135 results on '"Souccar C"'
Search Results
2. Anti-secretory, anti-inflammatory and anti- Helicobacter pylori activities of several fractions isolated from Piper carpunya Ruiz & Pav.
- Author
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Quílez, A., Berenguer, B., Gilardoni, G., Souccar, C., de Mendonça, S., Oliveira, L.F.S., Martín-Calero, M.J., and Vidari, G.
- Published
- 2010
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3. Inhibition of gastric acid secretion by a standardized aqueous extract of Cecropia glaziovii Sneth and underlying mechanism
- Author
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Souccar, C., Cysneiros, R.M., Tanae, M.M., Torres, L.M.B., Lima-Landman, M.T.R., and Lapa, A.J.
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- 2008
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4. Antidepressant-like effect of Cecropia glazioui Sneth and its constituents--In vivo and in vitro characterization of the underlying mechanism
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Rocha, F.F., Lima-Landman, M.T.R., Souccar, C., Tanae, M.M., De Lima, T.C.M., and Lapa, A.J.
- Subjects
Antidepressants -- Research ,Medicinal plants -- Research ,Monoamine oxidase -- Research ,Biological sciences ,Health ,Science and technology - Abstract
Abstract The present study aimed to characterize the antidepressant-like effect of a standardized aqueous extract (AE) of Cecropia glazioui Sneth and its purified fractions on in vivo (forced swimming test), [...]
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- 2007
5. Inhibition of histamine-induced bronchospasm in guinea pigs treated with Cecropia glaziovi Sneth and correlation with the in vitro activity in tracheal muscles
- Author
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Delarcina, Jr., S., Lima-Landman, M.T.R., Souccar, C., Cysneiros, R.M., Tanae, M.M., and Lapa, A.J.
- Subjects
Antihistamines -- Research ,Medicinal plants -- Research ,Antihypertensive drugs -- Research ,Pharmaceutical research -- Research ,Biological sciences ,Health ,Science and technology - Abstract
Abstract A standardized aqueous extract (AE) and a purified fraction (BuF) of Cecropia glaziovi Sneth leaves were tested in unrestrained guinea pigs challenged with histamine. Changes of the respiratory pressure [...]
- Published
- 2007
6. ACE activity during the hypotension produced by standardized aqueous extract of Cecropia glaziovii Sneth: a comparative study to captopril effects in rats
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Ninahuaman, M.F.M.L., Souccar, C., Lapa, A.J., and Lima-Landman, M.T.R.
- Subjects
ACE inhibitors -- Research ,Medicinal plants -- Research ,Pharmaceutical research -- Research ,Antihypertensive drugs -- Research ,Biological sciences ,Health ,Science and technology - Abstract
Abstract To evaluate the effect of the standardized aqueous extract (AE) of Cecropia glaziovii Sneth on the plasma angiotensin I converting enzyme (ACE-EC 3.4.15.1) activity, rats were treated with a [...]
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- 2007
7. Chemical standardization of the aqueous extract of Cecropia glaziovii Sneth endowed with antihypertensive, bronchodilator, antiacid secretion and antidepressant-like activities
- Author
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Tanae, M.M., Lima-Landman, M.T.R., De Lima, T.C.M., Souccar, C., and Lapa, A.J.
- Subjects
Medicine, Botanic -- Research ,Medicine, Herbal -- Research ,Antihypertensive drugs -- Research ,Biological sciences ,Health ,Science and technology - Abstract
Abstract This study reports the extraction process and standardization of the aqueous extract (AE) of a Cecropia species aiming its pharmacological characterization as a phytomedicine to be used in primary [...]
- Published
- 2007
8. Antihypertensive effect of a standardized aqueous extract of Cecropia glaziovii Sneth in rats: an in vivo approach to the hypotensive mechanism
- Author
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Lima-Landman, M.T.R., Borges, A.C.R., Cysneiros, R.M., De Lima, T.C.M., Souccar, C., and Lapa, A.J.
- Subjects
Medicinal plants -- Research ,Antihypertensive drugs -- Research ,Biological sciences ,Health ,Science and technology - Abstract
Abstract Cecropia glaziovii Sneth is a common tree at the Southeastern Brazilian coast. As many other species of the genus, it shares the reputed folk use to treat heart failure, [...]
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- 2007
9. Pharmacological study of Stachytarpheta cayennensis Vahl in rodents
- Author
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Mesia-Vela, S., Souccar, C., Lima-Landman, M.T.R., and Lapa, A.J.
- Subjects
Materia medica, Vegetable -- Research ,Antacids -- Research ,Medicinal plants -- Research ,Plant extracts -- Research ,Biological sciences ,Health ,Science and technology - Abstract
Abstract Freeze-dried aqueous extracts (AEs, 0.1-1 g/kg body wt., p.o.) obtained from entire or selected parts of Stachytarpheta cayennensis were tested for their effects on gastric secretion, gastric motility, inflammation [...]
- Published
- 2004
10. Nicotinic receptor/ionic channel complex (AChR) in androgen-dependent skeletal muscle cultures
- Author
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Bielavsky, M., Souccar, C., Lapa, A., and Lima-Landman, M.
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- 2002
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11. Solanum paniculatum L. (Jurubeba): potent inhibitor of gastric acid secretion in mice
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Mesia-Vela, S., Santos, M.T., Souccar, C., Lima-Landman, M.T.R., and Lapa, A.J.
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Biological sciences ,Health ,Science and technology - Abstract
Summary Solanum paniculatum L. is used commonly in Brazilian folk medicine for the treatment of liver and gastrointestinal disorders. The freeze-dried aqueous extracts (WEs) obtained from distinct parts of the [...]
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- 2002
12. Alpha-tocopherol in the hypothermic preservation of the rat small bowel: a functional study
- Author
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Brandão, S.C, Taha, M.O, Fagundes, D.J, Souccar, C, Lapa, A.J, and da Silva Pias, V.M
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- 2002
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13. THE TROPHIC FUNCTION OF TESTOSTERONE ON HORMONE SENSITIVE SKELETAL MUSCLES
- Author
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Souccar, C., primary, Lapa, A.J., additional, and Valle, J.R., additional
- Published
- 1978
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14. Altered acetylcholine release in the hippocampus of dystrophin-deficient mice
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Parames, S.F., primary, Coletta-Yudice, E.D., additional, Nogueira, F.M., additional, Nering de Sousa, M.B., additional, Hayashi, M.A., additional, Lima-Landman, M.T.R., additional, Lapa, A.J., additional, and Souccar, C., additional
- Published
- 2014
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15. Presence of mRNA of muscle nicotinic acetylcholine receptor subunits and an ɛ-subunit splice variant in the mouse brain
- Author
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Ghedini, P.C., primary, Honda, L., additional, Avellar, M.C.W., additional, and Souccar, C., additional
- Published
- 2010
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16. Projections From the Anterior Interposed Nucleus to the Red Nucleus Diminish With Age in the Mouse
- Author
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Olyntho-Tokunaga, H. H. V., primary, Pinto, M. L., additional, Souccar, C., additional, Schoorlemmer, G. H. M., additional, and Lapa, R. C. R. S., additional
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- 2008
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17. Neuromuscular activity of Bothrops neuwiedi pauloensis snake venom in mouse nerve-muscle preparations
- Author
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Durigon, A. M., primary, Borja-Oliveira, C. R., additional, Dal Belo, C. A., additional, Oshima-Franco, Y., additional, Cogo, J. C., additional, Lapa, A. J., additional, Souccar, C., additional, and Rodrigues-Simioni, L., additional
- Published
- 2005
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18. The pharmacological effect of Bothrops neuwiedii pauloensis (jararaca-pintada) snake venom on avian neuromuscular transmission
- Author
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Borja-Oliveira, C.R., primary, Durigon, A.M., additional, Vallin, A.C.C., additional, Toyama, M.H., additional, Souccar, C., additional, Marangoni, S., additional, and Rodrigues-Simioni, L., additional
- Published
- 2003
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19. Nicotinic receptor/ionic channel complex (AChR) in androgen-dependent skeletal muscle cultures
- Author
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Bielavsky, M., primary, Souccar, C., additional, Lapa, A., additional, and Lima-Landman, M., additional
- Published
- 2001
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20. Pharmacology of Piper marginatum Jacq. a folk medicinal plant used as an analgesic, antiinflammatory and hemostatic
- Author
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D’Angelo, L.C.A., primary, Xavier, H.S., additional, Torres, L.M.B., additional, Lapa, A.J., additional, and Souccar, C., additional
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- 1997
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21. Evaluation of the antiurolithiatic activity of the extract of Costus spiralis Roscoe in rats
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Viel, T. Araujo, Domingos, C. Diogo, Monteiro, A.P. da Silva, Lima-Landman, Riggio, M.T., Lapa, A.J., and Souccar, C.
