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Krzysztof Wędzony - One of the best experts on this subject based on the ideXlab platform.

  • ERK signalling pathway is not involved in PSA-NCAM-dependent alterations of hippocampal plasticity evoked by CB1 receptor activation
    Pharmacological Reports, 2009
    Co-Authors: Marzena Maćkowiak, Dorota Dudys, Krzysztof Wędzony
    Abstract:

    The present study investigated the potential role of the extracellular signal-regulated kinase (ERK) pathway in the alternation of polysialylated neural cell adhesion molecule (PSA-NCAM) expression and proliferation rates in the dentate gyrus (DG) evoked by activation of the CB1 receptor. When given at a dose of 0.1 mg/kg, the CB1 receptor agonist, 3-(1,1-dimethylheptyl)-11-hydroxy-Δ^8-tetrahydrocannabinol (HU-210), increased the levels of the phosphorylated forms of ERK (pERK1 and pERK2) in the hippocampus when measured 30 min after injection. This HU-210-induced effect was inhibited by α-amino[(4-aminophenyl)thio]methylene-2-(trifluoromethyl) benzeneacetonitrile (SL327, 30 mg/kg) - an inhibitor of mitogen-activated protein kinase kinase (MEK1/2), the upstream kinase of ERK - given 1 h before HU-210 administration. Additionally, SL327 alone significantly attenuated the basal level of both pERK1 and pERK2. HU-210 (0.1 mg/kg) decreased the number of PSA-NCAM-immunoreactive (IR) cells but did not affect the rate of proliferation, which was analyzed as the number of Ki-67-IR cells measured in the DG 2 days after HU-210 administration. The data indicated that SL327 (30 mg/kg) alone decreased the number of PSA-NCAM-IR cells 2 days after treatment. Joint administration of SL327 and HU-210 decreased the number of PSA-NCAM cells more robustly than did the administration of either alone. In addition, SL327 did not decrease the number of Ki-67-IR cells, while pretreatment with SL327 1 h before HU-210 administration did. These results suggest that stimulation of the ERK cascade caused by CB1 receptor activation is not involved in hippocampal plasticity governed by PSA-NCAM expression.

  • ERK signalling pathway is not involved in PSANCAM-dependent alterations of hippocampal plasticity evoked by CB1 receptor activation
    Pharmacological reports : PR, 2009
    Co-Authors: Marzena Maćkowiak, Dorota Dudys, Krzysztof Wędzony
    Abstract:

    Abstract The present study investigated the potential role of the extracellular signal-regulated kinase (ERK) pathway in the alternation of polysialylated neural cell adhesion molecule (PSA-NCAM) expression and proliferation rates in the dentate gyrus (DG) evoked by activation of the CB1 receptor. When given at a dose of 0.1 mg/kg, the CB1 receptor agonist, 3-(1,1-dimethylheptyl)-11-hydroxy-Δ 8 -tetrahydrocannabinol (HU-210), increased the levels of the phosphorylated forms of ERK (pERK1 and pERK2) in the hippocampus when measured 30 min after injection. This HU-210-induced effect was inhibited by α-(amino[(4-aminophenyl)thio]methylene}-2-(trifluoromethyl) benzeneacetonitrile (SL327, 30 mg/kg) – an inhibitor of mitogen-activated protein kinase kinase (MEK1/2), the upstream kinase of ERK – given 1 h before HU-210 administration. Additionally, SL327 alone significantly attenuated the basal level of both pERK1 and pERK2. HU-210 (0.1 mg/kg) decreased the number of PSA-NCAM-immunoreactive (IR) cells but did not affect the rate of proliferation, which was analyzed as the number of Ki-67-IR cells measured in the DG 2 days after HU-210 administration. The data indicated that SL327 (30 mg/kg) alone decreased the number of PSA-NCAM-IR cells 2 days after treatment. Joint administration of SL327 and HU-210 decreased the number of PSA-NCAM cells more robustly than did the administration of either alone. In addition, SL327 did not decrease the number of Ki-67-IR cells, while pretreatment with SL32 7 1 h before HU-210 administration did. These results suggest that stimulation of the ERK cascade caused by CB1 receptor activation is not involved in hippocampal plasticity governed by PSA-NCAM expression.

