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|The effects of methamphetamine (METH) on ...|
The effects of methamphetamine (METH) on pro-oxidant processes and on the production of reactive oxygen species were examined in vivo in the rat brain. The presence of oxidative damage in striatum, as revealed by the oxidation of lipid, also was assessed via the measurement of the lipid peroxidation product malonyldialdehyde. To elucidate further the mechanisms mediating METH-induced oxidative stress, we studied the possible reversal of the long-term METH-induced decrease in striatal dopamine content by antioxidants through iron chelation and trapping of free radicals. The uric acid concentration in the striata of rats killed 1 hr, but not 24 hr, after a four-injection regimen of METH was increased significantly compared with saline-injected control rats. METH increased the in vivo formation of the hydroxylated products of salicylate and d-phenylalanine, as evidenced by the elevated extracellular concentrations of 2,3 dihydroxybenzoic acid and p-tyrosine, respectively. The local perfusion of the striatum with the iron chelator deferroxamine attenuated the long-term depletions of striatal dopamine content produced by METH. In other experiments, malonyldialdehyde concentrations in incubated striatal homogenates were elevated significantly in METH-treated rats. Finally, pretreatment with the spin trapping agent phenylbutylnitrone before the METH injections attenuated the subsequent long-term depletions in striatal dopamine content. Overall, the results illustrate that METH increases pro-oxidant processes and offer supportive evidence that METH produces oxidative damage. These studies also demonstrate that iron may be involved in mediating the long-term damage to dopamine neurons after repeated administrations of METH.
Materials & Methods
High doses of METH produce losses in several markers of brain dopamine and serotonin neurons. Striatal dopamine and 5HT concentrations, dopamine and 5HT uptake sites, and tyrosine and tryptophan hydroxylase activities are reduced after the administration of METH (for review, see Seiden and Ricaurte, 1987). The exact mechanism(s) mediating these changes, however, is (are) unknown. The decreases in dopamine parameters appear to be mediated by the excessive acute increases in dopamine release produced by METH. Inhibition of dopamine synthesis before METH attenuates the decrease in tryptophan hydroxylase activity (Gibb and Kogan, 1979), and this attenuation is reversed by l-dopa administration (Schmidt et al., 1985). In addition, inhibition of dopamine release with dopamine uptake blockers attenuates METH-induced striatal dopamine depletions (Schmidt et al., 1985; Stephans and Yamamoto, 1994). Thus it appears that the magnitude of dopamine release is related to the long-term toxic effects of METH on dopamine neurons.
Glutamate also plays a role in METH-induced neurotoxicity to dopamine neurons. Glutamate antagonists block the METH-induced decreases in dopamine content and tyrosine hydroxylase activity (Sonsalla et al., 1989; 1991). METH also increases the extracellular concentrations of glutamate (Abekawa et al., 1994; Nash and Yamamoto, 1992; Stephans and Yamamoto, 1994; 1996). The increase in glutamate is blocked by dopamine antagonists, which also block the decreases in tyrosine hydroxylase activity and dopamine content produced by METH (Sonsalla et al., 1989; Stephans and Yamamoto, 1994).
A common underlying mechanism involving both dopamine and glutamate that may mediate the damage to dopamine neurons is through the production of ROS and oxidative stress. Dopamine itself can produce neurotoxicity (Filloux and Townsend, 1993) and generate hydroxyl radicals (Michel and Hefti, 1990; Rosenberg, 1988; Tanaka et al., 1991). The enzymatic degradation or auto-oxidation of dopamine results in the formation of hydrogen peroxide and superoxide radical. Hydrogen peroxide is susceptible to iron-catalyzed formation of hydroxyl free radicals via the Fenton reaction (Olanow, 1992; Kopin, 1992). Similarly, increases in glutamatergic transmission also can produce ROS (Bondy and Lee, 1993; Dugan et al., 1995; Lafon-Cazal et al., 1993) through the release of arachidonic acid (Dumuis et al., 1988) or through the activation of nitric oxide synthase and the generation of nitric oxide (Dawson et al., 1992). Nitric oxide can react with superoxide to form peroxynitrate ion (Huie and Padmaja, 1993), with the eventual formation of hydroxyl radical.
