates the Aβ-induced depletion of ER Ca 2+ content. KCN pre-treatment was also shown to enhance the rise of cytosolic Ca 2+ levels triggered by Aβ and thapsigargin, a widely used ER stressor. This effect was reverted in the presence of dantrolene, an inhibitor of ER Ca 2+ release through ryanodine receptors. Similarly, the increase in GRP78 and XBP-1 protein levels was shown to be higher in neurons treated with Aβ or thapsigargin in the presence of KCN in comparison with levels determined in neurons treated with the neurotoxins alone. Although the decrease in cell survival, the activation of caspase-9-and-3-mediated apoptotic cell death observed in Aβ-and thapsigargin-treated neurons were also potentiated by KCN, this effect is less pronounced than that observed in Ca 2+ signalling and UPR. Furthermore, in neurons treated with Aβ, the potentiating effect of the COX inhibitor in cell survival and death was not prevented by dantrolene. These results show that inhibition of mitochondrial COX activity potentiates Aβ-induced ER dysfunction and, to a less extent, neuronal cell death. Furthermore, data supports that the effect of impaired COX on Aβ-induced cell death occurs independently of Ca 2+ release through ER ryanodine receptors. Together, our data demonstrate that mitochondria dysfunction in AD enhances the neuronal susceptibility to toxic insults, namely to Aβ-induced ER stress, and strongly suggest that the close communication between ER and mitochondria can be a valuable future therapeutic target in AD.
Journal of Biological Physics and Chemistry, Jun 30, 2018
Neurophysiology, 2018
Several studies have highlighted a high comorbidity between epilepsy and autism. We hypothesized ... more Several studies have highlighted a high comorbidity between epilepsy and autism. We hypothesized that some similar etiological factors might affect both disorders; among such factors, gut microbiome neurotoxins may participate in the development of these neurological disorders. We found that course (21 day) i.p. injections of a gut microbiome toxin, p-cresol, in genetically epilepsy-prone Krushinski-Molodkina rats led to significantly shorter latent periods of tonico-clonic seizures in response to strong sound stimulation of these animals. Besides, i.p. injection of single doses of p-cresol resulted in 8-to 10-fold prolongation of stimulation-dependent EEG seizure discharges in the hippocampus of Wistar rats. Thus, introduction of p-cresol considerably increases the seizure readiness in rats. These data suggest a possibility of the common mechanism involved in the p-cresol-induced development of both autism and epilepsy.
Neurotoxicity research, Jan 10, 2017
The sigma1 receptor (σ1R) is a chaperone protein residing at mitochondria-associated endoplasmic ... more The sigma1 receptor (σ1R) is a chaperone protein residing at mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), where it modulates Ca(2+) exchange between the ER and mitochondria by interacting with inositol-1,4,5 trisphosphate receptors (IP3Rs). The σ1R is highly expressed in the central nervous system and its activation stimulates neuromodulation and neuroprotection, for instance in Alzheimer's disease (AD) models in vitro and in vivo. σ1R effects on mitochondria pathophysiology and the downstream signaling are still not fully understood. We here evaluated the impacts of σ1R ligands in mouse mitochondria preparations on reactive oxygen species (ROS) production, mitochondrial respiration, and complex activities, in physiological condition and after direct application of amyloid Aβ1-42 peptide. σ1R agonists (2-(4-morpholinethyl)-1-phenylcyclohexanecarboxylate hydrochloride (PRE-084), tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethanamine (ANAVEX1-41, AN1-41), ...
Journal of Protein Chemistry, Jun 1, 1989
Elsevier eBooks, 1980
Publisher Summary This chapter discusses the effects of Ca-binding proteins and biogenic amines. ... more Publisher Summary This chapter discusses the effects of Ca-binding proteins and biogenic amines. Cyclic AMP-dependent protein kinase phosphorylates both synaptic and microsomal membrane proteins. In the presence of Ca, the phosphorylation of these membranes is increased. An increased level of phosphorylation is coupled with the activation of Mg, Ca-ATPase, and uptake of 45 Ca by microsomes. At the low concentration of Ca 2+ , an acidic protein, with a molecular weight of 9000, is released from the membranes. This protein binds Ca ions and is heat stable. It inhibits both membrane bound and cytosolic cyclic AMP-dependent protein kinases. When the concentration of Ca is decreased, this modulator protein released from the membranes leads to the inhibition of soluble protein kinase, phosphorylation of membrane, and activity of Mg,Ca-ATPase. Increasing of the concentration of Ca caused linkage of this protein with membrane and activation of Mg,Ca-ATPase. It is revealed that interaction between biogenic amines and Mg,Ca-ATPase is realized not only by cyclic nucleotides. The results demonstrate that biogenic amines act directly on ATPase.