  • Activation of CB1 cannabinoid receptors impairs memory consolidation and hippocampal polysialylated neural cell adhesion molecule expression in contextual fear conditioning.
    Neuroscience, 2008
    Co-Authors: Marzena Maćkowiak, Dorota Dudys, Agnieszka Chocyk, Krzysztof Wędzony
    Abstract:

    Abstract We investigated the role of CB1 receptors in hippocampal-dependent memory consolidation mediated by polysialylated neural cell adhesion molecule (PSA-NCAM) during contextual fear conditioning (CFC). The CB1 receptor agonist 3-(1,1-dimethylheptyl)-(-)-11-hydroxy-Δ 8 -tetrahydrocannabinol (HU-210) (0.1 mg/kg) was given immediately after training during the memory consolidation phase, and freezing behavior was measured 24 h after conditioning. Administration of HU-210 attenuated freezing behavior measured in CFC. Western blot analysis showed that CFC induced a decrease in the expression of NCAM-180, but did not change the level of NCAM-140 and increased PSA-NCAM expression measured 24 h after training in the rat hippocampus. HU-210 (0.1 mg/kg) injection did not affect the reduction in NCAM-180 levels induced by CFC, but it blocked the increase in PSA-NCAM expression. Since the dentate gyrus (DG) of the hippocampus is known to be involved in memory consolidation and expresses a high level of PSA-NCAM protein, we measured the effects of CFC and HU-210 administration on PSA-NCAM-immunoreactive (IR) cells in the DG. CFC caused an increase in the number of PSA-NCAM-IR cells in the DG, but not K i -67- or doublecortin (DCX)-IR cells. This increase in PSA-NCAM-IR cells was abolished by HU-210 injection. Administration of the CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM-251) (3 mg/kg immediately before HU-210) inhibited the effects of HU-210 on freezing behavior and PSA-NCAM expression in the DG. These results indicate that activation of CB1 receptors disturbs consolidation of fear memory in CFC, likely by affecting PSA-NCAM expression in the DG, which plays an important role in synaptic rearrangement during the formation of memory traces.

  • Acute activation of CB1 cannabinoid receptors transiently decreases PSA-NCAM expression in the dentate gyrus of the rat hippocampus.
    Brain research, 2007
    Co-Authors: Marzena Maćkowiak, Agnieszka Chocyk, Katarzyna Markowicz-kula, Krzysztof Wędzony
    Abstract:

    Recent evidence indicates that the polysialylated neural cell adhesion molecule (PSA-NCAM) is involved in hippocampal plasticity. On the other hand, CB1 receptor activation is known to disturb some hippocampal processes involving plastic changes, such as learning and memory. Therefore, the present study investigated the effect of HU-210, a CB1 receptor agonist, on the expression of PSA-NCAM protein in the dentate gyrus (DG) and CA3 region of the rat hippocampus. It was found that at a dose of 0.1 mg/kg i.p. of HU-210, the number of PSA-NCAM immunoreactive (IR) cells in the DG declined in a time-dependent manner. The decrease in PSA-NCAM expression was observed at 1 and 2 days (ca. 21% and 30%, respectively), but not after 4 h and 4 days following HU-210 administration. However, HU-210 treatment did not change the length density of PSA-NCAM immunopositive processes in CA3 mossy fibers at all the time points measured. The effect observed in the DG on day 2 was blocked by AM-251 (1 mg/kg, i.p.), a CB1 receptor antagonist, given 30 min before HU-210. Neither the number of Ki-67 (IR) cells (a marker of proliferation) nor the number of doublecortin-IR cells (a marker of immature neurons) was affected by HU-210 (0.1 mg/kg, i.p.) treatment at any of the time points. An analysis of co-localization of CB1 receptor protein with PSA-NCAM protein revealed that both proteins were not present in the same population of neurons in the subgranular layer of the DG. The observed changes in PSA-NCAM expression were not related to the reduction of proliferation or differentiation of newly born cells, but were possible due to alternations in the synaptic activity in the DG. However, such alteration in the PSA-NCAM expression may change the timing of the functional maturation of newly born neurons. Moreover, the above finding suggests that acute activation of CB1 receptors may result in the stiffening of the hippocampal structure and susceptibility to plastic changes and may lead to functional impairment governed by alterations in the hippocampal structure.

Marzena Maćkowiak - One of the best experts on this subject based on the ideXlab platform.

  • ERK signalling pathway is not involved in PSA-NCAM-dependent alterations of hippocampal plasticity evoked by CB1 receptor activation
    Pharmacological Reports, 2009
    Co-Authors: Marzena Maćkowiak, Dorota Dudys, Krzysztof Wędzony
    Abstract:

    The present study investigated the potential role of the extracellular signal-regulated kinase (ERK) pathway in the alternation of polysialylated neural cell adhesion molecule (PSA-NCAM) expression and proliferation rates in the dentate gyrus (DG) evoked by activation of the CB1 receptor. When given at a dose of 0.1 mg/kg, the CB1 receptor agonist, 3-(1,1-dimethylheptyl)-11-hydroxy-Δ^8-tetrahydrocannabinol (HU-210), increased the levels of the phosphorylated forms of ERK (pERK1 and pERK2) in the hippocampus when measured 30 min after injection. This HU-210-induced effect was inhibited by α-amino[(4-aminophenyl)thio]methylene-2-(trifluoromethyl) benzeneacetonitrile (SL327, 30 mg/kg) - an inhibitor of mitogen-activated protein kinase kinase (MEK1/2), the upstream kinase of ERK - given 1 h before HU-210 administration. Additionally, SL327 alone significantly attenuated the basal level of both pERK1 and pERK2. HU-210 (0.1 mg/kg) decreased the number of PSA-NCAM-immunoreactive (IR) cells but did not affect the rate of proliferation, which was analyzed as the number of Ki-67-IR cells measured in the DG 2 days after HU-210 administration. The data indicated that SL327 (30 mg/kg) alone decreased the number of PSA-NCAM-IR cells 2 days after treatment. Joint administration of SL327 and HU-210 decreased the number of PSA-NCAM cells more robustly than did the administration of either alone. In addition, SL327 did not decrease the number of Ki-67-IR cells, while pretreatment with SL327 1 h before HU-210 administration did. These results suggest that stimulation of the ERK cascade caused by CB1 receptor activation is not involved in hippocampal plasticity governed by PSA-NCAM expression.

  • ERK signalling pathway is not involved in PSANCAM-dependent alterations of hippocampal plasticity evoked by CB1 receptor activation
    Pharmacological reports : PR, 2009
    Co-Authors: Marzena Maćkowiak, Dorota Dudys, Krzysztof Wędzony
    Abstract:

    Abstract The present study investigated the potential role of the extracellular signal-regulated kinase (ERK) pathway in the alternation of polysialylated neural cell adhesion molecule (PSA-NCAM) expression and proliferation rates in the dentate gyrus (DG) evoked by activation of the CB1 receptor. When given at a dose of 0.1 mg/kg, the CB1 receptor agonist, 3-(1,1-dimethylheptyl)-11-hydroxy-Δ 8 -tetrahydrocannabinol (HU-210), increased the levels of the phosphorylated forms of ERK (pERK1 and pERK2) in the hippocampus when measured 30 min after injection. This HU-210-induced effect was inhibited by α-(amino[(4-aminophenyl)thio]methylene}-2-(trifluoromethyl) benzeneacetonitrile (SL327, 30 mg/kg) – an inhibitor of mitogen-activated protein kinase kinase (MEK1/2), the upstream kinase of ERK – given 1 h before HU-210 administration. Additionally, SL327 alone significantly attenuated the basal level of both pERK1 and pERK2. HU-210 (0.1 mg/kg) decreased the number of PSA-NCAM-immunoreactive (IR) cells but did not affect the rate of proliferation, which was analyzed as the number of Ki-67-IR cells measured in the DG 2 days after HU-210 administration. The data indicated that SL327 (30 mg/kg) alone decreased the number of PSA-NCAM-IR cells 2 days after treatment. Joint administration of SL327 and HU-210 decreased the number of PSA-NCAM cells more robustly than did the administration of either alone. In addition, SL327 did not decrease the number of Ki-67-IR cells, while pretreatment with SL32 7 1 h before HU-210 administration did. These results suggest that stimulation of the ERK cascade caused by CB1 receptor activation is not involved in hippocampal plasticity governed by PSA-NCAM expression.

  • Activation of CB1 cannabinoid receptors impairs memory consolidation and hippocampal polysialylated neural cell adhesion molecule expression in contextual fear conditioning.
    Neuroscience, 2008
    Co-Authors: Marzena Maćkowiak, Dorota Dudys, Agnieszka Chocyk, Krzysztof Wędzony
    Abstract:

    Abstract We investigated the role of CB1 receptors in hippocampal-dependent memory consolidation mediated by polysialylated neural cell adhesion molecule (PSA-NCAM) during contextual fear conditioning (CFC). The CB1 receptor agonist 3-(1,1-dimethylheptyl)-(-)-11-hydroxy-Δ 8 -tetrahydrocannabinol (HU-210) (0.1 mg/kg) was given immediately after training during the memory consolidation phase, and freezing behavior was measured 24 h after conditioning. Administration of HU-210 attenuated freezing behavior measured in CFC. Western blot analysis showed that CFC induced a decrease in the expression of NCAM-180, but did not change the level of NCAM-140 and increased PSA-NCAM expression measured 24 h after training in the rat hippocampus. HU-210 (0.1 mg/kg) injection did not affect the reduction in NCAM-180 levels induced by CFC, but it blocked the increase in PSA-NCAM expression. Since the dentate gyrus (DG) of the hippocampus is known to be involved in memory consolidation and expresses a high level of PSA-NCAM protein, we measured the effects of CFC and HU-210 administration on PSA-NCAM-immunoreactive (IR) cells in the DG. CFC caused an increase in the number of PSA-NCAM-IR cells in the DG, but not K i -67- or doublecortin (DCX)-IR cells. This increase in PSA-NCAM-IR cells was abolished by HU-210 injection. Administration of the CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM-251) (3 mg/kg immediately before HU-210) inhibited the effects of HU-210 on freezing behavior and PSA-NCAM expression in the DG. These results indicate that activation of CB1 receptors disturbs consolidation of fear memory in CFC, likely by affecting PSA-NCAM expression in the DG, which plays an important role in synaptic rearrangement during the formation of memory traces.

