Biomedical subjects

S F Ali

Publications and source records attributed to S F Ali.

At least 37 records · Page 2Linked to original sources

PubMed2001

Peroxynitrite plays a role in methamphetamine-induced dopaminergic neurotoxicity: evidence from mice lacking neuronal nitric oxide synthase gene or overexpressing copper-zinc superoxide dismutase.

The use of methamphetamine (METH) leads to neurotoxic effects in mammals. These neurotoxic effects appear to be related to the production of free radicals. To assess the role of peroxynitrite in METH-induced dopaminergic, we investigated the production of 3-nitrotyrosine (3-NT) in the mouse striatum. The levels of 3-NT increased in the striatum of wild-type mice treated with multiple doses of METH (4 x 10 mg/kg, 2 h interval) as compared with the controls. However, no significant production of 3-NT was observed either in the striata of neuronal nitric oxide synthase knockout mice (nNOS -/-) or copper-zinc superoxide dismutase overexpressed transgenic mice (SOD-Tg) treated with similar doses of METH. The dopaminergic damage induced by METH treatment was also attenuated in nNOS-/- or SOD-Tg mice. These data further confirm that METH causes its neurotoxic effects via the production of peroxynitrite.

Animals↗

PubMed2001

Aging increases the susceptiblity to methamphetamine-induced dopaminergic neurotoxicity in rats: correlation with peroxynitrite production and hyperthermia.

Methamphetamine (METH) produces dopaminergic neurotoxicity by the production of reactive oxygen (ROS) and nitrogen (RNS) species. The role of free radicals has also been implicated in the process of aging. The present study was designed to evaluate whether METH-induced dopaminergic neurotoxicity and hyperthermia is a result of peroxynitrite production and if these effects correlate with age. One-, six- and 12-month-old male rats (n = 8) were administered a single dose of METH (0, 5, 10, 20, and 40 mg/kg, intraperitoneally). The formation of 3-nitrotyrosine (3-NT) as a marker of peroxynitrite production as well as dopamine and its metabolites DOPAC and HVA were measured in the striatum 4-h after METH-administration. Rectal temperature was monitored every 30 min after METH administration until 4 h. At 40 mg/kg METH, a 100% mortality in 12-month-old animals was observed, whereas no deaths occurred in 1- or 6-month-old rats. An age-dependent increase in hyperthermia was observed after METH-administration. A similar pattern of dose-dependent increase in the formation of 3-NT and in the depletion of dopamine and its metabolites with age was observed in the striatum. Furthermore, no effect was observed at 5 mg/kg METH in 1-month-old animals, whereas the effect was significant in 6- and 12-month-old animals. These data suggest that aging increases the susceptibility of the animals toward METH-induced peroxynitrite generation and striatal dopaminergic neurotoxicity.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2001

Oxidative stress and reactive nitrogen species generation during renal ischemia.

Previous evidence suggests that both oxygen radicals and nitric oxide (NO) are important mediators of injury during renal ischemia-reperfusion (I-R) injury. However, the generation of reactive nitrogen species (RNS) has not been evaluated in this model at early time points. The purpose of these studies was to examine the development of oxidant stress and the formation of RNS during I-R injury. Male Sprague-Dawley rats were anesthetized and subjected to 40 min of bilateral renal ischemia followed by 0, 3, or 6 h of reperfusion. Control animals received a sham operation. Plasma urea nitrogen and creatinine levels were monitored as markers of renal injury. Glutathione (GSH) oxidation and 4-hydroxynonenal (4-HNE)-protein adducts were used as markers of oxidant stress. 3-Nitrotyrosine (3-NT) was used as a biomarker of RNS formation. Significant increases in plasma creatinine concentrations and urea nitrogen levels were found following both 3 and 6 h of reperfusion. Increases in GSH oxidation, 4-HNE-protein adduct levels, and 3-NT levels were observed following 40 min of ischemia with no reperfusion. Since these results suggested RNS generation during the 40 min of ischemia, a time course of RNS generation following 0, 5, 10, 20, and 40 min of ischemia was evaluated. Significant increases in 3-NT generation was detected as early as 10 min of ischemia and rose to values nearly 10-fold higher than Control at 40 min of ischemia. No additional increase was observed following reperfusion. The data clearly demonstrate that oxidative stress and RNS generation occur in the kidney during ischemia.