Progress in Neurobiology, 1978
AIMS Neuroscience, 2020
Mislocalization and abnormal expression of N-methyl-D-aspartate glutamate receptor (NMDAR) subuni... more Mislocalization and abnormal expression of N-methyl-D-aspartate glutamate receptor (NMDAR) subunits is observed in several brain disorders and pathological conditions. Recently, we have shown that intraperitoneal injection of the gut neurotoxin p-cresol induces autism-like behavior and accelerates seizure reactions in healthy and epilepsy-prone rats, respectively. In this study, we evaluated the expression of GLUN2B and GLUN2A NMDAR subunits, and assessed the activity of cAMP-response element binding protein (CREB) and Rac1 in the hippocampi and nucleus accumbens of healthy and epilepsy-prone rats following p-cresol administration. We have found that subchronic intraperitoneal injection of p-cresol induced differential expression of GLUN2B and GLUN2A between the two brain regions, and altered the GLUN2B/GLUN2A ratio, in rats in both groups. Moreover, p-cresol impaired CREB phosphorylation in both brain structures and stimulated Rac activity in the hippocampus. These data indicate that p-cresol differently modulates the expression of NMDAR subunits in the nucleus accumbens and hippocampi of healthy and epilepsyprone rats. We propose that these differences are due to the specificity of interactions between dopaminergic and glutamatergic pathways in these structures.
Journal of Food, Nutrition and Population Health, Sep 20, 2019
Neurophysiology, 2019
The effects of p-cresol on the levels of subunit 2RB of NMDA receptors and also of AMPA and GABA ... more The effects of p-cresol on the levels of subunit 2RB of NMDA receptors and also of AMPA and GABA A receptors in the nucl. accumbens (NAc) of rats were studied. As was found, the content of the NR2B subunit of NMDA glutamate receptors is increased in p-cresol-treated rats, and this elevation is abrogated after intranasal administration of oxytocin. These effects of oxytocin were partly reversed after i.p. injections of naltrexone. We suggest that interplay between mesolimbic glutamatergic, oxytocinergic, and opioidergic systems in the NAc may be important in the development of p-cresol-dependent neurological disorders.
Journal of Biological Physics and Chemistry, 2001
The NMDA receptor is believed to be important in a wide range of nervous system functions includi... more The NMDA receptor is believed to be important in a wide range of nervous system functions including neuronal migration, synapse formation, learning and memory. In addition, it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders. Besides agonist/coagonist sites, other modulator sites, including the butyrophenone site, may regulate the NMDA receptor. It has been shown that many neuronal modulator mechanisms may be co-coordinated by a group of binding proteins that both clusters NMDA receptors and links them to signalling pathways within the cell. We have found that 5'-guanylylimidodiphosphate (Gpp(NH)p) inhibited the binding of [ 3 H]haloperidol to both the cortical and hippocampal synaptic membranes with high affinity and, reciprocally, haloperidol reduced the binding of [ 3 H]Gpp(NH)p to the membranes. Both effects are abolished by addition of anti-p21 Ras. Affinity-purified preparations of the NMDA receptor, which were immunoprecipitated by anti-p21 Ras contained only the ε2 (NR2A/NR2B) subunits of NMDA receptors and nNOS. These data suggest that the possible proteins participating in the formation of the macromolecular signalling complexes in postsynaptic density may be nNOS and p21 Ras .
