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3.219 EFFECTS OF THE NOVEL ANTIPARKINSONIAN DRUG HEMANTANE AND AMANTADINE ON MEMORY AND LEARNING IN RATS WITH INTRACEREBRAL POSTTRAUMATIC HAEMATOMA
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Wednesday, 14 December 2011 / Parkinsonism and Related Disorders 18S2 (2012) S161–S234
C57/Bl6 mice. We found that bilateral striatal CDNF injections, given 20-h before MPTP, improved horizontal and vertical motor behavior. CDNF pre-treatment increased tyrosine hydroxylase (TH)immunoreactivity in the striatum and in the substantia nigra pars reticulata (SNpr), as well as the number of TH-positive cells in substantia nigra pars compacta (SNpc). Post-treatment with CDNF, given 1 week after MPTP injections, increased horizontal and vertical behavior of mice, as well as dopamine fiber densities in the striatum and the number of TH-positive cells in SNpc. CDNF did not alter any of the analyzed dopaminergic biomarkers or locomotor behavior in MPTP-untreated animals. We conclude that striatal CDNF administration is both neuroprotective and neurorestorative for the nigrostriatal dopamine system in the MPTP model, which supports the development of CDNF-based treatment for Parkinson’s disease. 3.218 INVESTIGATION OF POTENTIAL NEUROPROTECTIVE EFFECTS OF HEMANTANE ON DNA DAMAGE AND LIPID PEROXIDATION IN MICE WITH MPTP-INDUCED PARKINSONISM A. Nepoklonov1 , A. Zhanataev2 , E. Anisina2 , K. Kolyasnikova3 , N. Zolotov1 . 1 Psychopharmacology, 2 Pharmacology of Mutagenesis, 3 Chemistry, Zakusov Institute of Pharmacology RAMS, Moscow, Russia Hemantane (H.) (N-2(adamantyl)hexamethylenimine hydrochloride) reduced motor disturbances in animal models and effective in patients with early stages of Parkinson’s disease. The aim of the study was to assess potential neuroprotective effects of H. against DNA damage and oxidative stress caused by 1-methyl4-phenyl-tetrahydropyridine (MPTP) in mice. Male C57BL/6 mice were divided in 4 groups (n = 10). 1-st was treated with saline, 2-nd – with H. 10 mg/kg for 10 days, 3-d – saline 5 days, then MPTP 20 mg/kg i.p. next 5 days, 4-th – H. 10 mg/kg 5 days, then H. with MPTP for next 5 days. Animals were decapitated 24 hours after last injection. Frontal cortex and striatum were used for further investigation. DNA damage was assessed in single gel electrophoresis (comet) assay. Malonic dialdehide (MDA) and conjugated dienes as a measure of lipid peroxidation were measured using spectrophotometry/MPTP treatment do not increase DNA damage Treatment with H. also had no effect on DNA. Significant increase in the MDA level was registered in striatum and cortex and conjugated dienes – in cortex of MPTP treated mice. In animals treated with H. before and in combination with MPTP levels of MDA and conjugated dienes were the same as in 1-st and 2-nd groups. MPTP in used dose, schedule of administration did not cause DNA damage but lead to increase in lipid peroxidation in mice brain. H. prevented increase in lipid peroxidation caused by MPTP. The results obtained prove that H is able to protect against neurotoxic effect of MPTP. 3.219 EFFECTS OF THE NOVEL ANTIPARKINSONIAN DRUG HEMANTANE AND AMANTADINE ON MEMORY AND LEARNING IN RATS WITH INTRACEREBRAL POSTTRAUMATIC HAEMATOMA S. Kotelnikova, A. Nepoklonov, V. Krayneva, E. Valdman, T. Voronina. Zakusov Institute of Pharmacology RAMS, Moscow, Russia Hemantane (H) (N-2(adamantyl)hexamethylenimine hydrochloride) was developed as antiparkinsonian drug at Zakusov Institute of Pharmacology. H. is effective in animal models and in patients with early stages of Parkinson’s disease. H. has complex mechanism of action, including properties of uncompetitive, low-affinity, NMDA receptor open-channel blocker, antiradical activity, which allows to suppose its neuroprotective effects in acute and chronic neurologic disorders. The aim of the study was to assess the effects of H. in comparison with amantadine (AMA) in rats with intracerebral posttraumatic hematoma.
