gehayw at hotmail.com
Sun May 25 23:14:32 EST 2003
Where neurons are not killed outright, to what extent is neuronal
damage caused by amphetamines reversible?
"John H." <johnh at faraway.xxx> wrote in message news:<3ed0aa49 at dnews.tpgi.com.au>...
> 03/02/02 20:05
> Neuroreport 1999 Oct 19;10(15):3155-8Related Articles, Influence of NOS
> inhibitors on changes in ACH release and NO level in the brain elicited by
> amphetamine neurotoxicity.
> Bashkatova V, Kraus M, Prast H, Vanin A, Rayevsky K, Philippu A.
> Institute of Pharmacology, Russian Academy of Medical Sciences, Moscow.
> We studied the possible role of neurotoxicity in the d,l-amphetamine
> (AMPH)-induced release of acetylcholine (ACH) in the nucleus accumbens (Nac)
> and the involvement of endogenous NO in this process. For determination of
> ACH release the Nac was superfused using the push-pull-technique. NO was
> directly measured using the electron paramagnetic resonance technique.
> Repeated administration of AMPH increased ACH release by about 400%.
> N-nitro-L-arginine (L-NNA) and 7-nitroindazole (7-NI) nearly abolished the
> AMPH-induced increase in ACH release. AMPH increased NO as well as lipid
> peroxidation (LPO) products in the cortex. L-NNA and 7-NI substantially
> diminished NO increase. AMPH-evoked LPO was only slightly reduced by these
> compounds. It is concluded that AMPH enhances ACH release through increased
> NO synthesis and induces neurotoxicity via NO and by LPO independent NO
> PMID: 10574552 [PubMed - indexed for MEDLINE]
> Article: Molecular Mechanism of the Inactivation of Tryptophan Hydroxylase
> by Nitric Oxide: Attack on Critical Sulfhydryls that Spare the Enzyme Iron
> Authors: Donald M. Kuhn 1,2 and Robert Arthur Jr 1
> Journal: The Journal of Neuroscience, October 1, 1997, 17(19):7245-7251
> NOS inhibits serotonin via tryto hyrodrox
> Date obtained: 31/01/00
> Web Page:
> Date Read: 27/02/00
> Date to Review: 15/10/00
> Key words: tryptophan hydroxylase; nitric oxide; sulfhydryls;
> catalytic iron site; serotonin; neurotoxic amphetamines, nos, flf, ros,
> ecstasy, mdma, 5ht neurons, depression,
> Tryptophan hydroxylase (TPH), the initial and rate-limiting en-zyme in the
> biosynthesis of the neurotransmitter serotonin (5- HT), is irreversibly
> inactivated by nitric oxide (NO). We have expressed brain TPH as a
> recombinant glutathione-S-transferase fusion protein and delineated the
> catalytic domain of the enzyme as the region spanning amino acids 99-444.
> Highly purified TPH catalytic core, like the native enzyme from brain, is
> inactivated by NO in a concentration-dependent man-ner. Removal of iron from
> TPH produces an apoenzyme with low activity that can be reconverted to its
> highly active holo-form by the addition of ferrous iron. Apo-TPH exposed to
> NO cannot be reactivated by iron. Treatment of holo-TPH (iron-loaded) with
> the disulfide 5,59-dithio-bis (2-nitrobenzoic acid) (DTNB) causes an
> inactivation of TPH that is readily reversed by dithiothreitol (DTT).
> DTNB-treated TPH [sulfhydryl (SH)-protected] exposed to NO is returned to
> full activity by thiol reduction with DTT. The inactivation of native TPH by
> NO cannot be reversed by either iron or DTT. These data indicate that NO
> inactivates TPH by selective action on critical SH groups (i.e., cysteine
> residues) while sparing catalytic iron sites within the enzyme. The results
> are interpreted with reference to the substituted amphetamines, which are
> neurotoxic to 5-HT neurons, that inactivate TPH in vivo and are now known to
> produce NO and other reactive oxygen species in vivo.
> Selected amphetamines have profound effects on the 5-HT neuronal system.
> Methylenedioxymethamphetamine (ecstasy) (MDMA) and p-chloroamphetamine cause
> extensive destruction of 5-HT neurons. An early manifestation of their
> effects is a significant inactivation of TPH (for reviews, see Gibb et al.,
> 1993; Steele et al., 1994; Seiden and Sabol, 1996). The mechanisms
> underlying these effects on TPH are not known, but emerging data implicate
> drug-induced production of reactive oxygen species (ROS) and nitric oxide
> (NO). The cellular effects of ROS or NO cannot be predicted a priori: NO can
> be toxic to some cells (Lipton et al., 1993; Dawson et al., 1994), it is a
> neurotransmitter- neuromodulator in other cells (Jaffrey and Snyder, 1996),
> and it can protect still other cells from known toxins (Wink et al., 1995,
> 1996). The recent demonstration that TPH is inactivated by NO in vitro (Kuhn
> and Arthur, 1996, 1997) establishes the possibility that this important
> brain enzyme is susceptible to inactivation by NO in vivo and could form the
> basis for loss of TPH activity when NO levels are elevated in brain (e.g.,
> By altering independently the iron or SH status of TPH, we demon-strate
> that NO inactivates TPH by selective attack on critical SH groups, sparing
> catalytic iron sites altogether.
> These experiments establish the importance of iron in TPH f unc-tion and
> demonstrate that TPH can be reversibly converted be-tween the apo- and
> The present results lead to several interesting conclusions about TPH.
