Summary
The aim of the present study was to evaluate the neuroprotective effect of the 5-hydroxytryptamine1A (5-HT1A) agnists, CM 57493 and urapidil, in vivo and in vitro, respectively. In vivo permanent occlusion of the middle cerebral artery (MCA) was performed in male Wistar rats. Forty-eight hours after electrocoagulation of the MCA and infarct volume was determined. Pretreatment of the rat with the 5-HT1A agonist urapidil significantly reduced infarct development. The neuroprotective effect of the agent was restricted to the cortical area; the striatal damage was not influence. As the stimulation of the 5-HT1A receptor by serotonin is supposed to induce inhibitory, hyperpolarizing effects by opening of a Ca2+-independent neuronal K+ ionophore, the efficacy of agonistic drugs directly on the neuron was investigated in vitro. Cyanide-induced cytotoxic hypoxia as well as glutamate-induced excitotoxicity were performedj using primary neuronal cell cultures from chick embryo cerebral hemispheres. Treatment with 5-HIT1A agonists urapidil and CM 57493 significantly increase protein content of hypoxic cultures. CM 57493 and added to the culture medium (1–10 μM) during and up to 24 h after glutamate exposure ameliorated viability of the neurons. The result demonstrate neuroprotective potency of the 5-HT1A agonists, urapidil and CM 57493, when applied under hypoxic, excitotoxic and ischemic conditions in vivo and in vitro, respectively. Both, presynaptically induced inhibition of glutamate release as well as postsynaptically induced inhibition of neuronal excitability could be discussed as possible mechanisms of action of the 5-HT1A receptor agonism.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Adrien J, Lanfumey L, Gozlan H, Fattaccini CM, Hamon M (1989) Biochemical and electrophysiological evidence for an agonist action of CM 57493 at pre- and postsynaptic 5-hydroxytryptamine1A receptor in brain. J Pharmacol Exp Ther 248: 1222–1230
Ahlemeyer B, Krieglstein J (1989) Testing drug effects against hypoxic damagej of cultured neurons during long-term recovery. Life Sci 45: 835–842
Andrade R, Nicoll RA (1985) The niovel anxiolytic buspirone elicits a small hyperpolarziation and reduced serotonin responses at putative 5-HT1A receptors on hippocampal CA1 cells. Soc Neurosci Abstr 11: 297
Andrade R, Malenka RC, Niucoll RA (1986) A G-protein couples serotonin and GABAB receptors to the same channel in hippocampus. Science 234: 1261–1265
Backhauß C, Karkoutly C, Welsch M, Krieglstein J (1992) A mouse model of focal ischemia for screening neuroprotective drug effects. J Pharmacol Meth 27(1): 27–32
Bielenberg GW, Burkhardt M (1990) 5-Hydroxytryptamine1A agonists. A new therapeutic principle for stroke treatment. Stroke 21: IV161-IV163
Bode-Greuel KM, Klisch J, Glaser T, Traber J (1990) Serotonin (5-HT)1A receptor agonists as neuroprotective agents in cerebral ischemia. In: Krieglstein J, Oberpichler H (eds) Pharmacology of cerebral ischemia 1990. Wissenschaftliche Verlasgesellschaft, Stuttgart, pp 485–491
Busto R, Dietrich WD, Globus MY-T, Valdés J, Ginsberg MD (1987) Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab 7: 729–738
Busto R, Dietrich WD, Globus MY-T, Ginsberg MD (1989) Postichemic moderate hypothermia inhibits CA1 hippocampal ischemic neuronal injury. Neurosci Lett 101: 299–304
Choi DW (1988) Glutamate neurotoxicity and diseases of the nervous system. Neuron 1: 623–634
Clarke WP, DeVivo M, Beck SG, Maayani S, Goldfarb J (1987) Serotonin dereases population spike amplitude in hippocampal cells through a pertussis toxin substrate. Brain Res 410: 357–361
Colino A, Halliwell JV (1987) Differential modulation of three seperate K+ conductances in hippocampal CA1 neurons by serotonin. Nature 328: 73–77
Croß G, Hanft G, Kolassa N (1987) Urapidil and some analogues with hypotensive properties show high affinities for 5-hydroxytryptamine (5-HT) binding sites of the 5-HT1A subtype and for β1-adrenoceptor binding sites. Naunyn Schmiedebergs Arch Pharmacol 336: 597–601
Gustafson I, Miyachi Y, Wieloch T (1989) Postischemic administration of idazoxan, and β1-adrenoceptor receptor antagonist, decreases neuronal damage in the rat brain. J Cereb Blood Flow Metab 9: 171–174
Gustafson I, Westerberg E, Wieloch T (1990) Protection against ischemia-induced neuronal damage by the β2-adrenoceptor antagonist idazoxan: influence of time of administration and possible mechanisms of action. J Cereb Blood Flow Metab 10(6): 885–894
Hartig P, Hoyer D (1993) A proposed new nomenclauture for 5-HT receptors. TIPS 14: 233–236
Hen R (1992) Of mice and files: commalities among 5-HT receptors. TIPS 13(4): 160–166
Kirino T (1982) Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res 239: 57–69
Lowry OH, Rosebrough NJ, Farr AY, Randall R (1951) Protein measurement with the folin phenol reagent. Biochem J 193: 265–275
