- Email: [email protected]
Antinociceptive effects of donepezil as an acetylcholinesterase inhibitor in a rat model of neuropathic pain
P.1.g. Basic and clinical neuroscience − Neuropharmacology therefore possible that voluntary physical exercise can facilitate and potentiate the patients’ response to the SSRI treatment. References [1] Greenwood, B.N., Foley, T.E., Day, H.E., Burhans, D., Brooks, L., Campeau, S., Fleshner, M., 2005. Wheel running alters serotonin (5-HT) transporter, 5-HT1A, 5-HT1B, and alpha1b-adrenergic receptor mRNA in the rat raphe nuclei. Biol Psychiatry 57, 559–568. [2] Blier, P., 2001. Pharmacology of rapid-onset antidepressant treatment strategies. J Clin Psychiatry 62, S12-S17. Disclosure statement: This work was supported by Slovak Academy of Sciences Scholarship and by VEGA grant 2/0024/15. Escitalopram was provided by Lundbeck A/S, Valby, Denmark.
P.1.g.022 Acute effect of d-opioid receptors agonist and antagonist on excitability of neonatal rat hippocampal neurons in primary cell culture L. Lap´ınov´a1 ° , E. Dremencov1,2 , L. Lacinov´a1 1 Institute of Molecular Physiology and Genetics of Slovak Academy of Sciences, Department of Cellular Physiology and Genetics, Bratislava, Slovak Republic; 2 Biomedical Research Center of Slovak Academy of Sciences, Institute of Experimental Endocrinology, Bratislava, Slovak Republic Background: Delta opioid receptors (DOR) play an important role in chronic pain, emotional processing, and mood disorders. These receptors are widely distributed across the brain, with relatively high density in the hippocampus [1]. In some brain regions DOR ligands suppress neuronal activity by inhibition of neuronal firing or by reduction of neurotransmitter release. The aim of the current study was to investigate the effect of DOR agonist SNC80 and antagonist naltrindole on the excitability of rat hippocampal pyramidal neurons in primary culture. Methods: Hippocampal neurons were isolated from newborn Wistar rats. Excitability of hippocampal neurons was measured in whole-cell patch clamp configuration using HEKA EPC-10 amplifier. Borosilicate glass electrodes (impedance 3 to 4 MW) were used. Depolarization-activated action potential (AP) firing was measured from day in vitro (DIV) 8 to day 10 from a holding potential of −70 mV. Spontaneous activity was measured on DIV 13 from a native membrane potential of each cell. Ion current was measured from DIV 10 to 12. Sodium currents were measured using depolarizing pulses of −70 mV to +70 mV from a holding potential of −90 mV. Calcium currents were measured using depolarizing pulses of −40 mV to +50 mV from a holding potential of −40 mV. Potassium currents were measured using depolarizing pulses of 40 mV to +80 mV from a holding potential of −80 mV. Statistical differences between groups were determined by parametric paired t-test. Probability p < 0.05 was considered as statistically significant. Results: Naltrindole significantly inhibited both depolarizationactivated and spontaneous AP firing in a dose-dependent manner. Concentration dependence was U-shaped with a maximum at a concentration of 10 mM. SNC80 significantly inhibited depolarization-activated AP firing. This effect decreased with increasing drug concentration, i.e., it was maximal at a concentration of 100 nM. Spontaneous activity was inhibited by low concentration of SNC80 and this inhibition increased with increasing drug concentration within the range 100 nM to 10 mM being significant at 10 mM. At higher concentration (100 mM) spontaneous activity was significantly enhanced. An effect of both drugs on
S227
voltage dependent ion channels was tested at a concentration, which affected depolarization-activated AP firing most effectively. Naltrindole inhibited calcium, sodium, peak potassium current and sustained potassium current. SNC80 inhibited calcium, sodium and sustained potassium current but potentiated peak potassium current. Observed inhibition of voltage dependent sodium current may suppress activation of an AP and therefore attenuate the AP firing. Potentiation of voltage dependent potassium currents supports rapid depolarization and therefore facilitates the AP firing while an inhibition of these channels may act in opposite, i.e., attenuate the AP firing. Voltage dependent calcium channels may contribute to initial depolarization and therefore support the AP firing and/or repolarization and thus attenuate also the AP firing. Conclusions: Effects of agonist and antagonist of d-opioid receptors on the excitability of hippocampal pyramidal neurons was not complementary suggesting more complex underlying mechanism arising from different effects on voltage dependent ion channels. References [1] Lutz, P.E., Kieffer, B.L., 2013. Opioid receptors: distinct roles in mood disorders. Trends Neurosci 36, 195–206. Disclosure statement: This work was supported by the SAS Scholarship, VEGA 2/0024/15 and APVV-0212−10.