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- 1999
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22. Pharmacology of Piper marginatumJacq. a folk medicinal plant used as an analgesic, antiinflammatory and hemostatic
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D’Angelo, L.C.A., Xavier, H.S., Torres, L.M.B., Lapa, A.J., and Souccar, C.
- Abstract
The pharmacological activities of the water extract of Piper marginatumJacq. (Piperaceae), a plant reputed in the Brazilian folk medicine for its analgesic/antiinflammatory, hemostatic and skin wound-healing properties, were assessed. Intraperitoneal injection (i. p.) of the extract (0.1 to 1 g/kg) in mice and rats caused piloerection, sialorrhea, lacrimation, muscle relaxation and dyspnea. At doses above 1 g/kg the extract caused respiratory arrest and death. Intravenous injection of the extract (0.1 to 0.5 mg/kg) into anesthetized rats caused a dose-related hypertension (by 27 to 48 %) that was blocked by prazosin (1 mg/kg) and yohimbine (2 mg/kg). Pithing, reserpine treatment and ganglionic blockade with hexamethonium (5 mg/kg) enhanced the effect. Oral treatment of unanesthetized rats and intragastric administration to anesthetized animals also produced hypertension. The sympathomimetic activity of the extract in isolated vas deferens, left atria and mesenteric arterial bed preparations paralleled that of noradrenaline, and was blocked to the same extent as noradrenaline by α-blockers. The plant extract (0.5 and 1 g/kg, p. o.) also reduced carrageenin-induced paw edema in rats by 80 to 90 % of the control, but it had less effect on the volume of exudate and leucocyte migration in carrageenin-induced pleurisy. Likewise, the extract had a small analgesic effect on the acetic acid-induced writhing test in mice.
- Published
- 1997
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23. Meproadifen reaction with the ionic channel of the acetylcholine receptor: potentiation of agonist-induced desensitization at the frog neuromuscular junction.
- Author
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Maleque, M A, Souccar, C, Cohen, J B, and Albuquerque, E X
- Abstract
The actions of the nicotinic noncompetitive antagonist meproadifen on both the acetylcholine (ACh) receptor-ion channel complex and electrically excitable membrane were examined in frog sciatic-nerve sartorius muscle preparations. Meproadifen (10-25 microM) blocked the nerve-evoked twitch without affecting the directly evoked twitch, the threshold, overshoot, amplitude, rate of rise, or falling phase of the directly elicited action potential in muscle. This suggests that this agent, at the concentrations that affect the nicotinic receptor, had negligible effect on the excitable membrane. In addition, the drug did not affect either the quantal content or quantal size of the end-plate potential. Meproadifen caused a voltage- and time-dependent decrease in the peak amplitude of the end-plate current (EPC) without significantly shortening the time constant of EPC decay. The voltage- and time-dependent effects of meproadifen were more pronounced at more negative potentials, as evidenced by hysteresis loops and nonlinearity in the current-voltage relationship of the EPC. Both hysteresis and nonlinearity in the current-voltage relationship of the EPC were eliminated when brief conditioning pulses were used for stepwise changes of membrane potentials. The decay time constant of the EPC in the presence of meproadifen remained an exponential function of time. Meproadifen blocked iontophoretically elicited EPCs but did not affect single-channel lifetime, conductance, or the decay time constant of the miniature EPC. Thus, the blockade was more marked on iontophoretically elicited EPCs than on miniature EPCs. Meproadifen also caused desensitization of both the junctional and extrajunctional ACh receptors, but, more important, meproadifen accelerated steady-state desensitization by several-fold (compared with the agonist). The marked depression of peak EPC amplitude and miniature EPC, its high affinity for the binding sites in the presence of the agonist, and acceleration of agonist-induced desensitization suggest that meproadifen interacts with the ACh-bound but nonconducting state of the ACh receptor-ion channel complex. Therefore, it appears that meproadifen interacts with the closed ionic channel of the ACh receptor in its resting and activated but nonconducting states, and only slightly affects the open conformation of the ionic channel.
- Published
- 1982
24. Interactions of gephyrotoxin with the acetylcholine receptor-ionic channel complex. I. Blockade of the ionic channel.
- Author
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Souccar, C, Varanda, W A, Daly, J W, and Albuquerque, E X
- Abstract
The novel tricyclic alkaloid, gephyrotoxin ( GyTX ), found in the skin secretions of the frog Dendrobates histrionicus , potentiates and blocks the indirectly elicited muscle twitch in a concentration-dependent manner. GyTX prolongs the falling phase of the muscle action potential and decreases delayed rectification, supporting the idea that the alkaloid blocks the voltage-sensitive potassium conductance of the electrically excitable membrane. The peak amplitude of the end-plate currents (EPC) and miniature end-plate currents ( MEPC ) were depressed, but no significant deviation from linearity relative to control was seen in the current-voltage relationship. The decay time constant of the EPC (tau EPC) was markedly shortened by GyTX , the effect being greater at 10 degrees than at 22 degrees. The relationship between the log of tau EPC and membrane potential disclosed a linear relationship at all concentrations tested, but a progressive loss of voltage sensitivity of tau EPC was seen when GyTX concentrations were increased. Also, the plot of 1/tau EPC against GyTX concentration revealed a linear relationship. The lack of voltage and time dependence suggests that GyTX has little effect on the ACh receptor-ionic channel complex in the closed conformation. Single-channel conductance studied by means of fluctuation analysis did not change after GyTX application, but the channel lifetime decreased by about 40% at clamp potentials of -105 mV and at a toxin concentration of 7.5 microM. Repetitive nerve stimulation led to a pronounced " rundown " in the EPCs which was frequency-dependent. These findings were taken as evidence that GyTX interacts with the acetylcholine receptor complex, causing a blockade of its channel mainly in the open conformation.
- Published
- 1984
25. Interactions of gephyrotoxin with the acetylcholine receptor-ionic channel complex. II. Enhancement of desensitization.
- Author
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Souccar, C, Varanda, W A, Aronstam, R S, Daly, J W, and Albuquerque, E X
- Abstract
The actions of the tricyclic alkaloid gephyrotoxin ( GyTX ) on the extrajunctional and junctional acetylcholine (ACh) sensitivity and desensitization were studied in the chronically denervated rat soleus muscle and cutaneous pectoris muscle of the frog. At low concentrations, GyTX greatly depressed the extrajunctional ACh sensitivity of the chronically denervated soleus muscles. In addition, GyTX produced a strong inhibition of junctional end-plate potentials evoked by ACh. Junctional and extrajunctional desensitizations induced by microiontophoretically applied ACh were greatly enhanced by the alkaloid in a frequency-dependent manner. These effects were readily reversible. The interaction of GyTX with binding sites on the acetylcholine receptor-channel (AChR) complex was studied on electroplax membranes from Torpedo californica. GyTX binds to the AChR complex at a site distinct from the ACh binding site, as revealed by its lack of inhibition of [125I]alpha-bungarotoxin ( [125I]BGT) binding. On the other hand, GyTX at a concentration range between 1 microM and 100 microM significantly increased the potency of the agonist carbamylcholine as an antagonist of binding of [125I]BGT. At low micromolar concentrations, GyTX inhibited the binding of [3H]perhydrohistrionicotoxin and [3H] phencyclidine to sites associated with the ionic channel of the AChR complex. The affinity of GyTX for these sites was increased 3- to 5-fold by carbamylcholine. Results of electrophysiological and binding studies indicate that GyTX not only blocks the open channel of the AChR but also enhances desensitization of the AChR complex by increasing receptor affinity for agonists.
- Published
- 1984
26. Diterpene from Baccharis trimera with a relaxant effect on rat vascular smooth muscle
- Author
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Torres, L. M., Gamberini, M. T., Roque, N. F., Lima-Landman, M. T., Souccar, C., and Lapa, A. J.
- Published
- 2000
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27. Early and late influences of testosterone on acetylcholinesterase activity of skeletal muscles from developing rats
- Author
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Souccar, C., Rosely Godinho, Dias, M. A., and Lapa, A. J.
28. Relative responsiveness (ϱ): A critical analysis of a new method in receptor differentiation
- Author
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Jurkiewicz, A., primary, Abdo, A.O., additional, Jurkiewicz, N.H., additional, Guedes, A.O., additional, and Souccar, C., additional
- Published
- 1976
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29. Intestine of dystrophic mice presents stretch resistance, muscle atrophy and impaired calcium-dependent contractility.
