Preventative effects of 1,3-dimethyl- and 1,3-dimethyl-N-propargyl-1,2,3,4-tetrahydroisoquinoline on MPTP-induced Parkinson's disease-like symptoms in mice.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is well known as an exogenous dopaminergic neurotoxin that induces Parkinson's disease-like symptoms. In addition, 1,2,3,4-tetrahydroisoquinoline (TIQ) derivatives have been investigated as endogenous MPTP mimetic compounds that structurally resemble selegiline, a commercially available drug for treating Parkinson's disease. In the present study, we examined the ability of 1,3-dimethyl-TIQ (1,3-diMeTIQ) and 1,3-dimethyl-N-propargyl-TIQ (1,3-diMe-N-proTIQ) to prevent MPTP-induced Parkinson's disease-like symptoms in mice and to prevent 1-methyl-4-phenylpyridinium ion (MPP+, an active metabolite of MPTP)-induced cytotoxicity in vitro, including its structural stereoselectivity. Repeated administration of MPTP induced bradykinesia, a symptom of behavioral abnormality; this was prevented by both 1,3-diMeTIQ and 1,3-diMe-N-proTIQ pretreatments. Pretreatment with 1,3-diMeTIQ did not prevent the MPTP-induced decrease in dopamine content in the striatum or the decrease in the number of tyrosine hydroxylase-positive cells in the substantia nigra. On the other hand, 1,3-diMe-N-proTIQ prevented these Parkinson's disease-like symptoms; in particular, the trans-isomer of this agent showed potent protective effects. However, the ability of the trans-1,3-diMe-N-proTIQ isomer to prevent MPP+-induced PC12 cell death was weaker than that of its cis-isomer. Thus, stereoisomers of 1,3-diMe-N-proTIQ exhibit different effects; cis-1,3-diMe-N-proTIQ inhibits MPP+-induced cytotoxicity while trans-1,3-diMe-N-proTIQ exhibits neuroprotective effects primarily through MPTP-related biological events in mice. These results also indicate the possibility of utilizing, at least in part, the stereoselective efficacy of 1,3-diMe-N-proTIQ against MPTP and/or MPP+-induced adverse states.
Katagiri
Nobuyuki
N
Department of Pharmacotherapeutics, Showa Pharmaceutical University, 3-3165 Higashitamagawagakuen, Machida, Tokyo 194-0042, Japan.
Chida
Satomi
S
Abe
Kenji
K
Nojima
Hiroshi
H
Kitabatake
Michikazu
M
Hoshi
Keiko
K
Horiguchi
Yoshie
Y
Taguchi
Kyoji
K
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018476:Hypokinesia / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D007150:Immunohistochemistry; D051379:Mice; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D020734:Parkinsonian Disorders / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013237:Stereoisomerism; D044005:Tetrahydroisoquinolines / Q000737:chemistry / Q000494:pharmacology*
D018696:Neuroprotective Agents; D044005:Tetrahydroisoquinolines; C014843:1,2,3,4-tetrahydroisoquinoline