פרופ' נאוה זיסאפל

Research Field:  Neurobiology, Neuropharmacology, Biological clock, Melatonin, Sleep .

 

Research Activity:  The Biological Clock and Melatonin Receptors- The daily light/dark cycle provides a reliable signal for coordination and seasonal adaptation of thermoregulation, reproduction, development, sleep and mood. The daily rhythm in production of melatonin by the pineal gland reflects the environmental light /dark cycles and thus plays an important role in the time-keeping system. Melatonin has two major biological effects: a) it provokes the changes in the neuroendocrine system needed to adapt the thermoregulatory and reproductive systems to the approaching season. b) It functions in concert with light to hold circadian rhythms in phase with prevailing environmental conditions. Melatonin has been used successfully in humans to treat circadian time based sleep disorders in adults and improve sleep initiation and maintenance in elderly, in whom the melatonin signal has decayed. Research focus is on :

• Cellular effects of melatonin:  Our knowledge of the molecular mechanisms involved is still limited. Melatonin, shown by us and others to inhibit regulated neurosecretion of dopamine from specific brain areas, also and modulates constitutive secretion of proteins from benign and tumor cells. In the brain and prostate cells, these responses strictly depend on the presence of sex steroids. Melatonin effects nuclear exclusion of the androgen receptor. The signal transduction of this pathway is being studied. The effects of melatonin on the intracellular localization and targeting of proteins have important implications in maintaining and optimizing the temporal order in cells and organs. Understanding the biochemical basis of melatonin responses is important in view of the role of this hormone in circadian rhythms, pubertal development, aging, reproductive and thermoregulatory functions and its oncostatic properties.
• Effects of melatonin on the human brain: brain imaging and clinical studies in healthy volunteers and insomnia patients:  Sleep, a state marked by lessened consciousness, lessened movement of the skeletal muscles, and slowed-down metabolism, has an essential, restorative function and an important role in memory consolidation. The sleep need is remarkably standardized in quality, quantity and timing. Sleep is an orchestrated neurochemical process involving sleep promoting and arousal centers in the brain. In humans sleep normally occurs during the night. Sleep disturbance results in fatigue and problems staying awake. Exogenous melatonin elicits all the physiological effects that occur in the evening during endogenous melatonin secretion: increases sleep propensity, lowers body temperature and phase shift the biological clock. The production of melatonin declines with aging and in about half of insomnia patients it is lower than normal for their age group. The question of where and how melatonin acts in the brain is of prime importance in our attempts to unravel the neuronal mechanisms underlying sleep regulation, the restorative value of sleep and consequently management of daytime fatigue .

 

Selected Publications (of 170)

Zisapel, N., Egozi, Y. and Laudon, M. Inhibition of dopamine release by melatonin: Regional distribution in the rat brain. Brain Res. 246: 161-163 (1982).

 

Zisapel, N. and Laudon, M. Inhibition by melatonin of dopamine release from rat hypothalamus: Regulation of calcium entry. Brain Res. 272: 378- 381 (1983).

 

Zisapel, N., Egozi, Y. and Laudon, M. Inhibition by melatonin of dopamine release from rat hypothalamus in vitro: Variations with sex and estrous cycle". Neuroendocrinology 37: 41-48 (1983).

 

Zurgil, N. and Zisapel, N. Ca_2+_ uptake and Ca_2+_-regulated phosphorylation during development of brain neurons in culture. Dev. Brain Res. 13: 293-303 (1984).

 

Zisapel, N., Egozi, Y. and Laudon, M. Circadian variations in the inhibition by melatonin of dopamine release from adult and newborn rat hypothalamus. Neuroendocrinology 40: 102-108 (1985).

 

Zurgil, N. and Zisapel, N. Phorbol ester and calcium act synergistically to enhance neurotransmitter release by brain neurons in culture. FEBS Lett. 185: 257-261 (1985).

 

Yarom, M., Zurgil, N. and Zisapel, N. Calcium permeability changes and neurotransmitter release in cultured brain neurons: Effects of stimulation on calcium fluxes. J. Biol. Chem. 250: 16286-16294 (1985).

 

Yarom, M., Zurgil, N. and Zisapel, N. Calcium permeability changes and neurotransmitter release in cultured brain neurons: Temporal analysis of neurotransmitter release. J. Biol. Chem. 260: 16295-16303 (1985).

 

Laudon, M. and Zisapel, N. Characterization of central melatonin receptors using 125I-melatonin. FEBS Lett. 197: 9-12 (1986).

 

Zurgil, N., Yarom, M. and Zisapel, N. Concerted enhancement of calcium influx, neurotransmitter release and protein phosphorylation by a phorobol ester in cultured brain neurons. Neuroscience 19: 1255-1264 (1986).