- Author
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Alves, G. A., Silva, L. R., Ribeiro, R. F., Rosa, E. F., Aboulafia, J., Freymüller, E., Souccar, C., and Nouailhetas, V. L.
- Subjects
DYSTROPHIN ,SYNTROPHINS ,CELL membranes - Abstract
The protein dystrophin is a component of the dystrophin-associated protein complex which links the contractile machinery to the plasma membrane to the extracellular matrix. The absence of dystrophin leads to a pathological condition known as the Duchenne muscular dystrophy (DMD), a disease characterized by a progressive skeletal muscle degeneration, disability, and early death. The mdx mice is the most common DMD animal model. Alterations in gastrointestinal tissues from DMD patients and mdx mice are scarcely described, and little understood. Using isolated tissue samples, explanted from mdx and control mice, we thus investigated the possible relationships between possible morphological and contractile properties impairments with alterations in the calcium handling due to the absence of the protein dystrophin in the mdx mice ileum. Absence of dystrophin caused 27% reduction in the longitudinal muscular layer thickness, accompanied by a partial damage to the mucosa layer (Chiu score of 2-4 by dystrophic animal in comparison with 0-2 score in control), and a partial damage to the mitochondria from the longitudinal muscular layer. Functionally, it was shown a higher resistance to basal tissue stretching (as the contractile response under 1 g- basal tension in mdx is maintained the same as under the optimal 0.5 g-basal tension in mdx mice. In control mice, the responses under 1 g-basal tension are already diminished) and impairment in the Emax (maximum effect) of both eletro- (mdx: 2.36 ± 0.09 g and control: 2.77 ± 0.13 g) and pharma- comechanical (mdx: 2.47 ± 0.09 g and control 2.95 ± 0.12 g) signaling associated with altered calcium influx (half-life time of 1.2 min in mdx mice compared to 0.4 in control stimulation with KCl successive stimuli), without any alteration in the sarcoplasmic reticulum calcium storage (maintenance of the caffeine-induced contraction, 1.12 ± 0.07 g in control and 0.98 ± 0.05 g in mdx mice), in the ileum isolated from the dystrophic animal as compared to control animals. It is thus concluded that intestine is sensitive to the dystrophic condition, as the protein dystrophin plays an important role in the preservation of both the micro and ultra structure of mice intestine, while exerting minor roles concerning both the intestinal contractile responsiveness and the SR calcium storage capacity and release in dystrophic mice. [ABSTRACT FROM AUTHOR]
- Published
- 2013
30. Estudo farmacológico do extrato bruto do Datura arborea L
- Author
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José Maria Serejo S. Jacinto, José Antonio Lapa, and Souccar Caden
- Subjects
Science (General) ,Q1-390 - Abstract
O trombeteiro é uma solanacea arbustiva comum na ilha de São Luís. Suas flores e Folhas são utilizadas popularmente na forma de cigarros durante as crises asmáticas agudas. Como no Maranhão são freqüentes as crises asmáticas relacionadas com a exploração de jaborandi para a produção de pilocarpina, procura-se neste trabalho, relacionar a atividade farmacológica das folhas com sua utilização popular. As folhas verdes foram extraídas a frio com etanol e o extrato bruto (EB) concentrado a vácuo. Para os testes farmacológicos e EB era disperso em salina/tween-80 (0,03ml100mg EB) e injetado i.p. ou e.v. Os testes gerais de atividade em ratos não indicaram ação farmacológica específica do EB (10 a 100 mg/kg i.p) além de midríose acentuada com as maiores doses. No jejuno isolado de ratos as curvas dose-efeito de acetilcolina (ACh) foram deslocadas para a direita na presença do EB sem alterar o efeito contrátil máximo da ACh. Na presença de EB (2 e 5 ug/ml) a DE50 da ACh foi deslocada de 46 e 160 vezes respectivamente. No íleo isolado de cobaia, a incubação de EB (2 ug/ml) por 3 min, bloqueou as contrações produzidas pela ACh (3 x 10-7 M) e pela histamina (3 x 10-7 M). Após a lavagem as respostas foram recuperadas em 35 e 15 min. respectivamente. Na pressão arterial de rato o EB / 1 a 5 mg/kg) não produziu efeitos constantes mas inibiu a hipotensão produzida pela ACh (1 a 5 ug/kg) deslocando paralelamente a curva dose-resposta. Doses maiores do EB (10 a 50 mg/kg) produziram hipertensão proporcional à dose. A hipertensão correspondente à dose mais elevada foi reduzida de 80% na presença de yoimbina (3 mg/kg), dose suficiente para reduzir de 95% a resposta pressórica à noradrenalina (2 ug/kg). Estes dados comprovam que a ação predominante da Datura arborea L. é parassimpaticolítica. No extrato da folha a substância com esta ação parece estar associada a outra(s) substância(s) de atividade alfa-simpaticomimética cujas ações vasoconstritoras poderiam ser sinérgicas na atividade anti-asmática.
- Published
- 1988
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31. Prejunctional effect of quaternary derivatives of l-hyoscyamine at the rat neuromuscular junction. A structure-activity relationship study
- Author
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Souccar, C., Soldera, J. Do Carmo, Cysneiros, R. M., and Goncalo, M. Do Carmo
- Published
- 1994
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32. Inhibition of the gastric H+,K+ -ATPase by plectrinone A, a diterpenoid isolated from Plectranthus barbatus Andrews.
- Author
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Schultz C, Bossolani MP, Torres LMB, Lima-Landman MTR, Lapa AJ, and Souccar C
- Abstract
This work assessed the mechanism underlying the antisecretory gastric acid effect of Plectranthus barbatus Andrews (Lamiaceae) and active constituents. Popularly known as 'false-boldo', this plant is used in Brazilian folk medicine to treat gastrointestinal and hepatic ailments. The plant aqueous extract (AE) and isolated compounds were assayed in vivo in pylorus-ligated mice, and in vitro on acid secretion measured as [(14)C]-aminopyrine ([(14)C]-AP) accumulation in rabbit gastric glands and gastric H(+),K(+)-ATPase preparations. Injected into the duodenal lumen, the AE of the plant leaves (0.5 and 1.0 g/kg) decreased the volume (62 and 76%) and total acidity (23 and 50%) of gastric acid secretion in pylorus-ligated mice. Bioguided purification of the AE yielded an active fraction (IC(50)=24 microg/ml) that inhibited acid secretion in rabbit gastric glands with a potency 10 to 18 times greater than that of the originating extract, on both the basal and stimulated acid secretion by histamine (His) (1 microM) or bethanechol (100 microM). At the same concentrations the gastric H(+),K(+)-ATPase activity was also inhibited. The active constituent was chemically identified as the abietanoid dienedione plectrinone A which reduced the H(+),K(+)-ATPase activity with IC(50)=171 microM. The results indicate that inhibition of the gastric proton pump by this diterpenoid may account for the antisecretory acid effect and reputed antiulcer activity of Plectranthus barbatus. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
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33. 1248 - THE TROPHIC FUNCTION OF TESTOSTERONE ON HORMONE SENSITIVE SKELETAL MUSCLES
- Author
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Souccar, C., Lapa, A.J., and Valle, J.R.
- Published
- 1978
- Full Text
- View/download PDF
34. Vasorelaxant effects of ellagitannins isolated from Cuphea carthagenensis.
- Author
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Isla KKY, Tanae MM, de Lima-Landman MTR, de Magalhães PM, Lapa AJ, and Souccar C
- Subjects
- Rats, Animals, Vasodilator Agents pharmacology, Hydrolyzable Tannins pharmacology, Rats, Wistar, Endothelial Cells, Vasodilation, Endothelium, Vascular, Nitric Oxide metabolism, Aorta, Thoracic metabolism, NG-Nitroarginine Methyl Ester pharmacology, Cuphea metabolism, Hypotension
- Abstract
Cuphea carthagenensis (Jacq.) J. F. Macbr. is a popular plant in Brazilian folk medicine owing to its hypotensive and central nervous system depressant effects. This study aimed to validate the hypotensive effect of the plant's aqueous extract (AE) in rats and examine the vascular actions of three hydrolyzable tannins, oenothein B, woodfordin C, and eucalbanin B, isolated from AE. Systolic blood pressure in unanesthetized rats was determined using the non-invasive tail-cuff method. Oral treatment of normotensive rats with 0.5 and 1.0 g/kg/day AE induced a dose-related hypotensive effect after 1 week. In rat aortic rings pre-contracted with noradrenaline, all ellagitannins (20 - 180 µM) induced a concentration-related vasorelaxation. This effect was blocked by either removing the endothelium or pre-incubating with N
G -nitro-l-arginine methyl ester (10 µM), an inhibitor of nitric oxide (NO) synthase. In KCl-depolarized rat portal vein preparations, the investigated compounds did not affect significantly the maximal contractile responses and pD2 values of the concentration-response curves to CaCl2 . Our results demonstrated the hypotensive effect of C. carthagenensis AE in unanesthetized rats. All isolated ellagitannins induced vasorelaxation in vitro via activating NO synthesis/NO release from endothelial cells, without altering the Ca2+ influx in vascular smooth muscle preparations. Considering the low oral bioavailability of ellagitannins, the determined in vitro actions of these compounds are unlikely to account for the hypotensive effect of AE in vivo . It remains to be determined the role of the bioactive ellagitannin-derived metabolites in the hypotensive effect observed after oral treatment of unanesthetized rats with the plant extract., Competing Interests: The authors declare that they have no conflicts of interest., (Thieme. All rights reserved.)- Published
- 2024
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35. Unlocking the role of dorsal hippocampal α4β2 nicotinic acetylcholine receptors in Ethanol-Induced conditioned place preference in mice.