  • Acute activation of CB1 cannabinoid receptors transiently decreases PSA-NCAM expression in the dentate gyrus of the rat hippocampus.
    Brain research, 2007
    Co-Authors: Marzena Maćkowiak, Agnieszka Chocyk, Katarzyna Markowicz-kula, Krzysztof Wędzony
    Abstract:

    Recent evidence indicates that the polysialylated neural cell adhesion molecule (PSA-NCAM) is involved in hippocampal plasticity. On the other hand, CB1 receptor activation is known to disturb some hippocampal processes involving plastic changes, such as learning and memory. Therefore, the present study investigated the effect of HU-210, a CB1 receptor agonist, on the expression of PSA-NCAM protein in the dentate gyrus (DG) and CA3 region of the rat hippocampus. It was found that at a dose of 0.1 mg/kg i.p. of HU-210, the number of PSA-NCAM immunoreactive (IR) cells in the DG declined in a time-dependent manner. The decrease in PSA-NCAM expression was observed at 1 and 2 days (ca. 21% and 30%, respectively), but not after 4 h and 4 days following HU-210 administration. However, HU-210 treatment did not change the length density of PSA-NCAM immunopositive processes in CA3 mossy fibers at all the time points measured. The effect observed in the DG on day 2 was blocked by AM-251 (1 mg/kg, i.p.), a CB1 receptor antagonist, given 30 min before HU-210. Neither the number of Ki-67 (IR) cells (a marker of proliferation) nor the number of doublecortin-IR cells (a marker of immature neurons) was affected by HU-210 (0.1 mg/kg, i.p.) treatment at any of the time points. An analysis of co-localization of CB1 receptor protein with PSA-NCAM protein revealed that both proteins were not present in the same population of neurons in the subgranular layer of the DG. The observed changes in PSA-NCAM expression were not related to the reduction of proliferation or differentiation of newly born cells, but were possible due to alternations in the synaptic activity in the DG. However, such alteration in the PSA-NCAM expression may change the timing of the functional maturation of newly born neurons. Moreover, the above finding suggests that acute activation of CB1 receptors may result in the stiffening of the hippocampal structure and susceptibility to plastic changes and may lead to functional impairment governed by alterations in the hippocampal structure.

Gabriella Coruzzi - One of the best experts on this subject based on the ideXlab platform.

  • Effects of cannabinoid receptor agonists on rat gastric acid secretion : Discrepancy between in vitro and in vivo data
    Digestive diseases and sciences, 2006
    Co-Authors: Gabriella Coruzzi, Maristella Adami, Elena Guaita, Alessandro Menozzi, Simone Bertini, Elena Giovannini, Giulio Soldani
    Abstract:

    The effects of the cannabinoid (CB)-receptor agonists WIN55,212-2 and HU-210 and the selective CB1-receptor antagonist SR141716A were tested on in vitro and in vivo acid secretion assays from the rat. In the isolated gastric fundus from immature rats, WIN55,212-2 (0.001–30 μ M), HU-210 (0.001–10 μ M), or SR141716A (0.1–10 μ M) did not change the basal acid output or acid responses to histamine, pentagastrin, or electrical field stimulation. HU-210 (0.3 μ mol/kg, intravenously) inhibited the acid response to pentagastrin in anesthetized adult, young, or immature rats with lumen-perfused stomachs; moreover, HU-210 reduced vagally induced acid secretion in adult animals, its antisecretory effect being reversed by SR141716A (0.65 μ mol/kg, intravenously). In vitro and in vivo data indicate that CB1 receptors are not located on parietal cells but, rather, on vagal pathways (possibly at preganglionic sites) supplying the gastric mucosa. The lack of effect of CB-receptor ligands in vitro cannot be ascribed to the use of immature rats, since HU-210 inhibited stimulated acid secretion in vivo, irrespective of the animal age.