H. (10 mg/kg) or AMA (20 mg/kg) were administered daily for 5 days, first injection – 4 hours after surgery, in two groups. Control groups were – sham-operated and with hematoma, both treated with saline. Animals were tested in passive avoidance step through apparatus – training at the 1-st day after surgery and retention – on days 1, 3, 7 and 14 after training. Motor activity was assessed in open field. H. and AMA did not improve disturbed motor activity. Time for the first enter to dark chamber during training procedure was the same in all four groups. Significant decrease in retention latencies was registered in non-treated rats with brain lesion compared to shamoperated animals. Animals treated with H. demonstrated significant increase in retention latencies compared to non-treated rats during all test sessions. AMA produced significant increase in retention latencies only on days 1 and 3. H. and AMA are able to improve learning and memory in rats with intracerebral posttraumatic hematoma. Effect of H. is more prolonged. 3.220 NIGROSTRIATAL DOPAMINERGIC SYSTEM OF CONDITIONAL GDNF KNOCK-OUT MICE DOES NOT DISPLAY INCREASED VULNERABILITY TO AGING J. Kopra1 , J.-O. Andressoo2 , J. Mijatovic1 , C. Amberg2 , P. Piepponen1 , M. Saarma2 . 1 Faculty of Pharmacy, Division of Pharmacology and Toxicology, 2 Viikki Biocenter, Institute of Biotechnology, University of Helsinki, Helsinki, Finland Glial cell line Derived Neurotrophic Factor (GDNF) promotes the survival and protects embryonic dopamine (DA) neurons in vitro, and has potent survival-promoting effects on adult DA neurons in in vivo animal models of Parkinson’s disease. However, the role of GDNF in the normal development and maintenance of midbrain DA systems has been difficult to study since the conventional GDNF knock-out mice are not viable. To overcome this problem a conditional knock-out (cKO) mouse model was created, where GDNF is deleted only in the central nervous system by using Nestin-Cre-Lox technique. With this model we have, for the first time, investigated the role of endogenous, physiological GDNF in the development and maintenance of nigrostriatal dopaminergic system. We aged these cKO mice for 3, 14 and 19 months and estimated the number of tyrosine hydroxylase (TH) positive cells in substantia nigra pars compacta (SNpc) with stereological microscopy and measured the optical density of TH staining in the striatum. We also collected striatal tissue from 3 months old mice for DA HPLC measurement. We didn’t find any differences between the cKO and wild type mice in any of the age groups studied. Thus, our findings so far do not support the view of GDNF as an essential survival and maintenance factor for nigrostriatal dopaminergic neurons, at least during normal development and aging. We will present data also on GDNF over-expressing, hypermorph mice. 3.221 AMANTADINE PROTECTS DOPAMINE NEURONS BY A DUAL ACTION: REDUCING ACTIVATION OF MICROGLIA AND INDUCING EXPRESSION OF GNDF IN ASTROGLIA B. Ossola1 , N. Schendzielorz1 , S.-H. Chen2 , G.S. Bird2 , R.K. Tuominen1 , P.T. Mannist ¨ o¨ 1 , J.-S. Hong2 . 1 University of Helsinki, 2 Helsinki, Finland; NIEHS/NIH, Research Triangle Park, NC, USA Amantadine is commonly given to alleviate L-DOPA-induced dyskinesia of Parkinson’s disease (PD) patients. Animal and human evidence showed that amantadine may also exert neuroprotection in several neurological disorders. Additionally, it is generally believed that this neuroprotection results from the ability of amantadine to inhibit glutamatergic NMDA receptor. However, several lines of evidence questioned the neuroprotection capacity of NMDA receptor antagonists in animal models of PD. Thus the cellular and molecular mechanism of neuroprotection of