> First, they reaffirm the importance of iron and SH groups (free cysteines)
> in TPH catalytic f unction. Second, they establish the feasibility and value
> of using highly purified, recom-binant TPH to probe the molecular mechanisms
> regulating this enzyme. Finally, they point to SH groups as targets for
> NO-induced inactivation of the enzyme.
> A distinction must be drawn between amphetamine-induced inactivation of TPH
> and 5-HT neurotoxicity. Although drugs such as MDMA cause both pro-cesses to
> occur, we are not implying that TPH inactivation itself is the direct cause
> of 5-HT depletion. These two processes may be linked to the same causal
> event (e.g., NO or ROS), or they could be independent. In either case, the
> similarities between NO-inactivated TPH (Kuhn and Arthur, 1996, 1997;
> present results) and MDMA-inactivated TPH (Stone et al., 1989a,b) are
> compel-ling. Furthermore, the potential role of NO in mediating apopto-sis
> (Brune et al., 1996; Jacobson, 1996; Simonian and Coyle, 1996) and the
> recent claim that MDMA induces apoptosis in a human serotonergic cell line
> (Simantov and Tauber, 1997) draws another interesting parallel between NO
> and amphetamine-induced alter-ations in 5-HT neurons. We are presently
> developing probes for NO-modified TPH in an attempt to identif y
> amphetamine-modified TPH in vivo.
> [[31/03/01 11:56
> Ann Neurol 2001 Jan;49(1):79-89 Related Articles, Books
> Role of mitochondrial dysfunction and dopamine-dependent oxidative stress in
> amphetamine-induced toxicity.
> Lotharius J, O'Malley KL
> Department of Anatomy and Neurobiology, Washington University School of
> Medicine, St Louis, MO, USA.
> To define the molecular mechanisms underlying amphetamine (AMPH)
> neurotoxicity, primary cultures of dopaminergic neurons were examined for
> drug-induced changes in dopamine (DA) distribution, oxidative stress,
> protein damage, and cell death. As in earlier studies, AMPH rapidly
> redistributed vesicular DA to the cytoplasm, where it underwent outward
> transport through the DA transporter. DA was concurrently oxidized to
> produce a threefold increase in free radicals, as measured by the
> redox-sensitive dye dihydroethidium. Intracellular DA depletion using the DA
> synthesis inhibitor alpha-methyl-p-tyrosine or the vesicular monoamine
> transport blocker reserpine prevented drug-induced free radical formation.
> Despite these AMPH-induced changes, neither protein oxidation nor cell death
> was observed until 1 and 4 days, respectively. AMPH also induced an early
> burst of free radicals in a CNS-derived dopaminergic cell line. However,
> AMPH-mediated attenuation of ATP production and mitochondrial function was
> not observed in these cells until 48 to 72 hours. Thus, neither metabolic
> dysfunction nor loss of viability was a direct consequence of AMPH
> neurotoxicity. In contrast, when primary cultures of dopaminergic neurons
> were exposed to AMPH in the presence of subtoxic doses of the mitochondrial
> complex I inhibitor rotenone, cell death was dramatically increased,
> mimicking the effects of a known parkinsonism-inducing toxin. Thus,
> metabolic stress may predispose dopaminergic neurons to injury by free
> radical-promoting insults such as AMPH.
> PMID: 11198300
> [[1/04/01 15:37
> : Brain Res 1998 Dec 14;814(1-2):120-6 Related Articles, Books
> Microgliosis and down-regulation of adenosine transporter induced by
> methamphetamine in rats.
> Escubedo E, Guitart L, Sureda FX, Jimenez A, Pubill D, Pallas M, Camins A,
> Camarasa J
> Unitat de Farmacologia i Farmacognosia, Facultat de Farmacia, Nucli
> Universitari de Pedralbes, 08028, Barcelona, Spain. escubedo at far.ub.es
> [Record supplied by publisher]
> Chronic administration of methamphetamine to rats induces neurotoxicity
> characterized by a loss of striatal dopaminergic terminals and reactive
> gliosis. Subcutaneous administration of methamphetamine in a scheduled
> procedure of four doses (10 mg/kg) at 2 h interval also induces a
> significant increase in the peripheral-type benzodiazepine receptor (PBR)
> density. This increase is maximum (76%) at 72 h post-treatment in the
> striatum and disappears at 7 days, suggesting that microglia may have a
> predominant role in necrosis-phagocytosis of neuronal debris rather than
> acting in a restorative manner. Microgliosis is not restricted to the
> striatum since it is also evident in cerebellum (75.4% of PBR increase) and
> hippocampus (37.2% of PBR increase). In the areas with high density of
> adenosine transporter, the microgliosis phenomenon correlates well with a
> decrease of this nucleoside transporter (about 39%). Although the
> microgliosis and the decrease in adenosine transporter could be parallel and
> not related events, we can speculate that when microglia are activated, a
> down-regulation of adenosine transporter occurs, playing a role in tissue
> homeostasis. With the same dosing schedule, methamphetamine induces HSP72
> expression in both cytoplasmic and nuclear fractions of the striatum,
> cerebellum and hippocampus. This expression is also evident in the cerebral
> cortex, where adenosine transporter population did not show any variation.
> Copyright 1998 Elsevier Science B.V.
> PMID: 9838075
> "anon" <anon at no.com> wrote in message news:BAF5FF86.5F0%anon at no.com...
> > Can you site any studies showing neurotoxicity from amphetamines?
> > > Interesting...
> > >
> > > I does anyone know the mechanism of amphetamine neurotoxicity? Is it the
> > > same as the hypothesised MDMA-esque MAO-B degrading DA, releasing ROS?
More information about the Neur-sci