 

Laudon, M. and Zisapel, N. Impact of circulating estradiol on melanonin binding sites in discrete areas of the female rat brain. Brain Res. 402: 146-151 (1987).

 

Zisapel, N. and Laudon, M. A novel melatonin antagonist affects melatonin-mediated processes in vitro and in vivo. Eur. J. Pharmacol. 136: 259-260 (1987).

 

Zisapel, N., Shaharabani, M. and Laudon, M. Regulation of melatonin's activity in the female rat brain by estradiol: Effects on neurotransmitter release and on iodomelatonin binding sites. Neuroendocrinology 46: 207-217 (1987).

 

Laudon, M., Yaron, Z. and Zisapel, N. N -(2,4-dinitro-phenyl)-5- methoxytryptamine - a novel melatonin antagonist: Effects on sexual maturation of the male and female rat and on oestrous cycles of the female rat. J. Endocrinol. 116: 43-53 (1988).

 

Zisapel, N., Nir, I. and Laudon, M. Circadian variations in melatonin binding sites in discrete areas of the male rat brain. FEBS Lett. 232: 172-176 (1988).

 

Laudon, M., Nir, I. and Zisapel, N. Melatonin receptors in discrete brain areas of the male rat: Impact of aging on density and circadian rhythmicity. Neuroendocrinology 48:577-584 (1988).

 

Zisapel, N. Melatonin receptors revisited. J. Neural Transm. 73: 1-6 (1988).

 

Zisapel, N. and Anis, Y. Impact of circulating testosterone on iodomelatonin binding sites in the male rat brain. Molec. Cell. Endocrinol. 48: 577-584 (1988).

 

Anis, Y., Nir, I. and Zisapel, N. Diurnal variations in melatonin binding sites in the hamster brain: Impact of melatonin. Molec. Cell. Endocrinol. 67: 121-129 (1989).

 

Anis, Y. and Zisapel, N. Castration affects brain iodomelatonin binding in hamsters maintained in long but not short days. Molec. Cell. Endocrinol. 76: 23-34 (1991).

 

Laudon, M. and Zisapel, N. Melatonin binding proteins identified in the rat brain by affinity labeling. FEBS Lett.288: 105-108 (1991).

 

Anis, Y., Nir, I., Schmidt, U. and Zisapel, N. Modification by oxazepam of the diurnal variations in brain melatonin binding sites in sham-operated and pinealectomized rats. J. Neural Trans. 89: 155-166 (1992).

 

Haimov, I., Laudon, M., Zisapel, N., Souroujon, M., Nof, D., Schlitner, A., and Lavie, P. The relationship between urinary 6 sulfatoxy melatonin rhythm and insomnia in old age. Adv. Pin. Res. 8: 433-438 (1994).

 

Haimov, I., Laudon, M., Zisapel, N., Souroujon, M., Nof, D., Schlitner, A., Herer, P., Tzischinsky, O. and Lavie, P. Sleep disorders and melatonin rhythms in elderly people. Brit. Med. J. 309: 167-168 (1994).

 

Haim, A. and Zisapel, N. Oxygen consumption and body temperature rhythms in the golden spiny mouse: response to change in daylength. Physiol. Behav. 58:775-778 (1995).

 

Haimov, I., Lavie, P. , Laudon, M., Herer, P., Vigder, C. and Zisapel, N.Melatonin replacement therapy of elderly insomniacs. Sleep 18: 598-603 (1995).

 

Bubis, M. and Zisapel, N. Modulation by melatonin of protein secretion from melanoma cells: is cAMP involved? Molec. Cell. Endocrinol. 112:169-175 (1995).

 

Bubis, M. and Zisapel, N. Facilitation and inhibition of G-protein regulated protein secretion bu melatonin. Neurochem. Int. 27: 177-183 (1995).

 

Oaknin-Bendahan S., Anis, Y., Nir, I., and Zisapel, N. Effects of long-term administration of melatonin and a putative antagonist on the aging rat. Neuroreport 6: 785-788 (1995).

 

Garfinkel, D., Laudon, M., Nof, D. and Zisapel, N. Improvement of sleep quality in elderly people by controlled release melatonin. The Lancet 364: 541-544 (1995).

 

Laudon, M., Gilad, E., Matzkin, H., Braf, Z. and Zisapel, N. Putative melatonin receptors in benign human prostate tissue. J. Clin Endocrinol. Metab. 81:1336-1342 (1996).

 

Oaknin-Bendahan S., Zisapel, N., and Mora, P. The modulatory effect of melatonin on the dopamine-glutamate interaction in the anterior hypothalamus during aging. Neuroreport 6:2399-2403 (1995).