Georgian medical news, 2006
Value of mannose-binding proteins was determined in plasma of pregnant women with no complication... more Value of mannose-binding proteins was determined in plasma of pregnant women with no complications and also in pregnant women with some infections using affinitive chromatography. It was found that the concentration of mannose-binding proteins in blood plasma of women equals 0.152+/-0.025 mg/ml. The concentration of mannose-binding proteins in blood plasma increase during the consecutive trimesters of noncomplicated pregnancy. In the first trimester it equals 0.198+/-0.032 mg/ml, in the second 0.257+/-0.027 mg/ml and in the third trimester 0.345+/-0.034 mg/ml. We also found that the concentration of mannose-binding proteins in blood plasma of pregnant woman suffering with chlamydial infection equals 1.025+/-0.115 mg/ml, and in blood plasma of pregnant woman suffering with cytomegalovirus infection 1.278+/-0.144 mg/ml. The obtained data confirm a hypothesis of increased activity of innate immune system during pregnancy. Also according to this results complications accompanied by chla...
American Journal of Biochemistry and Biotechnology
Differences in the composition and subcellular localization of heteroreceptors in the brain can t... more Differences in the composition and subcellular localization of heteroreceptors in the brain can trigger central nervous system diseases, including epilepsy and autism. Protein-protein interactions between Dopamine Receptors (DRs) and GLUN2A and GLUN2B subunits are critical mechanisms that regulate dopamine and glutamate coordinated signals. These interactions may be involved in the pathophysiological predisposition of epilepsy. We hypothesized that the specificity of dopaminergic neurotransmission in audiogenic Seizure-Prone (SP) rats could be underlined by the distribution and expression of the N-Methyl-D-Aspartate Glutamate Receptor (NMDAR) and Dopamine Receptor (NMDAR/DR) heterocomplex. We determined the oligomerization of synaptic and extra-synaptic NMDAR subunits with D1 and D2 receptors in the prefrontal cortex and Nucleus Accumbens (NAc) of healthy and epileptic males rats. Considering that the comorbidity of epilepsy and autism is more prevalent in females, we also studied the pattern of interaction. in NMDAR/DR heterocomplex formation in healthy female rats. The association of Dopamine Receptor type 1 (D1R) with the GLUN2A receptor, in the extra-synaptic fraction of epilepsy-prone rats, was lower than that in healthy female and male rats. In contrast, the interaction of D1R with the GLUN2B receptor was higher in the extra-synaptic membranes of epilepsyprone rats than that in healthy rats. Furthermore, we found that the D2R/GLUN2B ratio was higher in the synaptic NAc fraction of SP and female rats. Therefore, we suggest that the different subunit proportions of the NMDAR/DR heterocomplex in the prefrontal cortex and NAc of male, female, and SP rats can be attributed to their cognitive or emotional flexibility.
Journal of Biological Physics and Chemistry, 2008
PubMed, Apr 1, 2023
Objective: Thyroid hormones are involved in the pathogenesis of various neurological disorders. I... more Objective: Thyroid hormones are involved in the pathogenesis of various neurological disorders. Ischemia/hypoxia that induces rigidity of the actin filaments, which initiates neurodegeneration and reduces synaptic plasticity. We hypothesized that thyroid hormones via alpha-v-beta-3 (αvβ3) integrin could regulate the actin filament rearrangement during hypoxia and increase neuronal cell viability. Materials and methods: In this experimental study, we analysed the dynamics of actin cytoskeleton according to the G/F actin ratio, cofilin-1/p-cofilin-1 ratio, and p-Fyn/Fyn ratio in differentiated PC-12 cells with/without T3 hormone (3,5,3'-triiodo-L-thyronine) treatment and blocking αvβ3-integrin-antibody under hypoxic conditions using electrophoresis and western blotting methods. We assessed NADPH oxidase activity under the hypoxic condition by the luminometric method and Rac1 activity using the ELISA-based (G-LISA) activation assay kit. Results: The T3 hormone induces the αvβ3 integrin-dependent dephosphorylation of the Fyn kinase (P=0.0010), modulates the G/F actin ratio (P=0.0010) and activates the Rac1/NADPH oxidase/cofilin-1 (P=0.0069, P=0.0010, P=0.0045) pathway. T3 increases PC-12 cell viability (P=0.0050) during hypoxia via αvβ3 integrin-dependent downstream regulation systems. Conclusion: The T3 thyroid hormone may modulate the G/F actin ratio via the Rac1 GTPase/NADPH oxidase/ cofilin1signaling pathway and αvβ3-integrin-dependent suppression of Fyn kinase phosphorylation.