  • Gastric antisecretory effects of synthetic cannabinoids after central or peripheral administration in the rat.
    Brain research bulletin, 2004
    Co-Authors: Maristella Adami, Rossitsa Zamfirova, Emil Sotirov, Roman Tashev, Y. Dobrinova, S. Todorov, Gabriella Coruzzi
    Abstract:

    Abstract Previous studies have revealed that cannabinoid (CB)-receptor agonists inhibit gastric acid secretion stimulated by indirectly acting agents, but not by histamine. Aiming to investigate whether central or peripheral mechanisms are involved, the effects of the synthetic CB-receptor agonists WIN55,212-2 and HU-210, administered either intracerebroventricularly (i.c.v.) or intravenously (i.v.) to the anaesthetized rat with lumen-perfused stomach, against gastric acid secretion induced by pentagastrin were tested. Injected i.c.v., both WIN55,212-2 (50 and 100 μg/kg) and HU-210 (25, 50 and 100 μg/kg) were ineffective on either basal secretion or acid output induced by pentagastrin (7.7 μg/kg, i.v.). By contrast, i.v. injections of WIN55,212-2 (100 and 1000 μg/kg) or HU-210 (10–100 μg/kg) significantly inhibited pentagastrin-induced acid secretion, maximal reductions being 75.70 and 82.24% for WIN55,212-2 and HU-210, respectively. The gastric antisecretory effect of HU-210 was prevented by administration of the selective CB1-receptor antagonist SR141716A (1000 μg/kg, i.v.). These results show that CB1-receptors mediating inhibition of gastric acid secretion in the rat are mainly peripherally located.

  • Gastric antisecretory role and immunohistochemical localization of cannabinoid receptors in the rat stomach
    British journal of pharmacology, 2002
    Co-Authors: Maristella Adami, Gabriella Coruzzi, Simone Bertini, Paolo Frati, Anjali Kulkarni-narla, David R. Brown, Giuseppe De Caro, Giulio Soldani
    Abstract:

    The role of cannabinoid (CB) receptors in the regulation of gastric acid secretion was investigated in the rat by means of functional experiments and by immunohistochemistry. In anaesthetized rats with lumen-perfused stomach, the non selective CB-receptor agonist WIN 55,212-2 (0.30 – 4.00 μmol kg−1, i.v.) and the selective CB1-receptor agonist HU-210 (0.03 – 1.50 μmol kg−1, i.v.), dose-dependently decreased the acid secretion induced by both pentagastrin (30 nmol kg−1 h−1) and 2-deoxy-D-glucose (1.25 mmol kg−1, i.v.). By contrast, neither WIN 55,212-2 (1 – 4 μmol kg−1, i.v.) nor HU-210 (0.03 – 1.50 μmol kg−1, i.v.) did modify histamine-induced acid secretion (20 μmol kg−1 h−1). The selective CB2-receptor agonist JWH-015 (3 – 10 μmol kg−1, i.v.) was ineffective. The gastric antisecretory effects of WIN 55,212-2 and HU-210 on pentagastrin-induced acid secretion were prevented by the selective CB1-receptor antagonist SR141716A (0.65 μmol kg−1, i.v.) and unaffected by the selective CB2-receptor antagonist SR144528 (0.65 – 2 μmol kg−1, i.v.). Bilateral cervical vagotomy and ganglionic blockade with hexamethonium (10 mg kg−1, i.v., followed by continuous infusion of 10 mg kg−1 h−1) significantly reduced, but not abolished, the maximal inhibitory effect of HU-210 (0.3 μmol kg−1, i.v.) on pentagastrin-induced acid secretion; by contrast, pretreatment with atropine (1 mg kg−1, i.v.) did not modify the antisecretory effect of HU-210. Immunoreactivity to the CB1 receptor was co-localized with that of the cholinergic marker choline acetyltransferase in neural elements innervating smooth muscle, mucosa and submucosal blood vessels of rat stomach fundus, corpus and antrum. In contrast, CB2 receptor-like immunoreactivity was not observed. These results indicate that gastric antisecretory effects of cannabinoids in the rat are mediated by suppression of vagal drive to the stomach through activation of CB1 receptors, located on pre- and postganglionic cholinergic pathways. However, the ineffectiveness of atropine in reducing the effect of HU-210 suggests that the release of non cholinergic excitatory neurotransmitters may be regulated by CB1 receptors. British Journal of Pharmacology (2002) 135, 1598–1606; doi:10.1038/sj.bjp.0704625

  • Cannabinoid CB1 Receptors Are Involved in the Regulation of Rat Gastric Acid Secretion
    Pharmacy and Pharmacology Communications, 2000
    Co-Authors: Maristella Adami, Simone Bertini, Giulio Soldani, Paolo Frati, Gabriella Coruzzi
    Abstract:

    The effects of cannabinoid CB1 receptor activation (HU-210) and blockade (SR141716A) on gastric acid secretion were determined in anaesthetized rats with lumen perfused stomach. The selective CB1-receptor agonist HU-210 (0.01-0-1 mg kg−1, i.v.) did not affect basal acid secretion while causing inhibition (maximum reduction 74%) of the gastric acid secretion stimulated by pentagastrin (10μ kg−1, i.v.). The inhibitory effect of HU-210 was reversed by the selective cannabinoid CB1-receptor antagonist SR141716A (1 mg kg−1, i.v.), but not by the selective CB2-receptor antagonist SR144528 (1 mg kg−1, i.v.). These results suggest that cannabinoid CB1 receptors may mediate inhibitory effects on gastric acid secretion in the rat.