- Author
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Palombo P, Maeda R, Riberti Zaniboni C, Antonagi Engi S, Yokoyama T, Bonetti Bertagna N, Anesio A, Cristina Bianchi P, Righi T, Emily Boaventura Tavares G, Souccar C, da Silva FBR, and Cardoso Cruz F
- Subjects
- Mice, Animals, Hippocampus metabolism, Nicotinic Antagonists pharmacology, Ethanol pharmacology, Receptors, Nicotinic metabolism
- Abstract
Alcohol Use Disorder (AUD) presents a significant and challenging public health concern, marked by a dearth of effective pharmacological treatments. Understanding the neurobiological underpinnings of AUD is of paramount importance for the development of efficacious interventions. The process of addiction entails the acquisition of associative behaviors, prominently engaging the dorsal region of the hippocampus for encoding these associative memories. Nicotinic receptor systems have been implicated in mediating the rewarding effects of ethanol, as well as memory and learning processes. In our current investigation, we delved into the role of α4β2 nicotinic acetylcholine receptors (nAChRs) within the dorsal hippocampus in the context of ethanol-induced conditioned place preference (CPP), a robust model for scrutinizing the rewarding properties and drug-associated behaviors. To establish CPP, ethanol (2 g/kg) was administered intraperitoneally during a 8-day conditioning phase. Fos immunohistochemistry was employed to assess the involvement of discrete subregions within the dorsal hippocampus in ethanol-induced CPP. Additionally, we probed the influence of α4β2 nAChRs on CPP via microinjections of a selective nAChR antagonist, dihydro-β-erythroidine (DHBE, at dosages of 6, 12, and 18 µg/0.5 µL per hemisphere) within the hippocampus. Our results unveiled that ethanol-induced CPP was associated with an increase Fos -positive cells in various subregions of the dorsal hippocampus, including CA1, CA2, CA3, and the dentate gyrus. Intrahippocampal administration of DHBE (at doses of 6 and 18 µg/0.50 µL per hemisphere) effectively blocked ethanol-induced CPP, while leaving locomotor activity unaffected. These findings underscore the critical involvement of the dorsal hippocampus and α4β2 nAChRs in the acquisition of ethanol-associated learning and reward., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
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36. Bauhinia Protease Inhibitors Attenuate Gastric Ulcer by Blocking Neutrophil Enzymes.
- Author
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Valois MV, de Oliveira C, Lapa AJ, Souccar C, and Oliva MLV
- Subjects
- Animals, Leukocyte Elastase, Mice, Neutrophils, Plant Proteins, Protease Inhibitors, Rats, Serine Proteinase Inhibitors, Bauhinia, Stomach Ulcer chemically induced, Stomach Ulcer drug therapy
- Abstract
Proteases play a pivotal role in many signaling pathways; inhibitors of well-established proteases have shown a substantial therapeutic success. This study aimed to examine the in vivo effects of 3 protease inhibitors isolated from Bauhinia species: i) Bauhinia mollis elastase inhibitor, which blocks human neutrophil elastase (Ki
app 2.8 nM) and cathepsin G (Kiapp 1.0 nM) activities; ii) Bauhinia mollis trypsin inhibitor, a trypsin inhibitor (Kiapp 5.0 nM); and iii) Bauhinia bauhinioides cruzipain inhibitor, which inhibits elastase (Kiapp 2.6 nM), cathepsin G (Kiapp 160.0 nM), and the cysteine proteases cathepsin L (Kiapp 0.2 nM). Bauhinia bauhinioides cruzipain inhibitor, Bauhinia mollis elastase inhibitor, and Bauhinia mollis trypsin inhibitor were isolated using acetone and ammonium sulfate fractionations, DEAE-Sephadex, trypsin-Sepharose, and Resource-Q chromatographies. Mice and rats were treated intraperitoneally with 1 dose of inhibitor; gastric mucosal lesions were induced by cold-restraint stress. Oral pretreatment of mice with Bauhinia mollis elastase inhibitor or Bauhinia mollis trypsin inhibitor (1 - 10 mg/kg) did not show anti-ulcer effect, while Bauhinia bauhinioides cruzipain inhibitor (0.1 - 1.0 mg/kg) produced a similar reduction of the index of mucosal damage at all effective doses (30 to 33% < control). In rats at doses lower than those used in mice, Bauhinia mollis elastase inhibitor and Bauhinia bauhinioides cruzipain inhibitor reduced the index of mucosal damage by 66% and 54% of controls, respectively. The results indicate a protective effect against gastric mucosal lesions associated with elastase inhibition but not inhibition of trypsin activities. Moreover, the lack of Bauhinia mollis elastase inhibitor efficacy observed in mice may possibly be related to the reported structural differences of elastase in mice and rats., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)- Published
- 2021
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37. Altered release and uptake of gamma-aminobutyric acid in the cerebellum of dystrophin-deficient mice.
- Author
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Pereira da Silva JD, Campos DV, Nogueira-Bechara FM, Stilhano RS, Han SW, Sinigaglia-Coimbra R, Lima-Landman MTR, Lapa AJ, and Souccar C
- Subjects
- Animals, Cerebellum ultrastructure, Dystrophin genetics, Male, Mice, Mice, Inbred C57BL, Mice, Inbred mdx, Muscular Dystrophy, Duchenne genetics, Cerebellum metabolism, Dystrophin deficiency, Muscular Dystrophy, Duchenne metabolism, gamma-Aminobutyric Acid metabolism
- Abstract
Dystrophin deficiency caused by mutations of the related gene leads to muscle wasting in Duchenne muscular dystrophy (DMD). Some patients with DMD also present with intellectual disability and various degrees of neurological disorders, which have been related to a decreased number of postsynaptic gamma-aminobutyric acid type A receptors (GABA
A Rs) in the hippocampus (HPC) and cerebellum (CBL). The aim of this study was to examine the relevance of dystrophin in the presynaptic GABAergic function in brain regions in which this protein is normally abundant. [3 H]-GABA release, induced by nicotinic receptor (nAChR) activation or K+ depolarization, and [3 H]-GABA uptake were determined using synaptosomes extracted from the cortex (CTX), HPC, and CBL of littermate control and mdx mice. Superfusion of the synaptosomes with nicotine or high K+ solutions led to a concentration-dependent and Ca2+ -dependent [3 H]-GABA release in control and mdx synaptosomes. [3 H]-GABA release induced by 10 μM nicotine in mdx CBL synaptosomes was 47% less than that in control mice. K+ -induced [3 H]-GABA release did not differ between control and mdx synaptosomes. α7-containing and β2-containing nAChRs were involved in nicotine-induced [3 H]-GABA release in control and mdx synaptosomes. Kinetic analysis of [3 H]-GABA uptake in mdx CBL synaptosomes showed a reduced (50%) half-maximal uptake time (t1/2 ) and increased (44%) rate of [3 H]-GABA uptake (Vmax ) compared to controls. The apparent transporter affinity (Km ) for GABA was not altered. Our findings show that dystrophin deficiency in mdx mice is associated with significant changes in the release and uptake of GABA in the CBL. These presynaptic alterations may be related to the reported decrease in postsynaptic GABAA R in the same brain region. The results indicate possible dysfunction of GABAergic synapses associated with dystrophin deficiency in the CBL, which may contribute to the cognitive and neurobehavioral disorders in mdx mice and patients with DMD., (Copyright © 2018 Elsevier Ltd. All rights reserved.)- Published
- 2018
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38. Analysis of catalytic properties of tripeptidyl peptidase I (TTP-I), a serine carboxyl lysosomal protease, and its detection in tissue extracts using selective FRET peptide substrate.