Neurophysiology, Oct 1, 2018
At present, several studies have highlighted the relation between changes in the gut microbiota/ ... more At present, several studies have highlighted the relation between changes in the gut microbiota/ microbiome and a few pathologies of the CNS, including autism and other disorders of social behavior. We have checked out a hypothesis that gut microbiome-produced neurotoxins might participate in the development of these disorders. As was found, intraperitoneal injections of a gut toxin, p-cresol, induced changes in social behavior of rats, which could be interpreted as autism-like ones. Intranasal administration of oxytocin rescued the behavioral impairments in p-cresol-treated rats in the threechambered social approach test and neutralized the respective modifications of locomotor activity, research activity, and emotion-related indices in the open-field test. The effects of oxytocin were eliminated by administration of an opioid antagonist, naltrexone. These data suggest that there are functional interactions between the oxytocinergic and opioidergic systems in p-cresol-induced changes of social behavior under condtions of the animal model used.
PubMed, Jul 23, 2019
Previously we reported that amyloid-β (Aβ) leads to endoplasmic reticulum (ER) stress in cultured... more Previously we reported that amyloid-β (Aβ) leads to endoplasmic reticulum (ER) stress in cultured cortical neurons and that ER-mitochondria Ca 2+ transfer is involved in Aβ-induced apoptotic neuronal cell death. In cybrid cells which recreate the defect in mitochondrial cytochrome c oxidase (COX) activity observed in platelets from Alzheimer's disease (AD) patients, we have shown that mitochondrial dysfunction affects the ER stress response triggered by Aβ. Here, we further investigated the impact of COX inhibition on Aβ-induced ER dysfunction using a neuronal model. Primary cultures of cortical neurons were challenged with toxic concentrations of Aβ upon chemical inhibition of COX with potassium cyanide (KCN). ER Ca 2+ homeostasis was evaluated under these conditions, together with the levels of ER stress markers, namely the chaperone GRP78 and XBP-1, a mediator of the ER unfolded protein response (UPR). We demonstrated that COX inhibition potentiates the Aβ-induced depletion of ER Ca 2+ content. KCN pre-treatment was also shown to enhance the rise of cytosolic Ca 2+ levels triggered by Aβ and thapsigargin, a widely used ER stressor. This effect was reverted in the presence of dantrolene, an inhibitor of ER Ca 2+ release through ryanodine receptors. Similarly, the increase in GRP78 and XBP-1 protein levels was shown to be higher in neurons treated with Aβ or thapsigargin in the presence of KCN in comparison with levels determined in neurons treated with the neurotoxins alone. Although the decrease in cell survival, the activation of caspase-9-and-3-mediated apoptotic cell death observed in Aβ-and thapsigargin-treated neurons were also potentiated by KCN, this effect is less pronounced than that observed in Ca 2+ signalling and UPR. Furthermore, in neurons treated with Aβ, the potentiating effect of the COX inhibitor in cell survival and death was not prevented by dantrolene. These results show that inhibition of mitochondrial COX activity potentiates Aβ-induced ER dysfunction and, to a less extent, neuronal cell death. Furthermore, data supports that the effect of impaired COX on Aβ-induced cell death occurs independently of Ca 2+ release through ER ryanodine receptors. Together, our data demonstrate that mitochondria dysfunction in AD enhances the neuronal susceptibility to toxic insults, namely to Aβ-induced ER stress, and strongly suggest that the close communication between ER and mitochondria can be a valuable future therapeutic target in AD.
Journal of Biological Physics and Chemistry, Jun 30, 2018
Neurophysiology, 2018
Several studies have highlighted a high comorbidity between epilepsy and autism. We hypothesized ... more Several studies have highlighted a high comorbidity between epilepsy and autism. We hypothesized that some similar etiological factors might affect both disorders; among such factors, gut microbiome neurotoxins may participate in the development of these neurological disorders. We found that course (21 day) i.p. injections of a gut microbiome toxin, p-cresol, in genetically epilepsy-prone Krushinski-Molodkina rats led to significantly shorter latent periods of tonico-clonic seizures in response to strong sound stimulation of these animals. Besides, i.p. injection of single doses of p-cresol resulted in 8-to 10-fold prolongation of stimulation-dependent EEG seizure discharges in the hippocampus of Wistar rats. Thus, introduction of p-cresol considerably increases the seizure readiness in rats. These data suggest a possibility of the common mechanism involved in the p-cresol-induced development of both autism and epilepsy.
