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Taurine: Neuropharmacological Actions and Therapeutic Potential

This presentation reviews research on taurine and its potential therapeutic uses, including its effects on antipsychotic-induced catalepsy, cocaine-induced neurotoxicity, and its anti-addicting activity. It also explores taurine's interaction with the glutamate NMDA receptor and the mechanisms underlying its modes of action.

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Taurine: Neuropharmacological Actions and Therapeutic Potential

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  1. MODES OF NEUROPHARMACOLOGICAL ACTIONS OF TAURINE AND ITS POTENTIAL THERAPEUTIC USAGE Shailesh P. Banerjee, Christopher Y. Chan & Eitan Friedman CUNY School of Medicine, New York, NY 10031

  2. THIS PRESENTATION WILL BE A REVIEW OF OUR RESEARCH ON TAURINE • HOW AND WHY WE GOT INVOLVED IN STUDIES RELATED TO TAURINE? • ANTIPSYCHOTIC-INDUCED CATALEPSY a. Haldol (haloperidol)-induced catalepsy b. Protection by taurine • COCAINE-INDUCED NEUROTOXICITY a. Effects of perinatal cocaine exposure b. Endogenous taurine’s antagonsim of cocaine-induced neurotoxicity • TAURINE’S ANTI-ADDICTING ACTIVITY a. Inhibition of sensitization of locomotor activity induced by cocaine b. Inhibition of cocaine-induced conditioned place preferance • TAURINE’S INTERACTION WITH THE GLUTAMATE NMDA RECEPTOR a. Electrophysiological analysis b. Receptor binding assays c. Analysis of NMDA receptor subunits by immuno-blotting 6. MECHANISMS FOR TAURINE’S MODES OF ACTIONS a. Glycine-gated Chloride channel b. Taurine-gated Chloride channel c. Intracellular Calcium d. NMDA Glutamate receptor inhibition

  3. 1. Our Interest in Taurine

  4. Solvent Metoclopramide (5 mg/kg) Metoclopramide (10 mg/kg) Haloperidol (0.5 mg/kg) 2. ANTIPSYCHOTIC-INDUCED CATALEPSYi. Metoclopramide sensitizes haloperidol-induced catalepsy n=8 n=8 n=8 From Agovic et al., 2008. E. J. Pharm.

  5. ANTIPSYCHOTIC-INDUCED CATALEPSY ii. NMDA and D2 receptor binding [3H-Spiroperidol binding] [3H-MK 801 binding] Agovic et al., 2008. E. J. Pharm.

  6. ANTIPSYCHOTIC-INDUCED CATALEPSY HYPOTHESIS Antipsychotic-induced catalepsy involves • Augmentation of NMDA-mediated glutamatergic transmission; • Inhibition of dopamine D2 receptor mediated-transmission; and • Unchanged dopamine D1 receptor-mediated transmission.

  7. TWO POSSIBLE MECHANISMS FOR THE DEVELOPMENT OF CATALEPSY 1. Impairment Of Neurotransmitter Functions 2. Neurodegeneration

  8. Haldol + taurine Haldol only Taurine’s protection against haldol-induced catalepsy Lidsky et al., 1995 Brain Research

  9. Taurine’s protection against haldol-induced neurodegeneration a a a b b b From Lidsky et al., 1995 Brain Research

  10. Summary • Antipsychotic-induced catalepsy involves 1. Impairment Of Neurotransmitter Functions & 2. Neurodegeneration • TAURINE PREVENTS BOTH OF THESE EFFECTS.

  11. 3. COCAINE-INDUCED NEUROTOXICITY • Effects of perinatal cocaine exposure From Yablonski-Alter et al., 2005 JPET

  12. COCAINE-INDUCED NEUROTOXICITY B. Endogenous taurine’s antagonism of cocaine-induced neurotoxicity - I

  13. COCAINE-INDUCED NEUROTOXICITY B. Endogenous taurine’s antagonism of cocaine-induced neurotoxicity - II

  14. MECHANISMS FOR PROTECTION AGAINST COCAINE-INDUCED TOXICITY Inhibition of glycine release Stimulation of taurine release

  15. 4. TAURINE’S ANTI-ADDICTING ACTIVITY A. INHIBITION OF SENSITIZATION OF LOCOMOTOR ACTIVITY INDUCED BY COCAINE

  16. TAURINE’S ANTI-ADDICTING ACTIVITY B. INHIBITION OF COCAINE-INDUCED CONDITIONED PLACE PREFERANCE

  17. Taurine (2mM) inhibited the late part of N2. Portion removed by taurine ..but N1 is spared

  18. Does co-application of the slice with the NMDA antagonist, APV, prevent the inhibition caused by taurine. APV = 2 amino, 5-phosphonovalerate