- Author
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Kondo MY, Gouvea IE, Okamoto DN, Santos JA, Souccar C, Oda K, Juliano L, and Juliano MA
- Subjects
- Amino Acid Sequence, Animals, Fluorescence Resonance Energy Transfer, Humans, Kinetics, Male, Proteolysis, Rats, Tissue Extracts chemistry, Tripeptidyl-Peptidase 1, Aminopeptidases chemistry, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases chemistry, Serine Proteases chemistry
- Abstract
Tripeptidyl peptidase I (TPP-I), also named ceroid lipofuscinosis 2 protease (CLN2p), is a serine carboxyl lysosomal protease involved in neurodegenerative diseases, and has both tripeptidyl amino- and endo- peptidase activities under different pH conditions. We developed fluorescence resonance energy transfer (FRET) peptides using tryptophan (W) as the fluorophore to study TPP-I hydrolytic properties based on previous detailed substrate specificity study (Tian Y. et al., J. Biol. Chem. 2006, 281:6559-72). Tripeptidyl amino peptidase activity is enhanced by the presence of amino acids in the prime side and the peptide NH2-RWFFIQ-EDDnp is so far the best substrate described for TPP-I. The hydrolytic parameters of this peptide and its analogues indicated that the S4 subsite of TPP-I is occluded and there is an electrostatic interaction of the positively charged substrate N-terminus amino group and a negative locus in the region of the enzyme active site. KCl activated TPP-I in contrast to the inhibition by Ca(2+) and NaCl. Solvent kinetic isotope effects (SKIEs) show the importance of the free N-terminus amino group of the substrates, whose absence results in a more complex solvent-dependent enzyme: substrate interaction and catalytic process. Like pure TPP-I, rat spleen and kidney homogenates cleaved NH2-RWFFIQ-EDDnp only at F-F bond and is not inhibited by pepstatin, E-64, EDTA or PMSF. The selectivity of NH2-RWFFIQ-EDDnp to TPP-I was also demonstrated by the 400 times higher k(cat)/K(M) compared to generally used substrate, NH2-AAF-MCA and by its resistance to hydrolysis by cathepsin D that is present in high levels in kidneys., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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39. Effects of N-acetylcysteine on skeletal muscle structure and function in a mouse model of peripheral arterial insufficiency.
- Author
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Roseguini BT, Silva LM, Polotow TG, Barros MP, Souccar C, and Han SW
- Subjects
- Animals, Biomarkers metabolism, Collagen metabolism, Exercise Tolerance drug effects, Femoral Artery surgery, Ligation, Lipid Peroxidation drug effects, Male, Mice, Inbred BALB C, Muscle Contraction drug effects, Muscle, Skeletal metabolism, Muscle, Skeletal pathology, Muscle, Skeletal physiopathology, Oxidative Stress drug effects, Peripheral Arterial Disease metabolism, Peripheral Arterial Disease pathology, Peripheral Arterial Disease physiopathology, Protein Carbonylation drug effects, Recovery of Function, Time Factors, Acetylcysteine pharmacology, Antioxidants pharmacology, Muscle Fatigue drug effects, Muscle, Skeletal blood supply, Muscle, Skeletal drug effects, Peripheral Arterial Disease drug therapy
- Abstract
Objective: Abnormalities in skeletal muscle structure and function are important contributors to exercise intolerance and functional decline in peripheral arterial disease. In this study, we tested the hypothesis that administration of N-acetylcysteine (NAC) would improve fatigue resistance and ameliorate the histopathological changes in skeletal muscle in a mouse model of peripheral arterial disease. We also anticipated that NAC treatment would lower the levels of biomarkers of oxidative damage in the ischemic muscle., Methods: Male Balb/c mice were subjected to bilateral ligation of the femoral artery and, after 2 weeks of recovery, received daily intraperitoneal injections of either NAC (150 mg/kg) or saline for 15 days. At the end of the treatment, the extensor digitorium longus (EDL) and soleus muscles were excised for assessment of contractile function in vitro and histological analysis. Free malondialdehyde and protein carbonyl levels were measured in the gastrocnemius muscle., Results: In the soleus muscle, force after 10 minutes of submaximal tetanic stimulation (60 Hz, 300 ms trains, 0.3 trains/s) was higher (P < .05) in NAC-treated animals (45% ± 3% of the initial value; n = 7) when compared with controls (30.3% ± 3%; n = 8). No differences were found in fatigue development between groups in the EDL muscle (ligated NAC, 35.7% ± 1.9%; ligated saline, 37.5% ± 1.1%). In addition, there was a tendency for lower levels of connective tissue deposition in the soleus of animals treated with NAC (n = 6) when compared with those that received only saline (n = 9) (ligated NAC, 16% ± 2% vs ligated saline, 24% ± 2%; P = .057). No differences were found in lipid peroxidation or protein carbonyl levels between ligated saline and ligated NAC groups., Conclusions: Taken together, these results indicate that treatment with NAC improves fatigue resistance in the soleus but not the EDL muscle in a model of peripheral arterial insufficiency., Clinical Relevance: Despite the increasing burden of peripheral arterial disease (PAD) and its detrimental consequences on the quality of life of the patients, few pharmacological therapies have shown to evoke meaningful effects on functional performance in these individuals. N-acetylcysteine is approved for clinical use, has minimal side effects and most important, has shown to consistently improve exercise performance in animals and humans. In this study, we showed, for the first time, that treatment with this drug at a dose amenable for clinical application evoked marked effects on fatigue resistance in the soleus muscle in a mouse model of PAD. These encouraging findings set the stage for translational studies to determine the acute and long-term impact of this drug on walking capacity in patients with PAD., (Copyright © 2015 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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40. A comparative study of two clerodane diterpenes from Baccharis trimera (Less.) DC. on the influx and mobilization of intracellular calcium in rat cardiomyocytes.
- Author
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Garcia FA, Tanae MM, Torres LM, Lapa AJ, de Lima-Landman MT, and Souccar C
- Subjects
- Animals, Brazil, Cells, Cultured, Cytoplasm metabolism, Diterpenes, Clerodane chemistry, Diterpenes, Clerodane isolation & purification, Medicine, Traditional, Molecular Structure, Myocytes, Cardiac drug effects, Plant Components, Aerial chemistry, Plant Extracts chemistry, Plant Extracts isolation & purification, Portal Vein drug effects, Rats, Rats, Wistar, Baccharis chemistry, Calcium metabolism, Calcium Channels, L-Type drug effects, Diterpenes, Clerodane pharmacology, Plant Extracts pharmacology
- Abstract
Baccharis trimera (Less.) D.C. (Asteraceae) is a medicinal species native to South America and used in Brazilian folk medicine to treat gastrointestinal and liver diseases, kidney disorders and diabetes. The aqueous extract (AE) of the aerial parts of this species presented two mainly constituents: the ent-clerodane diterpene (Fig. 1) and the neo-clerodane diterpene (Fig. 2). The objective of this work was to study their activities on the blockade of Ca(2+)-induced contractions in KCL-depolarized rat portal vein preparations, and on the influx and mobilization of cytosolic calcium in rat cardiomyocytes by fluorescence measurements. The results showed that both the neo- and the ent-clerodane diterpenes reduced the maximal contractions induced by CaCl2, in KCl depolarized rat portal vein preparations, without modifying the EC50. The data on the concentration of cytosolic calcium ([Ca(2+)]c) showed that, while the neo-clerodane diterpene stimulates the mobilization of [Ca(2+)]c in rat cardiomyocytes, this effect was not observed with the ent-clerodane diterpene. On the other hand, the influx of calcium was not altered by the neo-clerodane diterpene, but was reduced in the presence of the ent-clerodane diterpene, indicating that this compound induces a blockade of the voltage-dependent calcium channels., (Copyright © 2014 Elsevier GmbH. All rights reserved.)
- Published
- 2014
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41. Intestine of dystrophic mice presents enhanced contractile resistance to stretching despite morphological impairment.