P.1.g.023 Antinociceptive effects of donepezil as an acetylcholinesterase inhibitor in a rat model of neuropathic pain A. Mesdaghinia1 ° , H.R. Banafshe1 , A. Abed1 , A. Hajnorouzali2 , E. Mesdaghinia2 1 Kashan University of Medical Sciences, Physiology Research Center, Kashan, Iran; 2 Kashan University of Medical Sciences, School of Medicine, Kashan, Iran Purpose of the study: Neuropathic pain results from lesions or diseases affecting the somatosensory system [1]. The management of patients with chronic neuropathic pain remains a challenge. Several studies report the analgesic effect of acetylcholinesterase inhibitors in different models of experimental pain [2]. The present study was designed to investigate the effect of systemic administration of donepezil, a central acetylcholinesterase inhibitor, on behavioral hyperalgesia and allodynia scores of neuropathic pain in chronic constriction injury (CCI) model in rat. Methods: Experiments were carried out on male SpragueDawley rats (230–280 g). Three or four rats were housed in a cage under a 12 h light/dark cycle with food and water available ad libitum. To induce the animal model of neuropathic pain, the CCI method was performed on the sciatic nerve as described in detail previously by Bennett and Xie [3]. Sham-operated rats had the same surgery, the left sciatic nerve was exposed but no ligation was made. The rats were housed individually in cages after the surgery. All experiments followed the guide lines on ethical standard for investigation of experimental pain in animals. The behavioral experiments included allodynia and hyperalgesia phenomena. The animals in the allodynia experiments were subdivided into cold and mechanical allodynia groups. Radiant heat was applied as thermal stimulation for heat hyperalgesia. The cold and mechanical stimulations were applied through acetone and von Frey filament, respectively. Generally, the stimulations were applied on the medial plantar surface of the left hind paw. Behavioral tests were carried out on the animals prior to the
S228
P.1.g. Basic and clinical neuroscience − Neuropharmacology
surgery (the day 0) and also on the days 7, 14 and 21 after surgery. Donepezil at the doses of 1, 2 and 4 mg/kg and its vehicle were injected intraperitoneally in two types of treatment; in chronic treatment, the animals were administered daily on days 7−14 after the surgery and in acute treatment they received the drug only on 7th, 14th and 21st day post-surgery, 30 minutes before the behavioral tests in order to assess its effect on expression of neuropathic pain. Results: In the behavioral tests of cold allodynia, both of acute and chronic treatment with donepezil (2 and 4 mg/kg i.p.) show significant reduction in the withdrawal frequency in comparison with CCI group (p < 0.001). Regarding the thermal hyperalgesia, acute administration of donepezil (4 mg/kg i.p.) 30 minute before plantar test on the 7th, 14th and 21st days after surgery blocked thermal hyperalgesia in ipsilateral paw (P < 0.001). Furthermore chronic treatment with donepezil (1, 2 and 4 mg/kg i.p.) from the first day after surgery produced significant anti-hyperalgesia compare to CCI group (p < 0.001). But about mechanical allodynia, acute as well as chronic treatment with donepezil couldn’t significantly modify withdrawal threshold of ipsilateral paw. Overall our data indicate that the systemic administration of donepezil reduces some behavioral scores of neuropathic pain. Conclusions: These results suggest that donepezil or cholinesterase inhibition could be considered as a new approach for management of neuropathic pain. References [1] Treede, R.D., Jensen, T.S., Campbell, J.N., Cruccu, G., Dostrovsky, J.O., Griffin, J.W., Hansson, P., Hughes, R., Nurmikko, T., Serra, J., 2008. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 70, 1630–1635. [2] Kimura, M., Hayashida, K., Eisenach, J.C., Saito, S., Obata, H., 2013. Relief of hypersensitivity after nerve injury from systemic donepezil involves spinal cholinergic and g-aminobutyric acid mechanisms. Anesthesiology 118(1), 173–180. [3] Bennett, G.J., Xie, Y.K.A., 1988. Peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33, 87–107.