Aldehydes↗

PubMed2001

Effect of L-carnitine pretreatment on 3-nitropropionic acid-induced inhibition of rat brain succinate dehydrogenase activity.

L-Carnitine (LC) plays an important regulatory role in the mitochondrial transport of long chain free fatty acids (FFA). 3-Nitropropionic acid (3-NPA) is known to induce cellular energy deficit and oxidative stress-related neurotoxicity via an irreversible inhibition of mitochondrial succinate dehydrogenase (SDH). In the present study, activity of SDH was measured in order to evaluate neuroprotective effects of LC against the 3-NPA-induced neurotoxicity. Male, CD Sprague-Dawley rats, three months old, were injected with either 50 or 100 mg/kg of LC, i.p., 30 min prior to 3-NPA (30 mg/kg, s.c.) or with 3-NPA alone. The activity of brain SDH was quantified spectrophotometrically in caudate nucleus (CN), frontal cortex (FC), and hippocampus (HIP) 60 min after the 3-NPA injection. The SDH activity in the animals treated with 3-NPA alone was 38% (CN), 50% (FC), and 36% (HIP) that of saline controls. Pretreatment with LC prior to 3-NPA injection attenuated decreases of SDH activity by approximately 15 and 29% (LC low and high dose, respectively). Despite the attenuation of SDH inhibition, the activity of SDH in these regions remained significantly lower in treated than in control rats (p < 0.05). It appears that the protective effect of LC against 3-NPA-induced oxidative stress cannot be explained by the direct action of LC to interfere with the SDH inhibition but are rather achieved by LC actions downstream of the SDH inhibition.

Animals↗

PubMed2001

Methamphetamine-induced dopaminergic neurotoxicity: role of peroxynitrite and neuroprotective role of antioxidants and peroxynitrite decomposition catalysts.

Oxidative stress, reactive oxygen (ROS), and nitrogen (RNS) species have been known to be involved in a multitude of neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Both ROS and RNS have very short half-lives, thereby making their identification very difficult as a specific cause of neurodegeneration. Recently, we have developed a high performance liquid chromatography/electrochemical detection (HPLC/EC) method to identify 3-nitrotyrosine (3-NT), an in vitro and in vivo biomarker of peroxynitrite production, in cell cultures and brain to evaluate if an agent-driven neurotoxicity is produced by the generation of peroxynitrite. We show that a single or multiple injections of methamphetamine (METH) produced a significant increase in the formation of 3-NT in the striatum. This formation of 3-NT correlated with the striatal dopamine depletion caused by METH administration. We also show that PC12 cells treated with METH has significantly increased formation of 3-NT and dopamine depletion. Furthermore, we report that pretreatment with antioxidants such as selenium and melatonin can completely protect against the formation of 3-NT and depletion of striatal dopamine. We also report that pretreatment with peroxynitrite decomposition catalysts such as 5, 10,15,20-tetrakis(N-methyl-4'-pyridyl)porphyrinato iron III (FeTMPyP) and 5, 10, 15, 20-tetrakis (2,4,6-trimethyl-3,5-sulfonatophenyl) porphinato iron III (FETPPS) significantly protect against METH-induced 3-NT formation and striatal dopamine depletion. We used two different approaches, pharmacological manipulation and transgenic animal models, in order to further investigate the role of peroxynitrite. We show that a selective neuronal nitric oxide synthase (nNOS) inhibitor, 7-nitroindazole (7-NI), significantly protect against the formation of 3-NT as well as striatal dopamine depletion. Similar results were observed with nNOS knockout and copper zinc superoxide dismutase (CuZnSOD)-overexpressed transgenic mice models. Finally, using the protein data bank crystal structure of tyrosine hydroxylase, we postulate the possible nitration of specific tyrosine moiety in the enzyme that can be responsible for dopaminergic neurotoxicity. Together, these data clearly support the hypothesis that the reactive nitrogen species, peroxynitrite, plays a major role in METH-induced dopaminergic neurotoxicity and that selective antioxidants and peroxynitrite decomposition catalysts can protect against METH-induced neurotoxicity. These antioxidants and decomposition catalysts may have therapeutic potential in the treatment of psychostimulant addictions.

Animals↗

PubMed2000

Exposure of mice to tobacco smoke attenuates the toxic effect of methamphetamine on dopamine systems.