- Author
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Alves GA, Silva LR, Rosa EF, Aboulafia J, Freymüller-Haapalainen E, Souccar C, and Nouailhetas VL
- Subjects
- Animals, Calcium metabolism, Disease Models, Animal, Intestinal Mucosa metabolism, Intestines physiopathology, Male, Mice, Mice, Inbred C57BL, Mice, Inbred mdx, Muscle, Skeletal metabolism, Muscle, Skeletal ultrastructure, Muscular Dystrophy, Duchenne metabolism, Muscular Dystrophy, Duchenne pathology, Sarcoplasmic Reticulum metabolism, Dystrophin metabolism, Intestines pathology, Muscle Contraction physiology, Muscle, Skeletal physiopathology, Muscular Dystrophy, Duchenne physiopathology
- Abstract
Protein dystrophin is a component of the dystrophin-associated protein complex, which links the contractile machinery to the plasma membrane and to the extracellular matrix. Its absence leads to a condition known as Duchenne muscular dystrophy (DMD), a disease characterized by progressive skeletal muscle degeneration, motor disability, and early death. In mdx mice, the most common DMD animal model, loss of muscle cells is observed, but the overall disease alterations are less intense than in DMD patients. Alterations in gastrointestinal tissues from DMD patients and mdx mice are not yet completely understood. Thus, we investigated the possible relationships between morphological (light and electron microscopy) and contractile function (by recording the isometric contractile response) with alterations in Ca²⁺ handling in the ileum of mdx mice. We evidenced a 27% reduction in the ileal muscular layer thickness, a partial damage to the mucosal layer, and a partial damage to mitochondria of the intestinal myocytes. Functionally, the ileum from mdx presented an enhanced responsiveness during stretch, a mild impairment in both the electromechanical and pharmacomechanical signaling associated with altered calcium influx-induced contraction, with no alterations in the sarcoplasmic reticulum Ca²⁺ storage (maintenance of the caffeine and thapsigargin-induced contraction) compared with control animals. Thus, it is evidenced that the protein dystrophin plays an important role in the preservation of both the microstructure and ultrastructure of mice intestine, while exerting a minor but important role concerning the intestinal contractile responsiveness and calcium handling.
- Published
- 2014
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42. Quantitative changes of nicotinic receptors in the hippocampus of dystrophin-deficient mice.
- Author
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Ghedini PC, Avellar MC, De Lima TC, Lima-Landman MT, Lapa AJ, and Souccar C
- Subjects
- Age Factors, Alkaloids pharmacokinetics, Analysis of Variance, Animals, Azocines pharmacokinetics, Bungarotoxins metabolism, Bungarotoxins pharmacokinetics, Dose-Response Relationship, Drug, Dystrophin genetics, Hippocampus drug effects, Isotopes pharmacokinetics, Male, Mice, Mice, Inbred C57BL, Mice, Inbred mdx, Nicotinic Antagonists pharmacokinetics, Protein Binding drug effects, Protein Binding genetics, Quinolizines pharmacokinetics, RNA, Messenger metabolism, Receptors, Nicotinic genetics, Dystrophin deficiency, Hippocampus metabolism, Receptors, Nicotinic metabolism
- Abstract
Lack of dystrophin in Duchenne muscle dystrophy (DMD) and in the mutant mdx mouse results in progressive muscle degeneration, structural changes at the neuromuscular junction, and destabilization of the nicotinic acetylcholine receptors (nAChRs). One-third of DMD patients also present non-progressive cognitive impairments. Considering the role of the cholinergic system in cognitive functions, the number of nAChR binding sites and the mRNA levels of α4, β2, and α7 subunits were determined in brain regions normally enriched in dystrophin (cortex, hippocampus and cerebellum) of mdx mice using specific ligands and reverse-transcription polymerase chain reaction assays, respectively. Membrane preparations of these brain regions were obtained from male control and mdx mice at 4 and 12 months of age. The number of [³H]-cytisine (α4β2) and [¹²⁵I]-α-bungarotoxin ([¹²⁵I]-αBGT, α7) binding sites in the cortex and cerebellum was not altered with age or among age-matched control and mdx mice. A significant reduction in [³H]-cytisine (48%) and [¹²⁵I]-αBGT (37%) binding sites was detected in the hippocampus of mdx mice at 12 months of age. When compared with the age-matched control groups, the mdx mice did not have significantly altered [³H]-cytisine binding in the hippocampus, but [¹²⁵I]-αBGT binding in the same brain region was 52% higher at 4 months and 20% lower at 12 months. mRNA transcripts for the nAChR α4, β2, and α7 subunits were not significantly altered in the same brain regions of all animal groups. These results suggest a potential alteration of the nicotinic cholinergic function in the hippocampus of dystrophin-deficient mice, which might contribute to the impairments in cognitive functions, such as learning and memory, that have been reported in the dystrophic murine model and DMD patients., (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Published
- 2012
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43. Effects of hecogenin and its possible mechanism of action on experimental models of gastric ulcer in mice.
- Author
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Santos Cerqueira G, dos Santos e Silva G, Rios Vasconcelos E, Fragoso de Freitas AP, Arcanjo Moura B, Silveira Macedo D, Lopes Souto A, Barbosa Filho JM, de Almeida Leal LK, de Castro Brito GA, Souccar C, and de Barros Viana GS
- Subjects
- Animals, Anti-Inflammatory Agents administration & dosage, Anti-Inflammatory Agents pharmacology, Anti-Inflammatory Agents therapeutic use, Anti-Ulcer Agents administration & dosage, Anti-Ulcer Agents pharmacology, Antioxidants administration & dosage, Antioxidants pharmacology, Antioxidants therapeutic use, Cyclooxygenase 2 metabolism, Dose-Response Relationship, Drug, Ethanol, Gastric Mucosa metabolism, Glutathione metabolism, Humans, Indomethacin, KATP Channels metabolism, Lipid Peroxidation drug effects, Male, Mice, Neutrophil Activation drug effects, Nitric Oxide metabolism, Prostaglandins metabolism, Random Allocation, Sapogenins administration & dosage, Sapogenins pharmacology, Stomach immunology, Stomach Ulcer immunology, Stomach Ulcer metabolism, Anti-Ulcer Agents therapeutic use, Disease Models, Animal, Sapogenins therapeutic use, Stomach drug effects, Stomach Ulcer drug therapy
- Abstract
This study investigates the gastroprotective effects of hecogenin, a steroid saponin isolated from Agave sisalana, on experimental models of gastric ulcer. Male Swiss mice were used in the models of ethanol- and indometacin-induced gastric ulcer. To clarify the hecogenin mechanism of action, the roles of nitric oxide (NO), sulfhydryls (GSH), K⁺(ATP) channels and prostaglandins were also investigated, and measurements of lipid peroxidation (TBARS assay) and nitrite levels in the stomach of hecogenin-treated and untreated animals were performed. Furthermore, the effects of hecogenin on myeloperoxidase (MPO) release from human neutrophils were assessed in vitro. Our results showed that hecogenin (3.1, 7.5, 15, 30, 60 and 90 mg/kg, p.o.) acutely administered, before ethanol or indomethacin, exhibited a potent gastroprotective effect. Although the pretreatments with L-NAME, an iNOS inhibitor, and capsazepine, a TRPV1 receptor agonist, were not able to reverse the hecogenin effect, this was reversed by glibenclamide, a K⁺(ATP) blocker, and indomethacin in the model of ethanol-induced gastric lesions. The hecogenin pretreatment normalized GSH levels and significantly reduced lipid peroxidation and nitrite levels in the stomach, as evaluated by the ethanol-induced gastric lesion model. The drug alone increased COX-2 expression and this effect was further enhanced in the presence of ethanol. It also decreased MPO release and significantly protected the gastric mucosa. In conclusion, we showed that hecogenin presents a significant gastroprotective effect that seems to be mediated by K⁺(ATP) channels opening and the COX-2/PG pathway. In addition, its antioxidant and anti-inflammatory properties may play a role in the gastroprotective drug effect., (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Published
- 2012
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44. Antisecretory actions of Baccharis trimera (Less.) DC aqueous extract and isolated compounds: analysis of underlying mechanisms.