 

Gilad, E., Laudon, M., Matzkin, H. Pick, . Sofer, M., Braf, Z. and Zisapel, N. (1996) Functional melatonin receptors in human prostate epithelial cells. Endocrinology 137;1412-1417.

 

Bubis, M., Anis, Y. and Zisapel, N. Enhancement by melatonin of GTP exchange and ADP ribosylation reactions. Molec. Cell. Endocrinol. 123:139- 148 (1996).

 

Gilad, E., Matzkin, H. and Zisapel, N. An interplay between sex steroids and melatonin in regulation of human benign prostate epithelial cells growth. J. Clin. Endocrinol. Metab. 82;2535-2541 (1997).

 

Gilad, E., Matzkin, H. and Zisapel, N. Inactivation of melatonin receptors by protein kinase C in human prostate epithelial cells. Endocrinology 138:4255-4261 (1997).

 

Gilad, E., Pick, E., Matzkin, H. and Zisapel, N. Melatonin receptors in benign prostate epithelial cells:evidence for thei involvement of cholera and pertussis toxins-sensitive G proteins in their signal transduction pathways. The Prostate 159:1069-1073(1997).

 

Gilad, E., Matzkin, H. and Zisapel, N. Evidence for local action of melatonin on rat prostate. J. Urol. 159:1069-1073 (1998).

 

Bubis, M. and Zisapel, N. A role for NAD+ and cADP-ribose in melatonin signal transduction. Molec. Cell. Endocrinol. 137; 59-67 (1998).

 

Zisapel, N., Barnea, E., Anis, Y., Izhaki, I., Reiter, R. and Haim, A. Involvement of the pineal gland in daily scheduling of the golden spiny mouse. Life Sciences 63: 751-757 (1998).

 

Zisapel, N., Barnea, E., Izhaki, I., Anis, Y., and Haim, A. Daily scheduling of the golden spiny mouse under phoroperiodic and social cues J. Exp. Zool. 284;100-106(1999).

 

Lupowitz Z. and Zisapel, N. hormonal interactions in human prostate tumor LNCaP cells. J. Steroid Biochem Molec. Biol. 68 :83-88 (1999).

 

Rimler A., matzkin, H. and Zisapel, N. Cross talk between melatonin and TGF*1 in human benign prostate epithelial cells. The prostate 40:211-217 (1999).

 

Bubis M. and Zisapel N. Involvement of cGMP in cellular melatonin responses Biol. Cell 91:45-49 (1999).

 

Zisapel, N. The use of melatonin in the treatment of insomnia. Biol Signals Recept. 8:84-89 (1999).

 

Garfinkel, D., Zisapel, N. and Laudon, M. Facilitation of benzodiazepine discontinuation by melatonin- a novel clinical use. Arch. Int. Med 159:2456-2460 (1999).

 

Elvert, R., Kronfeld, N., Dayan, T., Haim, A., Zisapel, N. and Heldmaier, G. Telemetric field studies of body temperature and activity rhythms of Acomys russatus and A. cahirinus in the Judean Desert of Israel Oecologia 119: 484-492 (1999).

 

Shamir, E., Laudon, M., Barak, Y., Anis, Y., Rotenberg, V., Elizur, A. and Zisapel N. Melatonin improves sleep quality of chronic schizophrenic patients. Journal Clin. Psychiatry 61:373-378 (2000).

 

Sivan Y. Laudon, M., Kuint, J., Zisapel N. Low melatonin production in infants with a life threatening event. Dev Med Child Neurol 42: 487-491(2000).

 

Sivan J Rivi Laudon M Zisapel, N Melatonin production in healthy infants:Evidence for seasonal variations Pediatric Res 49:63-68 (2001)

 

Zisapel N Circadian Rhythm Sleep Disorders: Pathophysiology and Potential Approaches to Management CNS Drugs 15:311-328 (2001).

 

Shamir E, Barak Y, Shalman I, Laudon M, Zisapel N, Tarrasch R, Elizur A , Weizman R Melatonin treatment for tardive - dyskinesia:A double-blind placebo-controlled cross-over study Arch Gen Psychiat 58 : 1049-1052 (2001).

 

Kronfeld N, Dayan T, Elvert R Haim A, Zisapel N Heldmaier G On the Use of the Time Axis for Ecological Separation: Diel Rhythms as an Evolutionary Constraint American Naturalist 158 : 451-457 (2001) .

 

Rimler A, Culig Z, Levy G, Lupowitz Z, Klocker H, Matzkin H, Bartsch G, Zisapel N Melatonin elicits nuclear exclusion of the human androgen receptor and attenuates its activity The Prostate 49:145-54 (2001).