Wednesday, 14 December 2011 / Parkinsonism and Related Disorders 18S2 (2012) S161–S234
C57/Bl6 mice. We found that bilateral striatal CDNF injections, given 20-h before MPTP, improved horizontal and vertical motor behavior. CDNF pre-treatment increased tyrosine hydroxylase (TH)immunoreactivity in the striatum and in the substantia nigra pars reticulata (SNpr), as well as the number of TH-positive cells in substantia nigra pars compacta (SNpc). Post-treatment with CDNF, given 1 week after MPTP injections, increased horizontal and vertical behavior of mice, as well as dopamine fiber densities in the striatum and the number of TH-positive cells in SNpc. CDNF did not alter any of the analyzed dopaminergic biomarkers or locomotor behavior in MPTP-untreated animals. We conclude that striatal CDNF administration is both neuroprotective and neurorestorative for the nigrostriatal dopamine system in the MPTP model, which supports the development of CDNF-based treatment for Parkinson’s disease. 3.218 INVESTIGATION OF POTENTIAL NEUROPROTECTIVE EFFECTS OF HEMANTANE ON DNA DAMAGE AND LIPID PEROXIDATION IN MICE WITH MPTP-INDUCED PARKINSONISM A. Nepoklonov1 , A. Zhanataev2 , E. Anisina2 , K. Kolyasnikova3 , N. Zolotov1 . 1 Psychopharmacology, 2 Pharmacology of Mutagenesis, 3 Chemistry, Zakusov Institute of Pharmacology RAMS, Moscow, Russia Hemantane (H.) (N-2(adamantyl)hexamethylenimine hydrochloride) reduced motor disturbances in animal models and effective in patients with early stages of Parkinson’s disease. The aim of the study was to assess potential neuroprotective effects of H. against DNA damage and oxidative stress caused by 1-methyl4-phenyl-tetrahydropyridine (MPTP) in mice. Male C57BL/6 mice were divided in 4 groups (n = 10). 1-st was treated with saline, 2-nd – with H. 10 mg/kg for 10 days, 3-d – saline 5 days, then MPTP 20 mg/kg i.p. next 5 days, 4-th – H. 10 mg/kg 5 days, then H. with MPTP for next 5 days. Animals were decapitated 24 hours after last injection. Frontal cortex and striatum were used for further investigation. DNA damage was assessed in single gel electrophoresis (comet) assay. Malonic dialdehide (MDA) and conjugated dienes as a measure of lipid peroxidation were measured using spectrophotometry/MPTP treatment do not increase DNA damage Treatment with H. also had no effect on DNA. Significant increase in the MDA level was registered in striatum and cortex and conjugated dienes – in cortex of MPTP treated mice. In animals treated with H. before and in combination with MPTP levels of MDA and conjugated dienes were the same as in 1-st and 2-nd groups. MPTP in used dose, schedule of administration did not cause DNA damage but lead to increase in lipid peroxidation in mice brain. H. prevented increase in lipid peroxidation caused by MPTP. The results obtained prove that H is able to protect against neurotoxic effect of MPTP. 3.219 EFFECTS OF THE NOVEL ANTIPARKINSONIAN DRUG HEMANTANE AND AMANTADINE ON MEMORY AND LEARNING IN RATS WITH INTRACEREBRAL POSTTRAUMATIC HAEMATOMA S. Kotelnikova, A. Nepoklonov, V. Krayneva, E. Valdman, T. Voronina. Zakusov Institute of Pharmacology RAMS, Moscow, Russia Hemantane (H) (N-2(adamantyl)hexamethylenimine hydrochloride) was developed as antiparkinsonian drug at Zakusov Institute of Pharmacology. H. is effective in animal models and in patients with early stages of Parkinson’s disease. H. has complex mechanism of action, including properties of uncompetitive, low-affinity, NMDA receptor open-channel blocker, antiradical activity, which allows to suppose its neuroprotective effects in acute and chronic neurologic disorders. The aim of the study was to assess the effects of H. in comparison with amantadine (AMA) in rats with intracerebral posttraumatic hematoma.
