Neurotoxicity of MPP+ (???)

[LuxEtVeritas]

I know this is an IC50, but is this not indicating a very weak effect and a potentially high amount required to create a neurotoxic effect...not an expert here so perhaps someone with greater insight can explain, but this number seem to indicate such

Inhibition of Complex I:
1-methyl-4-phenylpyridinium ion (MPP[+]) (IC[50] = 4.1 mM),

 

[hussness]

Can you post a ref/link or the actual journal article?

 

[LuxEtVeritas]

Inhibition of complex I by isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
Auteur(s) / Author(s)
MCNAUGHT K. S. P. (1) ; THULL U. ; CARRUPT P.-A. ; ALTOMARE C. ; CELLAMARE S. ; CAROTTI A. ; TESTA B. ; JENNER P. (1) ; MARSDEN C. D. ;
Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)
(1) King's coll., neurodegenerative diseases res. cent., pharmacology group, London SW3 6LX, ROYAUME-UNI
Résumé / Abstract
Mitochondrial respiratory failure secondary to complex I inhibition may contribute to the neurodegenerative process underlying nigral cell death in Parkinson's disease (PD). Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+) may be inhibitors of complex I, and have been implicated in the cause of PD as endogenous neurotoxins. To determine the potency and structural requirements of isoquinoline derivatives to inhibit mitochondrial function, we examined the effects of 22 neutral and quaternary compounds from three classes of isoquinoline derivatives (11 isoquinolines, 2 dihydroisoquinolines, and 9 1,2,3,4-tetrahydroisoquinolines) and MPP[+] on the enzymes of the respiratory chain in mitochondrial fragments from rat forebrain. With the exception of norsalsolinol and N,n-propylisoquinolinium, all compounds inhibited complex I in a time-independent, but concentration-dependent manner, with IC[50]s ranging from 0.36-22 mM. Several isoquinoline derivatives were more potent inhibitors of complex I than 1-methyl-4-phenylpyridinium ion (MPP[+]) (IC[50] = 4.1 mM), the most active being N-methyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline (IC[50] = 0.36 mM) and 6-methoxy-1,2,3,4-tetrahydroisoquinoline (IC[50] = 0.38 mM). 1,2,3,4-Tetrahydroisoquinoline was the least potent complex I inhibitor (IC[50] 22 mM). At 10 mM, only isoquinoline (23.1%), 6,7-dimethoxyisoquinoline (89.6%), and N-methylsalsolinol (34.8%) inhibited (P < 0.05) complex II-III, but none of the isoquinoline derivatives inhibited complex IV. There were no clear structure-activity relationships among the three classes of isoquinoline derivatives studied, but lipophilicity appears to be important for complex I inhibition. The effects of isoquinoline derivatives on mitochondrial function are similar to those of MPTP/MPP[+], so respiratory inhibition may underlie their reported neurotoxicity.
Revue / Journal Title
Biochemical pharmacology (Biochem. pharmacol.) ISSN 0006-2952 CODEN BCPCA6
Source / Source
1995, vol. 50, no11, pp. 1903-1911 (55 ref

 

[LuxEtVeritas]

Also on the topic of prevention of any potential neurotoxicity via use of adjunct neuroprotective agents...Food for thought:

Protective effect of 1-methyl-1,2,3,4-tetrahydroisoquinoline against dopaminergic neurodegeneration in the extrapyramidal structures produced by intracerebral injection of rotenone

--------------------------------------------------------------------------------
Lucyna Antkiewicz-Michaluk a1c1, Jadwiga Wardas a2, Jerzy Michaluk a1, Irena Romanska a1, Andrzej Bojarski a3 and Jerzy Vetulani a1

a1 Department of Biochemistry, Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, Poland
a2 Department of Neuropsychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, Poland
a3 Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, Poland