 

Lupowitz Z, Rimler A, Zisapel N Evaluation of signal transduction pathways mediating the nuclear exclusion of the androgen receptor by melatonin Cell. Molec. Life Sci. 58;2129-35 (2001).

 

Zisapel N  Melatonin-Dopamine Interactions: From Basic Neurochemistry to a Clinical Setting Molec Cell Neurobiol.  21:605-616 (2001).

 

Rimler A, Culig Z Lupowitz Z and Zisapel N Nuclear exclusion of the androgen receptor by melatonin. J  Steroid Biochem Molec Biol 81,   77-84 2002.

 

Zisapel N, Laudon M Subjective Assessment of the Effects of CNS-Active Drugs on Sleep by The Leeds Sleep Evaluation Questionnaire: A Review Human Neuropsychopharmacology: clinical & experimental (2003) 18:1-20.

 

Jonas M, Garfinkel, D., Zisapel, N., Laudon, M. Grossman E. Impaired Nocturnal melatonin Secretion  in non-dipper hypertensive patients Blood pressure (2003) 12:1-6

 

Zisapel N Nir T. Determination of the minimal clinically significant difference on a patient visual analog sleep quality scale. J Sleep Res. 2003;12:291-8.

 

Tarrasch R, Laudon, M, Zisapel N. The Leeds Sleep Evaluation Questionnaire (LSEQ): Validation of its four domains in clinical research and practice in insomnia patients Hum Psychopharmacol Clin Exp 2003; 18: 603–610.

 

Damien Leger,   Moshe Laudon,   Nava Zisapel,   Nocturnal melatonin excretion and its relationship to their response to melatonin replacement therapy Am  J Med  (2004) 116 (2): 91-95. 63.         

 

Rimler A, Jockers R, Lupowitz Z, Zisapel N Gi and RGS Proteins Provide Biochemical Control of Androgen Receptor Nuclear Exclusion J Mol Neurosci. 2007;31(1):1-12.

 

Rimler A, Jockers R, Lupowitz Z, Sampson SR, Zisapel N.  Differential effects of melatonin and its downstream effector PKCalpha on subcellular localization of RGS proteins. J Pineal Res. 2006;40(2):144-52.Sampson SR, Lupowitz Z, Braiman L, Zisapel N. Role of protein kinase Calpha in melatonin signal transduction. Mol Cell Endocrinol. 2006;252(1-2):82-7.

 

Gorfine T, Assaf Y, Goshen-Gottstein Y, Yeshurun Y, Zisapel N. Sleep-anticipating effects of melatonin in the human brain. Neuroimage. 2006;31(1):410-8.

 

Zisapel N,   Tarrasch R,    Laudon M.  The Relationship Between Melatonin And Cortisol Rhythms: Clinical Implications Of Melatonin Therapy. Drug Development Research 2005;65:119–125  

 

Grossman E, Laudon M, Yalcin R, Zengil H, Peleg E, Sharabi Y, Kamari Y, Shen-Orr Z, Zisapel N.  Melatonin Reduces Night Blood Pressure in Hypertensive Patients with Nocturnal Hypertension Am J Med. 2006;119(10):898-902.

 

Rozic-Kotliroff G, Zisapel N.  Ca2+ -dependent splicing of neurexin IIalpha. Biochem Biophys Res Commun. 2007;352(1):226-30.

 

Rimler A, Jockers R, Lupowitz Z, Zisapel N.  Gi and RGS proteins provide biochemical control of androgen receptor nuclear exclusion. J Mol Neurosci. 2007;31(1):1-12.

 

Zisapel N. Sleep and sleep disturbances: biological basis and clinical implications Cell Mol Life Sci. 2007 2007;64(10):1174-86. Review.

 

Gorfine, T Zisapel N Melatonin and The Human Hippocampus, A Time Dependant Interplay J. Pineal Res 2007;43 (1): 80-86

 

Gorfine, T, Yeshurun, Y, Zisapel, N Nap and melatonin-induced changes in hippocampal activation and their role in verbal memory consolidation J. Pineal Res 2007;43(4):336-42.

 

Lemoine P, Nir T, Laudon M Zisapel N. Prolonged-Release Melatonin Improves Sleep Quality and Morning Alertness in Insomnia Patients Aged 55 Years and Older and Has No Withdrawal Effects J Sleep Res 2007;16(4):372-80.

 

Wade AG,   Ford I, Crawford G,   McMahon AD,  Nir T, Laudon M  Zisapel N.  Efficacy of prolonged release melatonin in insomnia patients aged 55-80 years Current Medical Research and Opinion CMRO 2007;23(10):2597-605.

 

Gorfine T, Zisapel N. Late evening brain activation patterns and their relation to the internal biological time, melatonin, and homeostatic sleep debt. Hum Brain Mapp. 2007 Dec 19;