Effects of nicotine on hydroxyl free radical formation in vitro and on MPTP-induced neurotoxicity in vivo

B Ferger, C Spratt, C D Earl, Peter Teismann, W H Oertel, K Kuschinsky

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Parkinson's disease (PD) is one of the most frequent disorders of the basal ganglia. From epidemiological studies there is a controversial discussion on the question whether tobacco smoking is correlated with a decreased incidence of PD. The present study aimed to elucidate the role of nicotine and its potential neuroprotective effects in a rodent model of PD. These effects may be related to an altered hydroxyl radical formation; this possibility was studied in vitro. Nicotine and alpha-phenyl-N-tert-butyl nitrone (PBN) were examined in a cell-free in vitro Fenton system (Fe3+/EDTA + H2O2) for their radical scavenging properties using the salicylate trapping method. Salicylic acid (0.5 mM) was incubated in the presence and absence of nicotine or PBN and the main products of the reaction of hydroxyl radicals with salicylic acid, namely 2,3- and 2,5-dihydroxybenzoic acid, were immediately determined using HPLC in combination with electrochemical detection. Nicotine and PBN were both able to significantly reduce hydroxyl radical levels at concentrations of 1, 2.5 and 5 mM. Interestingly, at 5 mM nicotine was able to reduce hydroxyl radical levels significantly more than the radical scavenger PBN (5 mM). To investigate the in vivo effects of nicotine, male C57BL/6 mice were used in the MPTP mouse model of PD. Nicotine (0.1 or 0.4 mg/kg s.c.) was administered twice daily for a period of 14 days. On day 8 a single injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg s.c.) was given as well as an enhanced protocol of nicotine treatment (0.1 or 0.4 mg/kg s.c., 30 min before MPTP and 30, 90, 210, 330, 450, 570 min after MPTP) for a total of seven injections of nicotine. High dosage nicotine treatment significantly increased the MPTP-induced loss of body weight and resulted in a significantly decreased striatal dopamine content and an increased dopamine turnover in comparison with the MPTP-treated controls at day 15. However, the lower dosage of nicotine did not significantly alleviate the MPTP-induced effects, although some parameters showed a slight tendency in this direction. These results demonstrate that in vitro nicotine has radical scavenging properties which might suggest neuroprotective effects. In vivo experiments with nicotine, however, showed that a low dosage of nicotine did not alleviate the MPTP-induced dopamine depletion, but a large dosage even enhanced it.
Original languageEnglish
Pages (from-to)351-359
Number of pages9
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume358
Issue number3
DOIs
Publication statusPublished - 1 Sep 1998

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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Nicotine
Hydroxyl Radical
Free Radicals
Parkinson Disease
Dopamine
Salicylic Acid
Neuroprotective Agents
In Vitro Techniques
Basal Ganglia Diseases
Corpus Striatum
Injections
Salicylates
Clinical Protocols
Inbred C57BL Mouse
Edetic Acid

Keywords

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Animals
  • Body Weight
  • Cardiotonic Agents
  • Cyclic N-Oxides
  • Dopamine
  • Dopamine Agents
  • Drug Interactions
  • Free Radical Scavengers
  • Hydroxyl Radical
  • Locomotion
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nicotine
  • Nicotinic Agonists
  • Nitrogen Oxides
  • Parkinson Disease, Secondary
  • Nicotine
  • Hydroxyl radicals
  • PBN
  • MPTP
  • Neuroprotection
  • Parkinson’s disease

Cite this

Effects of nicotine on hydroxyl free radical formation in vitro and on MPTP-induced neurotoxicity in vivo. / Ferger, B; Spratt, C; Earl, C D; Teismann, Peter; Oertel, W H; Kuschinsky, K.

In: Naunyn-Schmiedeberg's Archives of Pharmacology, Vol. 358, No. 3, 01.09.1998, p. 351-359.

Research output: Contribution to journalArticle

Ferger, B ; Spratt, C ; Earl, C D ; Teismann, Peter ; Oertel, W H ; Kuschinsky, K. / Effects of nicotine on hydroxyl free radical formation in vitro and on MPTP-induced neurotoxicity in vivo. In: Naunyn-Schmiedeberg's Archives of Pharmacology. 1998 ; Vol. 358, No. 3. pp. 351-359.
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T1 - Effects of nicotine on hydroxyl free radical formation in vitro and on MPTP-induced neurotoxicity in vivo