The aim of this paper was to investigate whether rotenone, a pesticide causing experimental parkinsonism, causes direct damage to dopaminergic structure when injected intracerebrally and whether this action may be prevented by peripheral administration of 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), an endogenous compound with anti-dopaminergic activity. Male Wistar rats were injected unilaterally into the median forebrain bundle with 2 [mu]g rotenone, and received 1MeTIQ, 50 mg/kg i.p. 1 h before and then daily for 21 d. To compare the effect of intracerebral and peripheral treatment, rotenone was also given once or for 7 d in a dose of 10 mg/kg s.c. Dopamine, serotonin and their metabolites were assessed by HPLC in the substantia nigra and striatum. While a single subcutaneous rotenone dose did not produce any change in striatal dopamine metabolism, the multiple treatments resulted in changes suggesting a shift in the metabolism towards oxidative desamination and reduction of O-methylation. In contrast to systemic injections, intracerebral-administered rotenone produced a decrease in dopamine and its metabolites content in the striatum (dopamine decrease by 70%) and substantia nigra (dopamine decrease by 35%), without affecting the serotonin system. As those changes were observed 21 d after the injection of rotenone, they suggest a durable neurotoxic effect. The treatment with 1MeTIQ strongly reduced the fall of striatal dopamine concentration. The data suggest that rotenone given peripherally affects metabolic processes in dopaminergic neurons, and this seems to result from its neurotoxic action, which may be observed after an intracerebral injection. 1MeTIQ is able to counteract the damaging action of rotenone and seems to be a potential neuroprotective agent.

J Neurosci. 1996 Jun 15;16 (12):3807-16 8656275
[3H]dihydrorotenone binding to NADH: ubiquinone reductase (complex I) of the electron transport chain: an autoradiographic study.
[My paper] D S Higgins Jr , J T Greenamyre
Abnormalities of mitochondrial energy metabolism may play a role in normal aging and certain neurodegenerative disorders. In this regard, complex I of the electron transport chain has received substantial attention, especially in Parkinson's disease. The conventional method for studying complex I has been quantitation of enzyme activity in homogenized tissue samples. To enhance the anatomic precision with which complex I can be examined, we developed an autoradiographic assay for the rotenone site of this enzyme. [3H]dihydrorotenone ([3H]DHR) binding is saturable (KD = 15-55 nM) and specific, and Hill slopes of 1 suggest a single population of binding sites. Nicotinamide adenine dinucleotide (NADH) enhances binding 4- to 80-fold in different brain regions (EC50 = 20-40 microM) by increasing the density of recognition sites (Bmax). Nicotinamide adenine dinucleotide phosphate also increases binding, but NAD+ does not. In skeletal muscle, heart, and kidney, binding was less affected by NADH. [3H]DHR binding is inhibited by rotenone (IC50 = 8-20 nM), meperidine (IC50 = 34-57 microM), amobarbitol (IC50 = 375-425 microM), and MPP+ (IC50 = 4-5 mM), consistent with the potencies of these compounds in inhibiting complex I activity. Binding is heterogeneously distributed in brain with the density in gray matter structures varying more than 10-fold. Lesion studies suggest that a substantial portion of binding is associated with nerve terminals. [3H]DHR autoradiography is the first quantitative method to examine complex I with a high degree of anatomic precision. This technique may help to clarify the potential role of complex I dysfunction in normal aging and disease.
http://www.jneurosci.org/cgi/reprint/16/12/3807?ck=nck

1-Methyl-1,2,3,4-tetrahydroisoquinoline protects against rotenone-induced mortality and biochemical changes in rat brain
Authors: Antkiewicz-Michaluk L.1; Karolewicz B.; Romanska I.; Michaluk J.; Bojarski A.J.; Vetulani J.