The possibility that oxidative stress and ROS mediate METH-induced damage to dopamine neurons is supported by several findings. METH increases intracellular oxidation in vitro, as indicated by dichlorohydrofluorescein fluorescence in cultures of ventral midbrain dopamine neurons. Consistent with this finding is that Giovanni et al. (1995) have reported that the oxidation products of intraventricularly administered salicylate, which are indicative of ROS formation, were increased in vivo after METH. Conversely, antioxidants and free radical spin trapping agents acting as free radical scavengers attenuate the decrease in striatal dopamine content (Wagner et al., 1980; DeVito and Wagner, 1989; Wagner et al., 1985; Cappon et al., 1996). In addition, decreases in dopamine transporter function and tryptophan hydroxylase activity induced by METH appear to be mediated by ROS and oxidative stress (Stone et al., 1989a, 1989b; Fleckenstein et al., 1997a, b, c, d). Furthermore, the decreases in dopamine content and uptake sites produced by METH are attenuated in mice that overexpress the gene coding for the antioxidant defense enzyme copper-zinc superoxide dismutase (Cadet et al., 1994; Hirata et al., 1996).
In the present study, we used several approaches to examine whether METH increases pro-oxidant processes and the production of ROS in vivo in the striatum. To assess the presence of oxidative damage produced by METH, we evaluated the oxidation of lipid by measuring the lipid peroxidation product malonyldialdehyde. To elucidate further the mechanisms that mediate METH-induced oxidative stress, we studied the possible reversal of the long-term METH-induced decrease in striatal dopamine content by antioxidants with iron chelation and trapping of free radicals.
Neurodegenerative diseases: Iron is required for normal brain and nerve function through its involvement in cellular metabolism, as well as the synthesis of neurotransmitters and myelin. However, accumulation of excess iron can result in increased oxidative stress, and the brain is particularly susceptible to oxidative damage. Iron accumulation and oxidative injury are presently under consideration as potential contributors to a number of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease (36). The abnormal accumulation of iron in the brain does not appear to be a result of increased dietary iron, but rather, a disruption in the complex process of cellular iron regulation. Although the mechanisms for this disruption in iron regulation are not yet known, it is presently an active area of biomedical research (37).
In this Journal they say that methamphetmine may lead to long term damage on the dopamine nuerons due a possible iron uptake. Is this because if used for over a period of time it is basically causing an overload of iron in the brain. What other parts of the body what play a part with this possibly. Would iron chelation therapy possibly circumvent some of the possible effects on dopamine nuerons?
I took the one less traveled by,And that has made all the difference.
|antioxidants are good against oxidative stress|
It is even simpler - eat a healthy dose of antioxidants every day, and you may counteract all the oxidative stress created by the methamphetamine intake, regardless of this iron theory being correct or not.
The Hive - Clandestine Chemists Without Borders
|Ok, apparantly the hive doesn't have much free|
Ok, apparantly the hive doesn't have much free diskspace, so I'm not posting these full. But here are some articles that relate to the topic.
Adaptative response of antioxidant enzymes in different areas of rat brain after repeated d-amphetamine administration.
Authors: Carvalho, Félix
Tavares, Maria Amélia
Bastos, Maria De Lourdes1
Addiction Biology Jul2001, Vol. 6 Issue 3, p213, 9p
d-Amphetamine has been shown to be a potential brain neurotoxic agent, particularly to dopaminergic neurones. Reactive oxygen species indirectly generated by this drug have been indicated as an important factor in the appearance of neuronal damage but little is known about the adaptations of brain antioxidant systems to its chronic administration. In this study, the activities of several antioxidant enzymes in different areas of rat brain were measured after repeated administration of d-amphetamine sulphate (sc, 20 mg/kg/day, for 14 days), namely glutathione-S-transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GRed), catalase, and superoxide dismutase (SOD). When compared to a pair-fed control group, d-amphetamine treatment enhanced the activity of GST in hypothalamus to 167%, GPx in striatum to 127%, in nucleus accumbens to 192%, and in medial prefrontal cortex to 139%, GRed in hypothalamus to 139%, as well as catalase in medial prefrontal cortex to 153%. However, the same comparison revealed a decrease in the activity of GRed in medial pre-frontal cortex by 35%. Food restriction itself reduced GRed activity by 49% and enhanced catalase activity to 271% in nucleus accumbens. The modifications observed for the measured antioxidant enzymes reveal that oxidative stress probably plays a role in the deleterious effects of this drug in CNS and that, in general, the brain areas studied underwent adaptations which provided protection against the continuous administration of the drug.
Carnosine prevents methamphetamine-induced gliosis but not dopamine terminal loss in rats.