P.1.g.024 5-HT7 receptor-mediated alterations of hyperalgesia in neuropathic rats selectively depleted in spinal 5-HT by intra-bulbar injection of a recombinant lentiviral vector A. Gautier1 , H. El Ouaraki1 , S. Salam1 , G. Vodjdani1 , S. Bourgoin1 ° , J. Bernard1 , M. Hamon1 1 CPN - INSERM U894, Psychiatrie et Neurosciences, Paris, France The bulbo-spinal serotoninergic pathway originating in the B3 area of the rostro-ventro-medial medulla is known to play a key role in the modulation of nociceptive signaling within the dorsal horn of the spinal cord, where are relayed nociceptive signals. Indeed, electrolytical or chemical (by 5,7-dihydroxytrytamine) lesion of this pathway has been consistently shown to markedly reduce the analgesic effects of various drugs (including antidepressants) in murine models of neuropathic pain. However the receptor(s) mediating this modulatory action of 5-HT is still a matter of debate. By using an innovative shRNA approach to deplete 5-HT within bulbo-spinal projections, we further investigated the implication of endogenous 5-HT in modulatory controls of hyperalgesia in rats rendered neuropathic by unilateral chronic constriction to the sciatic nerve (CCI-SN). Whether or not 5-HT7 receptors
were implicated in spinal 5-HT depletion-induced changes in neuropathic pain was assessed by quantifying hyperalgesia in CCISN rats treated with selective 5-HT7 receptor ligands. Sprague-Dawley rats were stereotaxically injected into the bilateral B3 area with the lentiviral vector LV-shTPH2, to produce locally a short hairpin sh-RNA sequence directed against the tryptophan hydroxylase 2 (TPH2) transcript. The resulting 5-HT depletion in bulbo-spinal projections was measured by quantitative immunofluorescence with anti-5-HT antibodies. CCI-SN was made by ligating the right sciatic nerve with silk thread, and the resulting mechanical hyperalgesia was quantified by determination of the ipsilateral hindpaw pressure threshold value to trigger vocalization in the Randall Selitto test. This test was performed before CCI-SN, and two weeks after, at various times (up to 6 hours) after acute injection of the selective 5-HT7 receptor agonist E-55888 (10 mg/kg i.p.), the antagonist SB-269970 (3 mg/kg s.c.) or both drugs. Statistical analyses were performed using two-way ANOVA and repeated measures without post test or Bonferroni post hoc test (GraphPad prism 5 software). As compared to controls, a significant depletion (−35−50%) of 5-HT immunofluorescence within the dorsal horn, but not the ventral horn, at all levels (cervical, thoracic, lumbar) of the spinal cord was observed from two weeks up to (at least) eight weeks after intra-B3 injection of LV-shTPH2. Both LV-shTPH2-injected rats and na¨ıve controls developed mechanical hyperalgesia, as shown by a significant decrease (−30%) in vocalization threshold two weeks after CCI-SN. However, this effect was significantly more pronounced (+35%) in LV-shTPH2-injected rats, indicating that endogenous 5-HT normally exerts an inhibitory control of CCI-SN-induced hyperalgesia. Systemic administration of the agonist E-55888 (10 mg/kg i.p.) increasee vocalization threshold in all rats, and suppressed the differences between both groups that had been observed prior to treatment. Administration of the antagonist, SB-269970, prevented the effects of 55888, and produced, on its own, a decrease (−30%) in vocalization threshold value in na¨ıve, non-5-HT depleted, rats only. Thence, after SB269970 administration, the same high level of CCI-SN-induced hyperalgesia was noted in both LV-shTPH2-injected and na¨ıve rats. These data support the idea that spinal 5-HT7 receptors may play an important role in both the physiological control mechanisms of pain signaling processes and the anti-neuropathic pain effects of drugs such as antidepressants.