Source: European Journal of Pharmacology, Volume 466, Number 3, 18 April 2003 , pp. 263-269(7)


Neurochem Int. 2006 Feb 18; : 16490285
l-deprenyl protects against rotenone-induced, oxidative stress-mediated dopaminergic neurodegeneration in rats.
[My paper] Karuppagounder S Saravanan , Kizhakke M Sindhu , Karuppagounder S Senthilkumar , Kochupurackal P Mohanakumar


Pol J Pharmacol Pharm. ;31 (4):297-307 523338
Inhibition by deprenyl of dopamine uptake in rat striatum: a possible correlation between dopamine uptake and acetylcholine release inhibition.
[My paper] L G Harsing , K Magyar , K Tekes , E S Vizi , J Knoll
Optical isomers of deprenyl inhibit the resting and ouabain induced release of acetylcholine (ACh) in isolated striatal slices of the rat and this effect correlates with the capability of deprenyl to inhibit the uptake of 3H-dopamine in striatal homogenate in a concentration of 10(-4)--10(-4) M. The release of ACh is significantly increased in striatal slices taken from rats pretreated with a single dose of 250 micrograms of 6-hydroxydopamine. 5 mg/kg of deprenyl given 30 min prior to 6-hydroxydopamine treatment prevented completely the chemical destruction of the dopaminergic neurons. In contrast to deprenyl, clorgyline potentiated the effect of 6-hydroxydopamine

 

[EN21]

recent investigations indicate that compounds that protect against the neurotocic effects of MPP+ or related things, like 2,9-Me2-ß-carbolinium, act via the GDNF.
But I would guess that all those neurotoxic quats do not cross BBB.
What seems to be sure is, hat they are transported by the DAT into the cell. So there's no surprise that inhibitors of DAT can prevent their toxicity.

 

[LuxEtVeritas]

DAT-I likely are helopful for that reason'

Nerve factors likely elicit repair post-trauma i would suspect, but are not blocking agents

again what it appears blocks this form of NT is agents that directly block the effects of Complex I inhibitors such as MPP+, rotenone, et al.

simply as well powderful anti-oxidants seem to have a protective effect of value

 

[5-HT2]

^^^In research settings where MPTP is used, they keep deprenyl (MAO-B inhibitor) around as a protective agent in case somebody accidentally ingests MPTP. The reason is that MPTP must be cleaved to MPP+ within astrocytes before it can be transported via DAT.

 

[LuxEtVeritas]

correct as MPP+ is the active Complex I inhibitor

this is the same for any THIQ as they also must be cleaved to form the active ion that inhibits Complex I

still that IC50 number also seems odd again being so high...anyone?

DEP and other agents though i believe also protect in other ways, perhaops antagonizing CI inhibition itself

also some points of interest:

It has been reported recently that the immunosuppressant FK506 produced neurotrophic and neuroprotective effects on dopaminergic neurons in vitro and in vivo. We investigated whether tripchlorolide, an immunosuppressive extract of Chinese herb Tripterygium wilfordii Hook F, could exert similar neurotrophic and neuroprotective effects similar to those of FK506. It was found that tripchlorolide promoted axonal elongation and protected dopaminergic neurons from a neurotoxic lesion induced by 1-methyl-4-phenylpyridinium ion (MPP+) at concentrations of as low as 10-12 to 10-8 M.

The herbal remedy, ginseng, has recently been demonstrated to possess neurotrophic and neuroprotective properties, which may be useful in preventing various forms of neuronal cell loss including the nigrostriatal degeneration seen in Parkinson's disease (PD). In these studies, we examine the potential neuroprotective actions of the ginseng extract, G115, in two rodent models of PD. Animals received oral administration of G115 prior to and/or following exposure to the parkinsonism-inducing neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), in mice, or its toxic metabolite, 1-methyl-4-phenylpyridinium (MPP(+)), in rats. Such treatment significantly and dramatically blocked tyrosine hydroxylase-positive cell loss in the substantia nigra and reduced the appearance of locomotor dysfunction. Thus, oral administration of ginseng appears to provide protection against neurotoxicity in rodent models of PD. Further examination of the neuroprotective actions of ginseng and its various elements may provide a potential means of slowing the progress of PD