H. (10 mg/kg) or AMA (20 mg/kg) were administered daily for 5 days, first injection – 4 hours after surgery, in two groups. Control groups were – sham-operated and with hematoma, both treated with saline. Animals were tested in passive avoidance step through apparatus – training at the 1-st day after surgery and retention – on days 1, 3, 7 and 14 after training. Motor activity was assessed in open field. H. and AMA did not improve disturbed motor activity. Time for the first enter to dark chamber during training procedure was the same in all four groups. Significant decrease in retention latencies was registered in non-treated rats with brain lesion compared to shamoperated animals. Animals treated with H. demonstrated significant increase in retention latencies compared to non-treated rats during all test sessions. AMA produced significant increase in retention latencies only on days 1 and 3. H. and AMA are able to improve learning and memory in rats with intracerebral posttraumatic hematoma. Effect of H. is more prolonged. 3.220 NIGROSTRIATAL DOPAMINERGIC SYSTEM OF CONDITIONAL GDNF KNOCK-OUT MICE DOES NOT DISPLAY INCREASED VULNERABILITY TO AGING J. Kopra1 , J.-O. Andressoo2 , J. Mijatovic1 , C. Amberg2 , P. Piepponen1 , M. Saarma2 . 1 Faculty of Pharmacy, Division of Pharmacology and Toxicology, 2 Viikki Biocenter, Institute of Biotechnology, University of Helsinki, Helsinki, Finland Glial cell line Derived Neurotrophic Factor (GDNF) promotes the survival and protects embryonic dopamine (DA) neurons in vitro, and has potent survival-promoting effects on adult DA neurons in in vivo animal models of Parkinson’s disease. However, the role of GDNF in the normal development and maintenance of midbrain DA systems has been difficult to study since the conventional GDNF knock-out mice are not viable. To overcome this problem a conditional knock-out (cKO) mouse model was created, where GDNF is deleted only in the central nervous system by using Nestin-Cre-Lox technique. With this model we have, for the first time, investigated the role of endogenous, physiological GDNF in the development and maintenance of nigrostriatal dopaminergic system. We aged these cKO mice for 3, 14 and 19 months and estimated the number of tyrosine hydroxylase (TH) positive cells in substantia nigra pars compacta (SNpc) with stereological microscopy and measured the optical density of TH staining in the striatum. We also collected striatal tissue from 3 months old mice for DA HPLC measurement. We didn’t find any differences between the cKO and wild type mice in any of the age groups studied. Thus, our findings so far do not support the view of GDNF as an essential survival and maintenance factor for nigrostriatal dopaminergic neurons, at least during normal development and aging. We will present data also on GDNF over-expressing, hypermorph mice. 3.221 AMANTADINE PROTECTS DOPAMINE NEURONS BY A DUAL ACTION: REDUCING ACTIVATION OF MICROGLIA AND INDUCING EXPRESSION OF GNDF IN ASTROGLIA B. Ossola1 , N. Schendzielorz1 , S.-H. Chen2 , G.S. Bird2 , R.K. Tuominen1 , P.T. Mannist ¨ o¨ 1 , J.-S. Hong2 . 1 University of Helsinki, 2 Helsinki, Finland; NIEHS/NIH, Research Triangle Park, NC, USA Amantadine is commonly given to alleviate L-DOPA-induced dyskinesia of Parkinson’s disease (PD) patients. Animal and human evidence showed that amantadine may also exert neuroprotection in several neurological disorders. Additionally, it is generally believed that this neuroprotection results from the ability of amantadine to inhibit glutamatergic NMDA receptor. However, several lines of evidence questioned the neuroprotection capacity of NMDA receptor antagonists in animal models of PD. Thus the cellular and molecular mechanism of neuroprotection of