P.1.g.026 Effects of new low-molecular mimetic of NGF loop 3 on the activation of TrkA-receptor, PI3K/AKT and MAPK/ERK signaling pathways T.A. Antipova1 ° , T.A. Gudasheva2 , A.V. Tarasiuk2 , S.V. Nikolaev1 , I.O. Logvinov1 , S.V. Kruglov1 , S.B. Seredenin1 1 V.V. Zakusov Institute of Pharmacology Russian Academy of Medical Sciences RAMS, Pharmacogenetic, Moscow, Russia; 2 V.V. Zakusov Institute of Pharmacology Russian Academy of Medical Sciences RAMS, Chemistry, Moscow, Russia Introduction: Nerve growth factor (NGF), a member of the neurotrophin family, which plays an important role in pathogenesis of neurodegenetative diseases and survival of several populations of neurons. Despite this factor’s considerable therapeutic potential, the clinical application of NGF is limited by its strong side effects such as low blood brain barrier permeability,
P.1.g.022 Acute effect of d-opioid receptors agonist and antagonist on excitability of neonatal rat hippocampal neurons in primary cell culture L. Lap´ınov´a1 ° , E. Dremencov1,2 , L. Lacinov´a1 1 Institute of Molecular Physiology and Genetics of Slovak Academy of Sciences, Department of Cellular Physiology and Genetics, Bratislava, Slovak Republic; 2 Biomedical Research Center of Slovak Academy of Sciences, Institute of Experimental Endocrinology, Bratislava, Slovak Republic Background: Delta opioid receptors (DOR) play an important role in chronic pain, emotional processing, and mood disorders. These receptors are widely distributed across the brain, with relatively high density in the hippocampus [1]. In some brain regions DOR ligands suppress neuronal activity by inhibition of neuronal firing or by reduction of neurotransmitter release. The aim of the current study was to investigate the effect of DOR agonist SNC80 and antagonist naltrindole on the excitability of rat hippocampal pyramidal neurons in primary culture. Methods: Hippocampal neurons were isolated from newborn Wistar rats. Excitability of hippocampal neurons was measured in whole-cell patch clamp configuration using HEKA EPC-10 amplifier. Borosilicate glass electrodes (impedance 3 to 4 MW) were used. Depolarization-activated action potential (AP) firing was measured from day in vitro (DIV) 8 to day 10 from a holding potential of −70 mV. Spontaneous activity was measured on DIV 13 from a native membrane potential of each cell. Ion current was measured from DIV 10 to 12. Sodium currents were measured using depolarizing pulses of −70 mV to +70 mV from a holding potential of −90 mV. Calcium currents were measured using depolarizing pulses of −40 mV to +50 mV from a holding potential of −40 mV. Potassium currents were measured using depolarizing pulses of 40 mV to +80 mV from a holding potential of −80 mV. Statistical differences between groups were determined by parametric paired t-test. Probability p < 0.05 was considered as statistically significant. Results: Naltrindole significantly inhibited both depolarizationactivated and spontaneous AP firing in a dose-dependent manner. Concentration dependence was U-shaped with a maximum at a concentration of 10 mM. SNC80 significantly inhibited depolarization-activated AP firing. This effect decreased with increasing drug concentration, i.e., it was maximal at a concentration of 100 nM. Spontaneous activity was inhibited by low concentration of SNC80 and this inhibition increased with increasing drug concentration within the range 100 nM to 10 mM being significant at 10 mM. At higher concentration (100 mM) spontaneous activity was significantly enhanced. An effect of both drugs on
S227
voltage dependent ion channels was tested at a concentration, which affected depolarization-activated AP firing most effectively. Naltrindole inhibited calcium, sodium, peak potassium current and sustained potassium current. SNC80 inhibited calcium, sodium and sustained potassium current but potentiated peak potassium current. Observed inhibition of voltage dependent sodium current may suppress activation of an AP and therefore attenuate the AP firing. Potentiation of voltage dependent potassium currents supports rapid depolarization and therefore facilitates the AP firing while an inhibition of these channels may act in opposite, i.e., attenuate the AP firing. Voltage dependent calcium channels may contribute to initial depolarization and therefore support the AP firing and/or repolarization and thus attenuate also the AP firing. Conclusions: Effects of agonist and antagonist of d-opioid receptors on the excitability of hippocampal pyramidal neurons was not complementary suggesting more complex underlying mechanism arising from different effects on voltage dependent ion channels. References [1] Lutz, P.E., Kieffer, B.L., 2013. Opioid receptors: distinct roles in mood disorders. Trends Neurosci 36, 195–206. Disclosure statement: This work was supported by the SAS Scholarship, VEGA 2/0024/15 and APVV-0212−10.