AU - Ferger, B

AU - Spratt, C

AU - Earl, C D

AU - Teismann, Peter

AU - Oertel, W H

AU - Kuschinsky, K

PY - 1998/9/1

Y1 - 1998/9/1

N2 - Parkinson's disease (PD) is one of the most frequent disorders of the basal ganglia. From epidemiological studies there is a controversial discussion on the question whether tobacco smoking is correlated with a decreased incidence of PD. The present study aimed to elucidate the role of nicotine and its potential neuroprotective effects in a rodent model of PD. These effects may be related to an altered hydroxyl radical formation; this possibility was studied in vitro. Nicotine and alpha-phenyl-N-tert-butyl nitrone (PBN) were examined in a cell-free in vitro Fenton system (Fe3+/EDTA + H2O2) for their radical scavenging properties using the salicylate trapping method. Salicylic acid (0.5 mM) was incubated in the presence and absence of nicotine or PBN and the main products of the reaction of hydroxyl radicals with salicylic acid, namely 2,3- and 2,5-dihydroxybenzoic acid, were immediately determined using HPLC in combination with electrochemical detection. Nicotine and PBN were both able to significantly reduce hydroxyl radical levels at concentrations of 1, 2.5 and 5 mM. Interestingly, at 5 mM nicotine was able to reduce hydroxyl radical levels significantly more than the radical scavenger PBN (5 mM). To investigate the in vivo effects of nicotine, male C57BL/6 mice were used in the MPTP mouse model of PD. Nicotine (0.1 or 0.4 mg/kg s.c.) was administered twice daily for a period of 14 days. On day 8 a single injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg s.c.) was given as well as an enhanced protocol of nicotine treatment (0.1 or 0.4 mg/kg s.c., 30 min before MPTP and 30, 90, 210, 330, 450, 570 min after MPTP) for a total of seven injections of nicotine. High dosage nicotine treatment significantly increased the MPTP-induced loss of body weight and resulted in a significantly decreased striatal dopamine content and an increased dopamine turnover in comparison with the MPTP-treated controls at day 15. However, the lower dosage of nicotine did not significantly alleviate the MPTP-induced effects, although some parameters showed a slight tendency in this direction. These results demonstrate that in vitro nicotine has radical scavenging properties which might suggest neuroprotective effects. In vivo experiments with nicotine, however, showed that a low dosage of nicotine did not alleviate the MPTP-induced dopamine depletion, but a large dosage even enhanced it.

AB - Parkinson's disease (PD) is one of the most frequent disorders of the basal ganglia. From epidemiological studies there is a controversial discussion on the question whether tobacco smoking is correlated with a decreased incidence of PD. The present study aimed to elucidate the role of nicotine and its potential neuroprotective effects in a rodent model of PD. These effects may be related to an altered hydroxyl radical formation; this possibility was studied in vitro. Nicotine and alpha-phenyl-N-tert-butyl nitrone (PBN) were examined in a cell-free in vitro Fenton system (Fe3+/EDTA + H2O2) for their radical scavenging properties using the salicylate trapping method. Salicylic acid (0.5 mM) was incubated in the presence and absence of nicotine or PBN and the main products of the reaction of hydroxyl radicals with salicylic acid, namely 2,3- and 2,5-dihydroxybenzoic acid, were immediately determined using HPLC in combination with electrochemical detection. Nicotine and PBN were both able to significantly reduce hydroxyl radical levels at concentrations of 1, 2.5 and 5 mM. Interestingly, at 5 mM nicotine was able to reduce hydroxyl radical levels significantly more than the radical scavenger PBN (5 mM). To investigate the in vivo effects of nicotine, male C57BL/6 mice were used in the MPTP mouse model of PD. Nicotine (0.1 or 0.4 mg/kg s.c.) was administered twice daily for a period of 14 days. On day 8 a single injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg s.c.) was given as well as an enhanced protocol of nicotine treatment (0.1 or 0.4 mg/kg s.c., 30 min before MPTP and 30, 90, 210, 330, 450, 570 min after MPTP) for a total of seven injections of nicotine. High dosage nicotine treatment significantly increased the MPTP-induced loss of body weight and resulted in a significantly decreased striatal dopamine content and an increased dopamine turnover in comparison with the MPTP-treated controls at day 15. However, the lower dosage of nicotine did not significantly alleviate the MPTP-induced effects, although some parameters showed a slight tendency in this direction. These results demonstrate that in vitro nicotine has radical scavenging properties which might suggest neuroprotective effects. In vivo experiments with nicotine, however, showed that a low dosage of nicotine did not alleviate the MPTP-induced dopamine depletion, but a large dosage even enhanced it.

KW - 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

KW - Animals

KW - Body Weight

KW - Cardiotonic Agents

KW - Cyclic N-Oxides

KW - Dopamine

KW - Dopamine Agents

KW - Drug Interactions

KW - Free Radical Scavengers

KW - Hydroxyl Radical

KW - Locomotion

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Nicotine

KW - Nicotinic Agonists

KW - Nitrogen Oxides

KW - Parkinson Disease, Secondary

KW - Nicotine

KW - Hydroxyl radicals

KW - PBN

KW - MPTP

KW - Neuroprotection

KW - Parkinson’s disease

U2 - 10.1007/PL00005264

DO - 10.1007/PL00005264

M3 - Article

VL - 358

SP - 351

EP - 359

JO - Naunyn-Schmiedeberg's Archives of Pharmacology

JF - Naunyn-Schmiedeberg's Archives of Pharmacology

SN - 0028-1298

IS - 3

ER -