  19. a (3) APV+Tau (2) APV (1) Con N2 b c 73.15% 73.28% 100 50 % inhibition of Control amplitude N = 5 Taurine effect was prevented in slices treated with 100 mM DL-AVP, a specific NMDA receptor antagonist. 0 APV+Tau APV

  20. [3H] MK801, [3H] spermidine, [3H] taurine binding in rat cortical membranes • specific ligand membrane binding was performed in the presence of 30mM Glycine

  21. Spermine dose-dependently enhanced [3H] MK801 binding

  22. Taurine dose-dependently reduced spermine-enhanced [3H]MK801 binding 30mM glycine + 100mM spermine. Note that taurine had no direct effect on [3H] MK801 binding per se (not illustrated).

  23. Taurine reduced the affinity of glycine for the NMDA receptor by about 10 fold (100µM) (100µM)

  24. Polyamines displace both 3[H]spermine and 3[H]taurine from cortical tissue

  25. 2mM Tauine co-applied with 10 mM Ro25-6981 induced a slight additional inhibition, much less than the 33 +/- 4% inhibition caused by taurine alone. 2 mM taurine +10mM R025-6981 2 mM taurine alone P < 0.1 % inhibition of the N2 component [Ro25-6981], mM

  26. The inhibition of the N2 response component by 2mM taurine is progressively replaced by increasing doses of Ro25-6981: No additive interaction between the 2 modulators P < 0.01 Tau P < 0.05 % inhibition of the N2 response component [Ro25-6981], mM, in the absence or presence of 2mM taurine

  27. A hypothetical additive interaction • suggests independent mechanisms by the 2 modulators • would produce an equal upward shift of the % inhibition regardless of Ro25-6981 concentrations. % inhibition of N2 component Predicted action of Ro25 + Taurine Action of Ro25 [Ro25-6981]

  28. Long term taurine treatment increases the membrane expression of NMDA receptor subunit GluN2B Optical Intensity (Arbitrary Units) Long term (30d) taurine treatment increases the expression of NMDA receptor subunit GluN2B: significant increase in membrane expression of GluN2B subunit (p<0.05, unpaired T-test).

  29. Long term taurine treatment increases the membrane expression of NMDA receptor subunit GluN1

  30. Long term taurine treatment does not alter the membrane expression of AMPA receptor subunit GluR1 Optical Intensity (Arbitrary Units) Long term (30d) taurine treatment does not alter the synaptic membrane expression of AMPA receptor subunit GluR1:

  31. Long term taurine treatment reduces the membrane expression of AMPA receptor subunit GluR2 Optical Intensity (Arbitrary Units) Long term (30d) taurine treatment reduces the synaptic membrane expression of AMPA receptor subunit. p<0.05, unpaired T-test, N=5.

  32. 5. MECHANISMS FOR TAURINE’S MODES OF ACTIONS • Glycine-gated chloride channel in the spinal cord (Borghese et al., 2012 JPET). • Taurine-activated chloride influx (Yarbrough et al., 1981 JPET). • Decreasing the intracellular level of free calcium (El Idrissi and Trenkner, 2003 Adv.Exp.Med.Biol.). • Inhibition of NMDA glutamate receptor subtype (Chan et al., 2012 These Proceedings).

  33. Taurine’s Multiple Activities

  34. Acknowledgements: • Ted I. Lidsky, Ph.D. • Elena Yablonski-Alter, Ph.D. • Mervan Agovic, Ph.D. • Kalindi Bakshi, Ph.D. • Eleonora Gashi, D.O. • Brice le Francois, Ph.D. • Andre Ragnauth, Ph.D. • Louis Vidal, Ph.D. • Eitan Friedman, Ph.D.

  35. End

  36. Extra slides

  37. TAURINE’S ANTI-ADDICTING ACTIVITY C. CHRONIC TAURINE INHIBITS COCAINE-INDUCED DOPAMINE RELEASE A.T. (After taurine)

  38. Polyamines and Taurine compete for a common binding site 3H-Taurine competition 3H-Spermidine competition Crude membrane preparations were incubated with tritiated taurine (1μM) or spermidine (0.25 μM) in the presence of 30 µM glycine and non radioactive spermidine, spermine or taurine.

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