- Author
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Biondo TM, Tanae MM, Coletta ED, Lima-Landman MT, Lapa AJ, and Souccar C
- Subjects
- Aminopyrine metabolism, Animals, Antacids isolation & purification, Antacids pharmacology, Antacids therapeutic use, Chlorogenic Acid pharmacology, Chlorogenic Acid therapeutic use, Cyclohexanecarboxylic Acids therapeutic use, Disease Models, Animal, Diterpenes analysis, Diterpenes pharmacology, Diterpenes therapeutic use, Diterpenes, Clerodane analysis, Diterpenes, Clerodane pharmacology, Diterpenes, Clerodane therapeutic use, Flavonoids analysis, Flavonoids pharmacology, Flavonoids therapeutic use, Gastric Mucosa metabolism, Gastric Mucosa pathology, Histamine pharmacology, Male, Mice, Mice, Inbred Strains, Plant Components, Aerial, Plant Extracts chemistry, Plant Extracts pharmacology, Plant Extracts therapeutic use, Rabbits, Stomach injuries, Stomach Ulcer drug therapy, Stomach Ulcer etiology, Stress, Physiological, Baccharis chemistry, Cyclohexanecarboxylic Acids pharmacology, Gastric Acid metabolism, Gastric Mucosa drug effects, Phytotherapy, Stomach drug effects, Stomach Ulcer metabolism
- Abstract
Ethnopharmacological Relevance: Baccharis trimera (Less.) DC. (Asteraceae) is a species native to South America used in Brazilian folk medicine to treat gastrointestinal and liver diseases, kidney disorders and diabetes. Previous studies from this laboratory confirmed the antacid and antiulcer activities of the plant aqueous extract (AE) in rat and mouse models., Aim of the Study: To investigate the mechanisms involved in the antacid action of AE and isolated compounds from Baccharis trimera., Materials and Methods: AE was assayed in vivo in cold-restraint stress gastric ulcers and in pylorus-ligated mice. Nine fractions (F2-F10) previously isolated from AE were assayed in vitro on acid secretion measured as [(14)C]-aminopyrine ([(14)C]-AP) accumulation in rabbit gastric glands, and on gastric microsomal H(+), K(+)-ATPase preparations. Chlorogenic acids (F2, F3, F6, F7), flavonoids (F9), an ent-clerodane diterpene (F8) and a dilactonic neo-clerodane diterpene (F10) have been identified in these fractions., Results: Intraduodenal injection of AE (1.0 and 2.0 g/kg) in 4h pylorus-ligated mice decreased the volume (20 and 50%) and total acidity (34 and 50%) of acid secretion compared to control values. Administered orally at the same doses AE protected against gastric mucosal lesions induced in mice by restraint at 4°C. Exposure of isolated rabbit gastric glands to fractions F8 (10-100 μM) and F9 (10-300 μg/ml) decreased the basal [(14)C]-AP uptake by 50 and 60% of control (Ratio=6.2±1.1), whereas the remaining fractions were inactive. In the presence of the secretagogues F2 and F4 (30-300 μg/ml) decreased the [(14)C]-AP uptake induced by histamine (His) with a 100-fold lower potency than that of ranitidine. F5 and F6 reduced the [(14)C]-AP uptake stimulated by carbachol (CCh), but they were 10 to 20-fold less potent than atropine. F8 (diterpene 2) and F9 (flavonoids) decreased both the His- and CCh-induced [(14)C]-AP uptake, whereas F10 (diterpene 1) was inactive against the [(14)C]-AP uptake stimulated by secretagogues. Diterpene 2 was the most active of all tested compounds being 7-fold less potent than ranitidine and equipotent to atropine in reducing acid secretion in vitro. This compound also reduced the gastric H(+), K(+)-ATPase activity by 20% of control, while the remaining fractions were inactive on the proton pump in vitro., Conclusions: The results indicate that Baccharis trimera presents constituents that inhibit gastric acid secretion by acting mainly on the cholinergic regulatory pathway. The plant extract also contains compounds that exert moderate inhibition of the histaminergic regulatory pathway of acid secretion and the gastric proton pump. Altogether these active constituents appear to provide effective inhibition of acid secretion in vivo, which may explain the reputed antiulcer activity of the plant extract., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2011
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45. Presence of mRNA of muscle nicotinic acetylcholine receptor subunits and an epsilon-subunit splice variant in the mouse brain.
- Author
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Ghedini PC, Honda L, Avellar MC, and Souccar C
- Subjects
- Amino Acid Sequence, Animals, Base Sequence, Diaphragm metabolism, Male, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Muscle, Skeletal metabolism, Protein Isoforms genetics, Protein Isoforms metabolism, Receptors, Nicotinic genetics, Reverse Transcriptase Polymerase Chain Reaction, Cerebellum metabolism, Cerebral Cortex metabolism, Hippocampus metabolism, RNA, Messenger metabolism, Receptors, Nicotinic metabolism
- Abstract
Transcripts encoding for alpha1, beta1, delta, gamma and epsilon (and its splice variant epsilon(s)) subunits of the muscle-type nicotinic acetylcholine receptor (nAChR) were assessed using reverse transcription followed by polymerase chain reaction (RT-PCR) assays, with RNA extracted from the mouse skeletal muscle (diaphragm) and brain regions (cortex, hippocampus and cerebellum). The presence of alpha1, beta1, delta, gamma, epsilon and epsilon(s) transcripts was confirmed in the diaphragm muscle, used as positive control. mRNAs coding for muscle alpha1, beta1, delta, epsilon, epsilon(s), but not gamma subunits, were detected in adult mouse brain regions. An epsilon-subunit sequence variant, named epsilon(t), was also detected in all brain regions examined, but not in skeletal muscle. This new epsilon-subunit splice variant lacks a 115 bp cassette corresponding to exon 8 in the first intracellular transmembrane domain of the subunit, leading to a truncated protein. The data provide evidence for the presence of muscle-type nAChR subunits in the mouse central nervous system., (Copyright 2009 Elsevier Inc. All rights reserved.)
- Published
- 2010
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46. Natural compounds endowed with cholinergic or anticholinergic activity. Enhancement of acetylcholine release by a quaternary derivative of L-hyoscyamine.
- Author
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Souccar C, Salamanca AL, Tanae MM, Lima-Landman MT, and Lapa AJ
- Subjects
- Alkenes pharmacology, Animals, Atropine chemistry, Atropine Derivatives chemistry, Cholinergic Antagonists pharmacology, Dose-Response Relationship, Drug, Drug Synergism, Ganglia, Parasympathetic metabolism, Guinea Pigs, Muscarinic Antagonists chemistry, Myenteric Plexus metabolism, Nicotinic Agonists pharmacology, Potassium Channel Blockers pharmacology, Synaptic Transmission drug effects, Synaptic Transmission physiology, Tetraethylammonium pharmacology, Acetylcholine metabolism, Atropine pharmacology, Atropine Derivatives pharmacology, Ganglia, Parasympathetic drug effects, Muscarinic Antagonists pharmacology, Myenteric Plexus drug effects
- Abstract
New compounds that target nicotinic receptors (nAChRs) have been sought to correct disorders affecting cholinergic transmission in central and peripheral synapses. A quaternary derivate of l-hyoscyamine, phenthonium (Phen), was shown by our group to enhance the spontaneous acetylcholine (ACh) release without altering the nerve-induced transmitter release at the neuromuscular junction. The effect was unrelated to membrane depolarization, and was not induced by an increase of calcium influx into the nerve terminal. Phen also presented a competitive antimuscarinic activity and blocked noncompetitively the neuromuscular transmission. In this work we re-examined the mechanisms underlying the facilitatory actions of Phen on [(3)H]-ACh release in isolated ganglia of the guinea pig ileal myenteric plexus. Exposure of the preparations to Phen (10-50 microM) increased the release of [(3)H]-ACh by 81 to 68% over the basal. The effect was not affected by the ganglionic nAChR antagonist hexamethonium (1 nM) at a concentration that inhibited the increase of [(3)H]-ACh release induced by the nicotinic agonist dimethylphenylpiperazinium (DMPP, 30 microM). Association of Phen (10 microM) with DMPP potentiated the facilitatory effect of Phen. [(3)H]-ACh release was not altered by the muscarinic antagonists atropine (1 nM) or pirenzepine (1 microM). However, both antagonists inhibited the release of [(3)H]-ACh induced by either the muscarinic M1 agonist McN-343 (10 microM) or Phen (20 microM). The facilitatory effect of Phen was not altered by CdCl(2) (50 mM), but it was potentiated in the presence of tetraethylammonium (40 mM). The results indicate that the facilitatory action of Phen appears to be mediated by an increase of the inwardly rectifying potassium channels conductance probably related to the compound antimuscarinic activity.
- Published
- 2010
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47. Allosteric interaction of the anticholinergic drug [N-(4-phenyl)-phenacyl-l-hyoscyamine] (Phenthonium) with nicotinic receptors of post-ganglionic sympathetic neurons of the rat vas deferens.