Authors: Pubill, David1
Sureda, Francesc X.2
Escubedo, Elena1 email@example.com
European Journal of Pharmacology; Jul2002, Vol. 448 Issue 2/3, p165, 4p
The neuroprotective effect of carnosine, an endogenous antioxidant, was examined against methamphetamine-induced neurotoxicity in rats. Carnosine pretreatment had no effect on dopamine terminal loss induced by methamphetamine (assessed by [<sup loc="pre">3</sup>H]1-(2-[diphenylmethoxy]ethyl)-4-[3-phenylpropyl]piperazine([sup loc="pre">3</sup>H]GBR 12935) binding) but prevented microgliosis (increase in [<sup loc="pre">3</sup>H]1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide ([<sup loc="pre">3</sup>H]PK 11195) binding) in striatum. The 27-kDa heat-shock protein (HSP27) expression was used as indicator of astroglial stress. Methamphetamine treatment induced the expression of HSP27 in striatum and hippocampus, which was inhibited by carnosine, indicating a protective effect. Carnosine had no effect on methamphetamine-induced hyperthermia. Thus, carnosine prevents the microgliosis in striatum (where we did not detect loss of serotonergic terminals by [<sup loc="pre">3</sup>H]paroxetine binding) and the expression of HSP27 in all the areas, but fails to prevent methamphetamine-induced loss of dopamine reuptake sites. Therefore, carnosine inhibits only some of the consequences of methamphetamine neurotoxicity, where reactive oxygen species play an important role.
Manganese-Based complexes of radical scavengers as neuroprotective agents.
Authors: Vajragupta, Opa1 firstname.lastname@example.org
Bioorganic & Medicinal Chemistry May2003, Vol. 11 Issue 10, p2329, 9p
Manganese was incorporated in the structure of the selected antioxidants to mimic the superoxide dismutase (SOD) and to increase radical scavenging ability. Five manganese complexes (1–5) showed potent SOD activity in vitro with IC50 of 1.18–1.84 µM and action against lipid peroxidation in vitro with IC50 of 1.97–8.00 µM greater than their ligands and trolox. The manganese complexes were initially tested in vivo at 50 mg/kg for antagonistic activity on methamphetamine (MAP)-induced hypermotility resulting from dopamine release in the mice brain. Only manganese complexes of kojic acid (1) and 7-hydroxyflavone (3) exhibited the significant suppressions on MAP-induced hypermotility and did not significantly decrease the locomotor activity in normal condition. Manganese complex 3 also showed protective effects against learning and memory impairment in transient cerebral ischemic mice. These results supported the brain delivery and the role of manganese in SOD activity as well as in the modulation of brain neurotransmitters in the aberrant condition. Manganese complex 3 from 7-hydroxyflavone was the promising candidate for radical implicated neurodegenerative diseases
The methamphetamine experience: a NIDA partnership
(Rated as: good read)
The methamphetamine experience: a NIDA partnership.
Glen R. Hanson, Kristi S. Rau, Annette E. Fleckenstein
Neuropharmacology 47 (2004) 92–100
The neurotoxic properties of the amphetamines such as methamphetamine (METH) were originally described about the time of the National Institute on Drug Abuse’s organization, in the early 1970s. It required more than 20 years to conﬁrm these neurotoxic properties in humans. Much like Parkinson’s disease, multiple high-dose administration of METH somewhat selectively damages the nigrostriatal dopamine (DA) projection of the brain. This eﬀect appears to be related to the intracellular accumulation of cytosolic DA and its ability to oxidize into reactive oxygen species. Both the dopamine plasmalemmal transporter and the vesicular monoamine transporter-2 seem to play critical roles in this neurotoxicity. METH and related analogs such as methylenedioxymethamphetamine (MDMA) can also damage selective CNS serotonin neurons. The mechanism of the serotonergic neurotoxicity is not as well characterized, but also appears to be related to the formation of reactive oxygen species and monoamine transporters. Studies examining the pharmacological and neurotoxicological properties of the amphetamines have helped to elucidate some critical features of monoamine regulations as well as helped to improve our understanding of the processes associated with degenerative disorders such as Parkinson’s disease.
Keywords: Methamphetamine; Dopamine transporter; Vesicular monoamine transporter; Neurotoxicity; Methylphenidate
Unipolar Mania, It's good for life...
I remember reading calcium ascorbate can alieviate oxidative stress if ingested in large ammounts pre/during and post MDMA.
Forget where though
|Alpha-lipoic acid is also an antioxidant ...|
Alpha-lipoic acid is also an antioxidant that's known to work well. As far as preventing oxidative damage following drug use, I'm not sure, but I wouldn't be surprised to see it being quite effective.
|Red Wine & Green Tea|
Would a daily dose of either green tea or red wine provide ample enough anti oxidizing?
can't flush this