Maristella Adami - One of the best experts on this subject based on the ideXlab platform.

  • Effects of cannabinoid receptor agonists on rat gastric acid secretion : Discrepancy between in vitro and in vivo data
    Digestive diseases and sciences, 2006
    Co-Authors: Gabriella Coruzzi, Maristella Adami, Elena Guaita, Alessandro Menozzi, Simone Bertini, Elena Giovannini, Giulio Soldani
    Abstract:

    The effects of the cannabinoid (CB)-receptor agonists WIN55,212-2 and HU-210 and the selective CB1-receptor antagonist SR141716A were tested on in vitro and in vivo acid secretion assays from the rat. In the isolated gastric fundus from immature rats, WIN55,212-2 (0.001–30 μ M), HU-210 (0.001–10 μ M), or SR141716A (0.1–10 μ M) did not change the basal acid output or acid responses to histamine, pentagastrin, or electrical field stimulation. HU-210 (0.3 μ mol/kg, intravenously) inhibited the acid response to pentagastrin in anesthetized adult, young, or immature rats with lumen-perfused stomachs; moreover, HU-210 reduced vagally induced acid secretion in adult animals, its antisecretory effect being reversed by SR141716A (0.65 μ mol/kg, intravenously). In vitro and in vivo data indicate that CB1 receptors are not located on parietal cells but, rather, on vagal pathways (possibly at preganglionic sites) supplying the gastric mucosa. The lack of effect of CB-receptor ligands in vitro cannot be ascribed to the use of immature rats, since HU-210 inhibited stimulated acid secretion in vivo, irrespective of the animal age.

  • Gastric antisecretory effects of synthetic cannabinoids after central or peripheral administration in the rat.
    Brain research bulletin, 2004
    Co-Authors: Maristella Adami, Rossitsa Zamfirova, Emil Sotirov, Roman Tashev, Y. Dobrinova, S. Todorov, Gabriella Coruzzi
    Abstract:

    Abstract Previous studies have revealed that cannabinoid (CB)-receptor agonists inhibit gastric acid secretion stimulated by indirectly acting agents, but not by histamine. Aiming to investigate whether central or peripheral mechanisms are involved, the effects of the synthetic CB-receptor agonists WIN55,212-2 and HU-210, administered either intracerebroventricularly (i.c.v.) or intravenously (i.v.) to the anaesthetized rat with lumen-perfused stomach, against gastric acid secretion induced by pentagastrin were tested. Injected i.c.v., both WIN55,212-2 (50 and 100 μg/kg) and HU-210 (25, 50 and 100 μg/kg) were ineffective on either basal secretion or acid output induced by pentagastrin (7.7 μg/kg, i.v.). By contrast, i.v. injections of WIN55,212-2 (100 and 1000 μg/kg) or HU-210 (10–100 μg/kg) significantly inhibited pentagastrin-induced acid secretion, maximal reductions being 75.70 and 82.24% for WIN55,212-2 and HU-210, respectively. The gastric antisecretory effect of HU-210 was prevented by administration of the selective CB1-receptor antagonist SR141716A (1000 μg/kg, i.v.). These results show that CB1-receptors mediating inhibition of gastric acid secretion in the rat are mainly peripherally located.

  • Gastric antisecretory role and immunohistochemical localization of cannabinoid receptors in the rat stomach
    British journal of pharmacology, 2002
    Co-Authors: Maristella Adami, Gabriella Coruzzi, Simone Bertini, Paolo Frati, Anjali Kulkarni-narla, David R. Brown, Giuseppe De Caro, Giulio Soldani
    Abstract:

    The role of cannabinoid (CB) receptors in the regulation of gastric acid secretion was investigated in the rat by means of functional experiments and by immunohistochemistry. In anaesthetized rats with lumen-perfused stomach, the non selective CB-receptor agonist WIN 55,212-2 (0.30 – 4.00 μmol kg−1, i.v.) and the selective CB1-receptor agonist HU-210 (0.03 – 1.50 μmol kg−1, i.v.), dose-dependently decreased the acid secretion induced by both pentagastrin (30 nmol kg−1 h−1) and 2-deoxy-D-glucose (1.25 mmol kg−1, i.v.). By contrast, neither WIN 55,212-2 (1 – 4 μmol kg−1, i.v.) nor HU-210 (0.03 – 1.50 μmol kg−1, i.v.) did modify histamine-induced acid secretion (20 μmol kg−1 h−1). The selective CB2-receptor agonist JWH-015 (3 – 10 μmol kg−1, i.v.) was ineffective. The gastric antisecretory effects of WIN 55,212-2 and HU-210 on pentagastrin-induced acid secretion were prevented by the selective CB1-receptor antagonist SR141716A (0.65 μmol kg−1, i.v.) and unaffected by the selective CB2-receptor antagonist SR144528 (0.65 – 2 μmol kg−1, i.v.). Bilateral cervical vagotomy and ganglionic blockade with hexamethonium (10 mg kg−1, i.v., followed by continuous infusion of 10 mg kg−1 h−1) significantly reduced, but not abolished, the maximal inhibitory effect of HU-210 (0.3 μmol kg−1, i.v.) on pentagastrin-induced acid secretion; by contrast, pretreatment with atropine (1 mg kg−1, i.v.) did not modify the antisecretory effect of HU-210. Immunoreactivity to the CB1 receptor was co-localized with that of the cholinergic marker choline acetyltransferase in neural elements innervating smooth muscle, mucosa and submucosal blood vessels of rat stomach fundus, corpus and antrum. In contrast, CB2 receptor-like immunoreactivity was not observed. These results indicate that gastric antisecretory effects of cannabinoids in the rat are mediated by suppression of vagal drive to the stomach through activation of CB1 receptors, located on pre- and postganglionic cholinergic pathways. However, the ineffectiveness of atropine in reducing the effect of HU-210 suggests that the release of non cholinergic excitatory neurotransmitters may be regulated by CB1 receptors. British Journal of Pharmacology (2002) 135, 1598–1606; doi:10.1038/sj.bjp.0704625

  • Cannabinoid CB1 Receptors Are Involved in the Regulation of Rat Gastric Acid Secretion
    Pharmacy and Pharmacology Communications, 2000
    Co-Authors: Maristella Adami, Simone Bertini, Giulio Soldani, Paolo Frati, Gabriella Coruzzi
    Abstract:

    The effects of cannabinoid CB1 receptor activation (HU-210) and blockade (SR141716A) on gastric acid secretion were determined in anaesthetized rats with lumen perfused stomach. The selective CB1-receptor agonist HU-210 (0.01-0-1 mg kg−1, i.v.) did not affect basal acid secretion while causing inhibition (maximum reduction 74%) of the gastric acid secretion stimulated by pentagastrin (10μ kg−1, i.v.). The inhibitory effect of HU-210 was reversed by the selective cannabinoid CB1-receptor antagonist SR141716A (1 mg kg−1, i.v.), but not by the selective CB2-receptor antagonist SR144528 (1 mg kg−1, i.v.). These results suggest that cannabinoid CB1 receptors may mediate inhibitory effects on gastric acid secretion in the rat.

Raphael Mechoulam - One of the best experts on this subject based on the ideXlab platform.

  • Effect of the synthetic cannabinoid HU-210 on quorum sensing and on the production of quorum sensing-mediated virulence factors by Vibrio harveyi
    BMC Microbiology, 2015
    Co-Authors: Divya Soni, Aviva Breuer, Raphael Mechoulam, Reem Smoum, Doron Steinberg
    Abstract:

    BackgroundBacterial populations communicate through the cell density-dependent mechanism of quorum sensing (QS). Vibrio harveyi, one of the best studied model organisms for QS, was used to explore effects of the synthetic cannabinoid HU-210 on QS and different QS-regulated physiological processes in bacteria.ResultsAnalysis of QS-regulated bioluminescence in wild-type and mutant strains of V. harveyi revealed that HU-210 affects the autoinducer-2 (AI-2) pathway, one of three known QS cascades of V. harveyi. Furthermore, QS-mediated biofilm formation and swimming motility in the mutant strain BB152 (AI-1−, AI-2+) were significantly reduced in the presence of HU-210. HU-210 inhibited QS-mediated virulence factor production without any inhibitory effect on bacterial growth. It also alters the expression of several genes, which are regulated by QS, specifically downregulating the genes of the AI-2 QS cascade.ConclusionFirst evidence is being provided for interference of bacterial signal-transduction systems by a synthetic cannabinoid. The effect of HU-210 was specific to the AI-2 cascade in V. harveyi. AI-2 is known as a "universal autoinducer" and interference with its activity opens a broad spectrum of applications for synthetic cannabinoids in future research as a potential anti-QS agent.