- Author
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Munhoz E, De Lima TC, Souccar C, Lapa AJ, and Lima-Landman MT
- Subjects
- Adenosine Triphosphate pharmacology, Allosteric Regulation, Animals, Atropine pharmacology, Cholinergic Antagonists metabolism, Cholinergic Antagonists pharmacology, Dimethylphenylpiperazinium Iodide pharmacology, Dose-Response Relationship, Drug, Electric Stimulation, Ganglia, Sympathetic drug effects, Ganglia, Sympathetic metabolism, In Vitro Techniques, Male, Motor Activity drug effects, Muscle Contraction drug effects, Neurons cytology, Neurons metabolism, Nicotine pharmacology, Norepinephrine pharmacology, Prazosin pharmacology, Rats, Rats, Wistar, Suramin pharmacology, Synaptic Transmission drug effects, Vas Deferens drug effects, Vas Deferens metabolism, Vas Deferens physiology, Atropine Derivatives metabolism, Atropine Derivatives pharmacology, Ganglia, Sympathetic cytology, Neurons drug effects, Receptors, Nicotinic metabolism, Vas Deferens innervation
- Abstract
Phenthonium (Phen), a quaternary analog of hyoscyamine, is a blocker of muscarinic activity and an allosteric blocker of alpha(1)2betagammaepsilon nicotinic receptors. Specifically, Phenthonium increases the spontaneous release of acetylcholine at the motor endplate without depolarizing the muscle or inhibiting cholinesterase activity. This paper compares Phenthonium's effects on sympathetic transmission and on ganglionic nicotinic receptor activation. Neurotransmitter release and twitch of the rat vas deferens were induced either by electrical stimulation or by 1,1-dimethyl-4-phenylpiperazine (DMPP) activation of nicotinic receptors. Contractions independent of transmitter release were induced by noradrenaline and adenosine 5'-triphosphate (ATP). Phenthonium inhibited transmitter release and depressed twitch without changing the responsiveness to noradrenaline or ATP. Twitch depression did not occur after K(+)-channel blockade with 4-aminopyridine (4-AP) or charybdotoxin. DMPP had a similar effect, but high concentrations induced contraction of non-stimulated organs. Incubation of Phenthonium inhibited further DMPP twitch depression and non-competitively depressed the contractile responses elicited by DMPP. Furthermore, mecamylamine, but neither methyllycaconitine nor atropine, blocked the contraction elicited by DMPP. Phenthonium and DMPP are K(+)-channel openers that primarily inhibit sympathetic transmission. Contraction induced by DMPP was probably mediated by neuronal nicotinic receptor other than the alpha7 subtype. The blockade of DMPP contractile response was unrelated to Phenthonium's antimuscarinic or K(+)-channel opening activities. Since Phenthonium's quaternary chemical structure limits its membrane diffusion, the non-competitive inhibition of DMPP excitatory responses should be linked to allosteric interaction with neuronal nicotinic receptors that putatively qualify Phenthonium as a novel modulator of cholinergic synapses.
- Published
- 2009
- Full Text
- View/download PDF
48. Increased expression of acetylcholine receptors in the diaphragm muscle of MDX mice.
- Author
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Ghedini PC, Viel TA, Honda L, Avellar MC, Godinho RO, Lima-Landman MT, Lapa AJ, and Souccar C
- Subjects
- Animals, Bungarotoxins, Data Interpretation, Statistical, Immunohistochemistry, Male, Mice, Mice, Inbred C57BL, Mice, Inbred mdx, Reverse Transcriptase Polymerase Chain Reaction, Diaphragm metabolism, Receptors, Cholinergic biosynthesis, Receptors, Cholinergic genetics
- Abstract
The absence of dystrophin in Duchenne muscular dystrophy (DMD) and in the mutant mdx mouse causes muscle degeneration and disruption of the neuromuscular junction. Based on evidence from the denervation-like properties of these muscles, we assessed the ligand-binding constants of nicotinic acetylcholine receptors (nAChRs) and the mRNA expression of individual subunits in membrane preparations of diaphragm muscles from adult (4-month-old) and aged (20-month-old) control and mdx mice. The concentration of nAChRs as determined by the maximal specific [(125)I]-alpha-bungarotoxin binding (Bmax) in the muscle membranes did not change with aging in both animal strains. When compared to age-matched control groups, the Bmax in mdx muscles was increased by 65% in adults, and by 103% in aged mice with no alteration of toxin affinity for nAChRs. Reverse-transcription polymerase chain reaction assays showed that mRNA transcripts for the nAChR alpha1, gamma, alpha7, and beta2, but not the epsilon subunits, were more abundant in mdx than in control muscles. The results indicate increased expression of extrajunctional nAChRs in the mdx diaphragm and reflect impairment of nAChR regulation in dystrophin-deficient muscles. These observations may be related to the resistance to nondepolarizing muscle relaxants and the high sensitivity to depolarizing agents reported in DMD patients.
- Published
- 2008
- Full Text
- View/download PDF
49. Loss of neuronal projections in the dystrophin-deficient mdx mouse is not progressive.
- Author
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Pinto ML, Tokunaga HH, Souccar C, Schoorlemmer GH, and da Silva Lapa Rde C
- Subjects
- Animals, Axons ultrastructure, Brain Mapping, Cell Count, Cell Death genetics, Disease Models, Animal, Male, Mice, Mice, Inbred C57BL, Mice, Inbred mdx, Nerve Degeneration genetics, Nerve Degeneration physiopathology, Nervous System Malformations genetics, Nervous System Malformations metabolism, Nervous System Malformations physiopathology, Neural Pathways abnormalities, Neural Pathways cytology, Neural Pathways metabolism, Red Nucleus cytology, Red Nucleus metabolism, Stilbamidines, Trigeminal Nerve abnormalities, Trigeminal Nerve cytology, Trigeminal Nerve metabolism, Trigeminal Nucleus, Spinal cytology, Trigeminal Nucleus, Spinal metabolism, Wallerian Degeneration genetics, Wallerian Degeneration metabolism, Wallerian Degeneration physiopathology, Axons metabolism, Dystrophin genetics, Nerve Degeneration metabolism, Red Nucleus abnormalities, Trigeminal Nucleus, Spinal abnormalities
- Abstract
Lack of dystrophin is known to reduce several cerebral fiber systems. To investigate if the loss of fibers is progressive, we analyzed projections of the trigeminal sensory system to the red nucleus in 3, 6, and 12 month old dystrophin-deficient mdx mice. The retrograde tracer fluorogold was injected in the magnocellular part of the red nucleus, and the number of labeled neurons in the oral part of the spinal trigeminal nucleus (Sp5O) was counted. We found that the number of labeled Sp5O neurons was reduced by 50% in mdx mice compared to age-matched control mice. The number of labeled Sp5O neurons did not change significantly between 3 and 12 months neither in mdx nor in control mice. In addition, the number of labeled neurons in the interstitial system of the trigeminal nerve was reduced by 43% in mdx mice. We conclude that fiber loss did not continue beyond the age of 3 months. Our data suggest that lack of full-length dystrophin impairs neuronal migration or axonal outgrowth, or increases neuronal death during fetal or early life.
- Published
- 2008
- Full Text
- View/download PDF
50. The interstitial system of the trigeminal spinal tract projects to the red nucleus in mice.
- Author
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Pinto ML, Olyntho-Tokunaga HH, Souccar C, Schoorlemmer GH, and Lapa Rde C
- Subjects
- Afferent Pathways metabolism, Animals, Biological Transport, Active, Indicators and Reagents metabolism, Male, Mice, Mice, Inbred C57BL, Nerve Fibers metabolism, Neurons cytology, Neurons metabolism, Red Nucleus metabolism, Spinal Cord metabolism, Trigeminal Nerve metabolism, Afferent Pathways cytology, Red Nucleus cytology, Spinal Cord cytology, Trigeminal Nerve cytology
- Abstract
We studied projections from the interstitial system of the spinal trigeminal tract (InSy-S5T) to the red nucleus of the mouse with retrograde tracers (fluorogold and latex microbeads impregnated with rhodamine and fluorescein). Injections in the magnocellular part of the red nucleus caused labeling of cells in the rostral, intermediate, and caudal paratrigeminal nucleus (Pa5), dorsal paramarginal nucleus (PaMD), insular trigemeo-lateral cuneate nucleus (I5CuL), and the trigeminal extension of the parvocellular reticular formation (5RPC). All projections were bilateral, but contralateral projections were stronger. The number of retrogradely labeled cells in the InSy-S5T in 3-, 6-, and 12-month-old mice was similar. Injections restricted to the parvocellular red nucleus did not label the nuclei of the InSy-S5T. This projection from the InSy-S5T to the red nucleus may mediate modulation of the facial muscles by pain and other sensory information.
- Published
- 2007
- Full Text
- View/download PDF
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