P.1.g.023 Antinociceptive effects of donepezil as an acetylcholinesterase inhibitor in a rat model of neuropathic pain A. Mesdaghinia1 ° , H.R. Banafshe1 , A. Abed1 , A. Hajnorouzali2 , E. Mesdaghinia2 1 Kashan University of Medical Sciences, Physiology Research Center, Kashan, Iran; 2 Kashan University of Medical Sciences, School of Medicine, Kashan, Iran Purpose of the study: Neuropathic pain results from lesions or diseases affecting the somatosensory system [1]. The management of patients with chronic neuropathic pain remains a challenge. Several studies report the analgesic effect of acetylcholinesterase inhibitors in different models of experimental pain [2]. The present study was designed to investigate the effect of systemic administration of donepezil, a central acetylcholinesterase inhibitor, on behavioral hyperalgesia and allodynia scores of neuropathic pain in chronic constriction injury (CCI) model in rat. Methods: Experiments were carried out on male SpragueDawley rats (230–280 g). Three or four rats were housed in a cage under a 12 h light/dark cycle with food and water available ad libitum. To induce the animal model of neuropathic pain, the CCI method was performed on the sciatic nerve as described in detail previously by Bennett and Xie [3]. Sham-operated rats had the same surgery, the left sciatic nerve was exposed but no ligation was made. The rats were housed individually in cages after the surgery. All experiments followed the guide lines on ethical standard for investigation of experimental pain in animals. The behavioral experiments included allodynia and hyperalgesia phenomena. The animals in the allodynia experiments were subdivided into cold and mechanical allodynia groups. Radiant heat was applied as thermal stimulation for heat hyperalgesia. The cold and mechanical stimulations were applied through acetone and von Frey filament, respectively. Generally, the stimulations were applied on the medial plantar surface of the left hind paw. Behavioral tests were carried out on the animals prior to the
S228
P.1.g. Basic and clinical neuroscience − Neuropharmacology
surgery (the day 0) and also on the days 7, 14 and 21 after surgery. Donepezil at the doses of 1, 2 and 4 mg/kg and its vehicle were injected intraperitoneally in two types of treatment; in chronic treatment, the animals were administered daily on days 7−14 after the surgery and in acute treatment they received the drug only on 7th, 14th and 21st day post-surgery, 30 minutes before the behavioral tests in order to assess its effect on expression of neuropathic pain. Results: In the behavioral tests of cold allodynia, both of acute and chronic treatment with donepezil (2 and 4 mg/kg i.p.) show significant reduction in the withdrawal frequency in comparison with CCI group (p < 0.001). Regarding the thermal hyperalgesia, acute administration of donepezil (4 mg/kg i.p.) 30 minute before plantar test on the 7th, 14th and 21st days after surgery blocked thermal hyperalgesia in ipsilateral paw (P < 0.001). Furthermore chronic treatment with donepezil (1, 2 and 4 mg/kg i.p.) from the first day after surgery produced significant anti-hyperalgesia compare to CCI group (p < 0.001). But about mechanical allodynia, acute as well as chronic treatment with donepezil couldn’t significantly modify withdrawal threshold of ipsilateral paw. Overall our data indicate that the systemic administration of donepezil reduces some behavioral scores of neuropathic pain. Conclusions: These results suggest that donepezil or cholinesterase inhibition could be considered as a new approach for management of neuropathic pain. References [1] Treede, R.D., Jensen, T.S., Campbell, J.N., Cruccu, G., Dostrovsky, J.O., Griffin, J.W., Hansson, P., Hughes, R., Nurmikko, T., Serra, J., 2008. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 70, 1630–1635. [2] Kimura, M., Hayashida, K., Eisenach, J.C., Saito, S., Obata, H., 2013. Relief of hypersensitivity after nerve injury from systemic donepezil involves spinal cholinergic and g-aminobutyric acid mechanisms. Anesthesiology 118(1), 173–180. [3] Bennett, G.J., Xie, Y.K.A., 1988. Peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33, 87–107.