Neurotoxicity research, Jan 10, 2017
The sigma1 receptor (σ1R) is a chaperone protein residing at mitochondria-associated endoplasmic ... more The sigma1 receptor (σ1R) is a chaperone protein residing at mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), where it modulates Ca(2+) exchange between the ER and mitochondria by interacting with inositol-1,4,5 trisphosphate receptors (IP3Rs). The σ1R is highly expressed in the central nervous system and its activation stimulates neuromodulation and neuroprotection, for instance in Alzheimer's disease (AD) models in vitro and in vivo. σ1R effects on mitochondria pathophysiology and the downstream signaling are still not fully understood. We here evaluated the impacts of σ1R ligands in mouse mitochondria preparations on reactive oxygen species (ROS) production, mitochondrial respiration, and complex activities, in physiological condition and after direct application of amyloid Aβ1-42 peptide. σ1R agonists (2-(4-morpholinethyl)-1-phenylcyclohexanecarboxylate hydrochloride (PRE-084), tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethanamine (ANAVEX1-41, AN1-41), ...
Journal of Protein Chemistry, Jun 1, 1989
Elsevier eBooks, 1980
Publisher Summary This chapter discusses the effects of Ca-binding proteins and biogenic amines. ... more Publisher Summary This chapter discusses the effects of Ca-binding proteins and biogenic amines. Cyclic AMP-dependent protein kinase phosphorylates both synaptic and microsomal membrane proteins. In the presence of Ca, the phosphorylation of these membranes is increased. An increased level of phosphorylation is coupled with the activation of Mg, Ca-ATPase, and uptake of 45 Ca by microsomes. At the low concentration of Ca 2+ , an acidic protein, with a molecular weight of 9000, is released from the membranes. This protein binds Ca ions and is heat stable. It inhibits both membrane bound and cytosolic cyclic AMP-dependent protein kinases. When the concentration of Ca is decreased, this modulator protein released from the membranes leads to the inhibition of soluble protein kinase, phosphorylation of membrane, and activity of Mg,Ca-ATPase. Increasing of the concentration of Ca caused linkage of this protein with membrane and activation of Mg,Ca-ATPase. It is revealed that interaction between biogenic amines and Mg,Ca-ATPase is realized not only by cyclic nucleotides. The results demonstrate that biogenic amines act directly on ATPase.
Progress in Neurobiology, 1978
AIMS Neuroscience, 2020
Mislocalization and abnormal expression of N-methyl-D-aspartate glutamate receptor (NMDAR) subuni... more Mislocalization and abnormal expression of N-methyl-D-aspartate glutamate receptor (NMDAR) subunits is observed in several brain disorders and pathological conditions. Recently, we have shown that intraperitoneal injection of the gut neurotoxin p-cresol induces autism-like behavior and accelerates seizure reactions in healthy and epilepsy-prone rats, respectively. In this study, we evaluated the expression of GLUN2B and GLUN2A NMDAR subunits, and assessed the activity of cAMP-response element binding protein (CREB) and Rac1 in the hippocampi and nucleus accumbens of healthy and epilepsy-prone rats following p-cresol administration. We have found that subchronic intraperitoneal injection of p-cresol induced differential expression of GLUN2B and GLUN2A between the two brain regions, and altered the GLUN2B/GLUN2A ratio, in rats in both groups. Moreover, p-cresol impaired CREB phosphorylation in both brain structures and stimulated Rac activity in the hippocampus. These data indicate that p-cresol differently modulates the expression of NMDAR subunits in the nucleus accumbens and hippocampi of healthy and epilepsyprone rats. We propose that these differences are due to the specificity of interactions between dopaminergic and glutamatergic pathways in these structures.
Journal of Food, Nutrition and Population Health, Sep 20, 2019
Neurophysiology, 2019
The effects of p-cresol on the levels of subunit 2RB of NMDA receptors and also of AMPA and GABA ... more The effects of p-cresol on the levels of subunit 2RB of NMDA receptors and also of AMPA and GABA A receptors in the nucl. accumbens (NAc) of rats were studied. As was found, the content of the NR2B subunit of NMDA glutamate receptors is increased in p-cresol-treated rats, and this elevation is abrogated after intranasal administration of oxytocin. These effects of oxytocin were partly reversed after i.p. injections of naltrexone. We suggest that interplay between mesolimbic glutamatergic, oxytocinergic, and opioidergic systems in the NAc may be important in the development of p-cresol-dependent neurological disorders.