Maura G, Roccatagliata E, Ulivi MS, Raiteri M (1988) Serotonin-glutamate interaction in rat cerebellum: involvement of 5-HT1 and 5-HT2 receptors. Eur J Pharmacol 145: 31–38
Nedergaard S, Engberg I, Flatman JA (1986) Serotonin facilitates NMDA responses of cat neocortical neurons. Acta Physiol Scand 128: 323–325
Nevander G, Ingvar M, Lindvall O (1986) Mechanisms of epileptic brain damage: evidence for a protective role of the noradrenergic locus coeruleus system in the rat. Exp Brain Res 425: 146–158
Nuglish J, Karkoutly C, Peruche B, Prehn JHM, Welsch M, Mennel HD, Roßberg C, Krieglstein J (1990) Effect of the 5-HT1A agonist CM 57493 on infarct area, infarct volume and hippocampal neuronal damage after focal and global ischemia in mice and rats. In: Krieglstein J, Oberpichler H (eds) Pharmacology of cerebral ischemia 1990. Wissenschaftliche Verlagsgesellschaft, Stuttgart, pp 493–497
Paul J (1975) Cell and tissue culture, 5th ed. Churchill Livingstone, Edinburgh
Pazos A, Palacios M (1985) Quantitative autoradiographic mapping of serotonergic receptors in the rat brain. I. Serotonin-1 receptors. Brain Res 346: 205–230
Peroutka SJ, Snyder SH (1979) Multiple serotonin receptors: differential finding of [3H]-5-hydroxytryptamine, [3H]-lysergic acid diethylamide and [3H]-spiroperidol. Mol Pharmacol 16: 687–699
Peruche B, Ahlemeyer B, Brungs H, Krieglstein J (1990) Cultured neurons for testing antihypoxic drug effects. J Pharmacol Meth 23: 63–67
Peruche B, Krieglstein J (1993) Mechanisms of drug actions against neuronal damage caused by ischemia — an overiview. Prog. Neuropsychopharmacol Biol Psychiatry 17: 21–70
Pettmann B, Louis JC, Sensenbrenner M (1979) Morphological and biochemical maturation of neurons cultured in the absence of glial cells. Nature 281: 378–380
Prehn JHM, Bakhauß C, Karkoutly C, Nuglisch J, Peruche B, Krieglstein J (1991) Neuroprotective properties of 5-HT1A dreceptor agnosits in rodent models of focal and global cerebral ischemia. Eur J Pharmacol 203: 213–222
Prehn JHM, Krieglstein J (1992) Potential role of 5-hydroxytryptamine1A recptors in cerebral ischemia. In: Globus MY-T, Ditrich WD (eds) The role of the neurotransmitters in brain injury. Plenum Publ Corp, New York, pp 137–146 (Proceedings of the official stalite symposium of Brain '91)
Prehn JHM, Welsch M, Backhauß C, Nuglisch J, Ausmeier F, Karkoutly C, Krieglstein JS (1993) Effects of serotonergic drugs in experimental brain ischemia: evidence for a protective role serotonin in cerebral ischemia. Brain Res 630: 10–20
Radja F, Daval G, Hamon M, Verge D (1992) Pharmacological and physiolochemical properties of pre- versus postsynaptic 5-hydroxytryptamine1A receptor binding sites in the rat brain: a quantative autoradiographic study. Neurochem 58: 1338–1346
Raiteri M, Maura G, Barzizza A (1991) Activation of presynaptic 5-hydroxytryptamine1-like receptors on glutamatergic terminals inhibits N-methl-D-aspartate-induced cyclic GMP production in rat cerebellar slices. J Pharmacol Exp Ther 257: 1184–1188
Sarna GS, Obrenovitch TP, Matsumoto T, Symon L, Curzon G (1990) Effect of transient cerebral ischemia and carfdiac arrest on brain extracellular dopamine and serotonin as determined by in vivo dialysis in the rat. J Neurochem 55: 973–940
Sauer D, Nuglisch J, Roßberg C, Mennel HD, Beck T, Bielenberg GW, Krieglstein J (1988) Phencyclidine reduces postischemic neuronal necrosis in rat hippocampus without changing blood flow. Neurosci Lett 91: 327–332
Seif el Nars M, Peruche B, Roßberg C, Mennel HD, Krieglstein J (1990) Neuroprotective effect of memantine demonstrated in vivo and in vitro. Eur J Pharmacol 185: 19–24
Seif el Narr M, Nuglisch J, Krieglstein J (1992) The prevention of ischemia-induced cerebral hypothermia by controlling the environmental temperture. J Pharmacol Meth 27: 23–26
Sensenbrenner M, Maderspach K, Latzkovits K, Jaros GG (1978) Neuronal cells from chick embryo cerebral hemispheres cultivated on Polylysine-coated surfaces. Dev Neurosci 1: 90–101
Siesjö BK (1988) Historical overvies: calcium, ischemia and death of brain cells. Ann NY Acad Sci 522: 638–661
Smith ML, Auer RN, Siesjö BK (1984) The density and distribution of ischemic brain injury in the rat following 2–10 min of forabrain ischemia. Acta Neuropathol 64: 319–332
Tamura A, Graham DI, McCulloch J, Teasdale GM (1981) Focal cerebral ischemia in the rat. 1. Description of technique and early neuropathological consequences following middle cerebral artery procussion. J Cereb Blood Flow Metab 1: 53–60
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Peruche, B., Backhauß, C., Prehn, J.H.M. et al. Protective effects of 5-HT1A receptor agonists against neuronal damage demonstrated in vivo and in vitro. J Neural Transm Gen Sect 8, 73–83 (1994). https://doi.org/10.1007/BF02250918
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02250918