P.1.g.024 5-HT7 receptor-mediated alterations of hyperalgesia in neuropathic rats selectively depleted in spinal 5-HT by intra-bulbar injection of a recombinant lentiviral vector A. Gautier1 , H. El Ouaraki1 , S. Salam1 , G. Vodjdani1 , S. Bourgoin1 ° , J. Bernard1 , M. Hamon1 1 CPN - INSERM U894, Psychiatrie et Neurosciences, Paris, France The bulbo-spinal serotoninergic pathway originating in the B3 area of the rostro-ventro-medial medulla is known to play a key role in the modulation of nociceptive signaling within the dorsal horn of the spinal cord, where are relayed nociceptive signals. Indeed, electrolytical or chemical (by 5,7-dihydroxytrytamine) lesion of this pathway has been consistently shown to markedly reduce the analgesic effects of various drugs (including antidepressants) in murine models of neuropathic pain. However the receptor(s) mediating this modulatory action of 5-HT is still a matter of debate. By using an innovative shRNA approach to deplete 5-HT within bulbo-spinal projections, we further investigated the implication of endogenous 5-HT in modulatory controls of hyperalgesia in rats rendered neuropathic by unilateral chronic constriction to the sciatic nerve (CCI-SN). Whether or not 5-HT7 receptors
were implicated in spinal 5-HT depletion-induced changes in neuropathic pain was assessed by quantifying hyperalgesia in CCISN rats treated with selective 5-HT7 receptor ligands. Sprague-Dawley rats were stereotaxically injected into the bilateral B3 area with the lentiviral vector LV-shTPH2, to produce locally a short hairpin sh-RNA sequence directed against the tryptophan hydroxylase 2 (TPH2) transcript. The resulting 5-HT depletion in bulbo-spinal projections was measured by quantitative immunofluorescence with anti-5-HT antibodies. CCI-SN was made by ligating the right sciatic nerve with silk thread, and the resulting mechanical hyperalgesia was quantified by determination of the ipsilateral hindpaw pressure threshold value to trigger vocalization in the Randall Selitto test. This test was performed before CCI-SN, and two weeks after, at various times (up to 6 hours) after acute injection of the selective 5-HT7 receptor agonist E-55888 (10 mg/kg i.p.), the antagonist SB-269970 (3 mg/kg s.c.) or both drugs. Statistical analyses were performed using two-way ANOVA and repeated measures without post test or Bonferroni post hoc test (GraphPad prism 5 software). As compared to controls, a significant depletion (−35−50%) of 5-HT immunofluorescence within the dorsal horn, but not the ventral horn, at all levels (cervical, thoracic, lumbar) of the spinal cord was observed from two weeks up to (at least) eight weeks after intra-B3 injection of LV-shTPH2. Both LV-shTPH2-injected rats and na¨ıve controls developed mechanical hyperalgesia, as shown by a significant decrease (−30%) in vocalization threshold two weeks after CCI-SN. However, this effect was significantly more pronounced (+35%) in LV-shTPH2-injected rats, indicating that endogenous 5-HT normally exerts an inhibitory control of CCI-SN-induced hyperalgesia. Systemic administration of the agonist E-55888 (10 mg/kg i.p.) increasee vocalization threshold in all rats, and suppressed the differences between both groups that had been observed prior to treatment. Administration of the antagonist, SB-269970, prevented the effects of 55888, and produced, on its own, a decrease (−30%) in vocalization threshold value in na¨ıve, non-5-HT depleted, rats only. Thence, after SB269970 administration, the same high level of CCI-SN-induced hyperalgesia was noted in both LV-shTPH2-injected and na¨ıve rats. These data support the idea that spinal 5-HT7 receptors may play an important role in both the physiological control mechanisms of pain signaling processes and the anti-neuropathic pain effects of drugs such as antidepressants.
P.1.g.026 Effects of new low-molecular mimetic of NGF loop 3 on the activation of TrkA-receptor, PI3K/AKT and MAPK/ERK signaling pathways T.A. Antipova1 ° , T.A. Gudasheva2 , A.V. Tarasiuk2 , S.V. Nikolaev1 , I.O. Logvinov1 , S.V. Kruglov1 , S.B. Seredenin1 1 V.V. Zakusov Institute of Pharmacology Russian Academy of Medical Sciences RAMS, Pharmacogenetic, Moscow, Russia; 2 V.V. Zakusov Institute of Pharmacology Russian Academy of Medical Sciences RAMS, Chemistry, Moscow, Russia Introduction: Nerve growth factor (NGF), a member of the neurotrophin family, which plays an important role in pathogenesis of neurodegenetative diseases and survival of several populations of neurons. Despite this factor’s considerable therapeutic potential, the clinical application of NGF is limited by its strong side effects such as low blood brain barrier permeability,