Journal of Biological Physics and Chemistry, 2001
The NMDA receptor is believed to be important in a wide range of nervous system functions includi... more The NMDA receptor is believed to be important in a wide range of nervous system functions including neuronal migration, synapse formation, learning and memory. In addition, it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders. Besides agonist/coagonist sites, other modulator sites, including the butyrophenone site, may regulate the NMDA receptor. It has been shown that many neuronal modulator mechanisms may be co-coordinated by a group of binding proteins that both clusters NMDA receptors and links them to signalling pathways within the cell. We have found that 5'-guanylylimidodiphosphate (Gpp(NH)p) inhibited the binding of [ 3 H]haloperidol to both the cortical and hippocampal synaptic membranes with high affinity and, reciprocally, haloperidol reduced the binding of [ 3 H]Gpp(NH)p to the membranes. Both effects are abolished by addition of anti-p21 Ras. Affinity-purified preparations of the NMDA receptor, which were immunoprecipitated by anti-p21 Ras contained only the ε2 (NR2A/NR2B) subunits of NMDA receptors and nNOS. These data suggest that the possible proteins participating in the formation of the macromolecular signalling complexes in postsynaptic density may be nNOS and p21 Ras .
Georgian medical news, 2006
Value of mannose-binding proteins was determined in plasma of pregnant women with no complication... more Value of mannose-binding proteins was determined in plasma of pregnant women with no complications and also in pregnant women with some infections using affinitive chromatography. It was found that the concentration of mannose-binding proteins in blood plasma of women equals 0.152+/-0.025 mg/ml. The concentration of mannose-binding proteins in blood plasma increase during the consecutive trimesters of noncomplicated pregnancy. In the first trimester it equals 0.198+/-0.032 mg/ml, in the second 0.257+/-0.027 mg/ml and in the third trimester 0.345+/-0.034 mg/ml. We also found that the concentration of mannose-binding proteins in blood plasma of pregnant woman suffering with chlamydial infection equals 1.025+/-0.115 mg/ml, and in blood plasma of pregnant woman suffering with cytomegalovirus infection 1.278+/-0.144 mg/ml. The obtained data confirm a hypothesis of increased activity of innate immune system during pregnancy. Also according to this results complications accompanied by chla...
American Journal of Biochemistry and Biotechnology
Differences in the composition and subcellular localization of heteroreceptors in the brain can t... more Differences in the composition and subcellular localization of heteroreceptors in the brain can trigger central nervous system diseases, including epilepsy and autism. Protein-protein interactions between Dopamine Receptors (DRs) and GLUN2A and GLUN2B subunits are critical mechanisms that regulate dopamine and glutamate coordinated signals. These interactions may be involved in the pathophysiological predisposition of epilepsy. We hypothesized that the specificity of dopaminergic neurotransmission in audiogenic Seizure-Prone (SP) rats could be underlined by the distribution and expression of the N-Methyl-D-Aspartate Glutamate Receptor (NMDAR) and Dopamine Receptor (NMDAR/DR) heterocomplex. We determined the oligomerization of synaptic and extra-synaptic NMDAR subunits with D1 and D2 receptors in the prefrontal cortex and Nucleus Accumbens (NAc) of healthy and epileptic males rats. Considering that the comorbidity of epilepsy and autism is more prevalent in females, we also studied the pattern of interaction. in NMDAR/DR heterocomplex formation in healthy female rats. The association of Dopamine Receptor type 1 (D1R) with the GLUN2A receptor, in the extra-synaptic fraction of epilepsy-prone rats, was lower than that in healthy female and male rats. In contrast, the interaction of D1R with the GLUN2B receptor was higher in the extra-synaptic membranes of epilepsyprone rats than that in healthy rats. Furthermore, we found that the D2R/GLUN2B ratio was higher in the synaptic NAc fraction of SP and female rats. Therefore, we suggest that the different subunit proportions of the NMDAR/DR heterocomplex in the prefrontal cortex and NAc of male, female, and SP rats can be attributed to their cognitive or emotional flexibility.