  • The synthetic cannabinoid HU-210 attenuates neural damage in diabetic mice and hyperglycemic pheochromocytoma PC12 cells.
    Neurobiology of disease, 2007
    Co-Authors: Yossi Dagon, Raphael Mechoulam, Yosefa Avraham, Gabriela Link, Olga Zolotarev, Elliot M. Berry
    Abstract:

    Diabetic neuropathy (DN) is a common complication of diabetes mellitus resulting in cognitive dysfunction and synaptic plasticity impairment. Hyperglycemia plays a critical role in the development and progression of DN, through a number of mechanisms including increased oxidative stress. Cannabinoids are a diverse family of compounds which can act as antioxidative agents and exhibit neuroprotective properties. We investigated the effect of the synthetic cannabinoid HU-210 on brain function of streptozotocin (STZ)-induced diabetic mice. These animals exhibit hyperglycemia, increased cerebral oxidative stress and impaired brain function. HU-210, through a receptor independent pathway, alleviates the oxidative damage and cognitive impairment without affecting glycemic control. To study the neuroprotective mechanism(s) involved, we cultured PC12 cells under hyperglycemic conditions. Hyperglycemia enhanced oxidative stress and cellular injuries were all counteracted by HU-210-in a dose dependent manner. These results suggest cannabinoids might have a therapeutic role in the management of the neurological complications of diabetes.

  • Drug-Induced Hypothermia Reduces Ischemic Damage Effects of the Cannabinoid HU-210
    Stroke, 2003
    Co-Authors: Ronen R. Leker, Raphael Mechoulam, Naomi Gai, Haim Ovadia
    Abstract:

    Background and Purpose— Cannabinoids confer neuroprotection in several experimental paradigms, but the responsible mechanisms remain unknown. Therefore, we sought to examine whether the synthetic CB1 agonist HU-210 is capable of reducing ischemic damage and to determine the mechanisms responsible for such protection. Methods— Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (PMCAO). After dose-response and therapeutic time window-finding experiments, the rats were injected with HU-210 (45 μg/kg IV) or vehicle 1 hour after PMCAO. Physiological parameters and cerebral blood flow in the peri-infarct zone were monitored. The animals were examined with a motor disability scale, and the infarct volumes were measured 72 hours later. We also examined the effects of the selective CB1 antagonist SR-141716 and of controlled warming on the neuroprotection conferred by HU-210. Results— HU-210 reduced blood pressure and heart rate but did not alter the cerebral blood flow in the infarct border z...

  • Activation of Cannabinoid Receptors Decreases the Area of Ischemic Myocardial Necrosis
    Bulletin of Experimental Biology and Medicine, 2002
    Co-Authors: D. S. Ugdyzhekova, A. V. Krylatov, Raphael Mechoulam, L N Maslov, N. A. Bernatskaya, R. G. Pertwee
    Abstract:

    We studied the possibility of decreasing the area of ischemic necrosis during myocardial infarction with HU-210, a selective cannabinoid receptor agonist. Activation of cannabinoid receptors with HU-210 had practically no effect on collateral blood flow in the myocardium, but considerably decreased the area of necrosis. There results indicate that cannabinoid receptor agonist HU-210 possesses cardioprotective activity and delays the formation of necrotic zones during coronary occlusion and reperfusion.

  • CANNABINOID ENANTIOMER ACTION ON THE CYTOARCHITECTURE
    Cell biology international, 1996
    Co-Authors: Ronald G. Wilson, Raphael Mechoulam, Stephen K. Tahir, Selma Zimmerman, Arthur M. Zimmerman
    Abstract:

    Abstract The negative and positive enantiomers of 7-hydroxy- Δ6-tetrahydrocannabinol-dimethylheptyl (designated HU-210 and HU-211 respectively) differentially affect undifferentiated and differentiating cultured pheochromocytoma cells (PC-12 cells). In general, cell viability and cell proliferation were suppressed to a much greater extent with HU-210 than with HU-211 in differentiating cells. The effects of these synthetic cannabinoids on the cytoskeleton of PC-12 cells were examined by epifluorescence and confocal microscopy. In both undifferentiated and differentiating PC-12 cells, HU-211 has little effect on the cytoarchitecture whereas HU-210 disrupts the distribution of microtubules and microfilaments. Vacuoles (2 –4 μm) were evident in the cytoplasm of HU-210-treated cells but not in the cytoplasm of HU-211-treated cells or in vehicle controls. Tubulin and actin mRNA levels were reduced to 5 and 40 %, respectively (relative to untreated controls) in 10 μmHU-210-treated cells whereas the same concentration of HU-211 reduced tubulin and actin mRNA levels to 90 and 95 %, respectively. A comparison of the effects of the paired enantiomers and Δ1-THC on the cellular parameters studied reveals that in differentiating cells the action of Δ1-THC is intermediate between that of HU-210 and HU-211. This study demonstrates that compared to HU-210 and Δ1-THC the positive enantiomer HU-211 has little cellular activity.