Methamphetamine treatment of mice rapidly and severely depleted levels of dopamine and its metabolites, homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) in the caudate nucleus. Exposure of mice to cigarette smoke by means of nose-only breathing apparatus for 20 min twice daily over 3 days prior to drug treatment significantly attenuated the neurotoxicity of methamphetamine as judged by a lesser depletion of dopamine, DOPAC and HVA. The lesser effect of methamphetamine upon content of serotonin level was unaltered by prior inhalation of smoke. Results suggest a specific protective effect of inhaled tobacco smoke upon the effects of methamphetamine upon dopaminergic circuitry.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2000

DNA damage in brain mitochondria caused by aging and MPTP treatment.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment leads to marked depletion of dopamine (DA) levels in the nigrostriatal pathway and dopaminergic neuronal degeneration in caudate-putamen and substantia nigra. MPTP is believed to inhibit complex I of the electron transport system leading to the generation of reactive oxygen species. We sought to test the hypotheses that MPTP treatment: (1) leads to dopamine depletion; (2) causes extensive mitochondrial DNA damage, and (3) that these effects would be age dependent. The levels of dopamine and its metabolites, DOPAC and HVA were analyzed by HPLC equipped with electrochemical detection. DNA damage was measured by quantitative PCR in both mitochondrial and nuclear (beta-polymerase) targets from the caudate-putamen, substantia nigra and cerebellum regions of control and MPTP-treated mice. The age groups studied were 22 days and 12 months. MPTP produced no significant effect on the levels of dopamine and its metabolites in young mice whereas in old, there was a significant decrease in this neurotransmitter system after MPTP administration. These 12-month-old mice, when compared to the young mice, showed a significant increase in mitochondrial DNA damage in the caudate-putamen and cerebellum. The latter region also displayed a significant increase in DNA damage in a nuclear gene. After treatment with MPTP, there was an age-dependent increase in DNA damage in mitochondria of the caudate-putamen while there was no significant DNA damage in the nuclear target. MPTP treatment led to damage in both mitochondrial and nuclear DNA of the substantia nigra, while there was no damage in either mitochondria or nucleus in cerebellum which was used as a negative control.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2000

Cellular determinants of reduced adaptability of the aging brain: neurotransmitter utilization and cell signaling responses after MDMA lesions.

Senescence is accompanied by the loss of neurons and synapses, and the maintenance of function depends on adaptive change at the levels of synaptic activity and cellular responsiveness. In the current study, we administered the neurotoxin MDMA, to young and aged mice and assessed the effects on indices of neuronal activity and cell signaling mediated through adenylyl cyclase. Young mice given MDMA showed 80% depletion of dopamine in the caudate and 30% depletion in the cerebral cortex; measurements of dopamine turnover indicated a compensatory upregulation of the activity of the remaining neurons in the caudate but downregulation in the cerebral cortex. Serotonin levels were comparatively less affected but serotonin turnover was decreased significantly in both regions. At the level of cell signaling, the young mice showed heterologous upregulation of adenylyl cyclase activity and a consequent enhancement of responses mediated through neurotransmitter receptors. In aged mice, MDMA treatment produced the same degree of lesioning but substantially different changes in neuronal activity and cell signaling. In the cerebral cortex, dopamine turnover was increased, and serotonin turnover decreased, effects opposite in direction to those seen in young mice. In the aged group, MDMA elicited heterologous loss of adenylyl cyclase responses instead of displaying the supersensitivity that had been seen in the young group. The aging brain thus displays maladaptation to the loss of monoaminergic input, effects that may augment the functional impairment associated with neurodegenerative disorders or stroke.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2000

Dopamine toxicity following long term exposure to low doses of 3-nitropropionic acid (3-NPA) in rats.

A toxin produced by legumes of the genus Astragalus and Arthrinium fungi, 3-NPA is a suicide inhibitor of succinate dehydrogenase and causes acute encephalopathy and late onset dystonia. It has been suggested that dopamine (DA) toxicity plays a role in 3-NPA induced brain damage. In order to simulate natural conditions of toxicant intake, adult, male, Sprague-Dawley rats were exposed to 3-NPA weekly for 24-h periods at 10 and 20 mg/40 ml in drinking water. This dosing regimen continued for 3 months with animals from both high and low dose groups sacrificed at the end of each month. Dopamine and its metabolites, 3,4-dihydroxylphenylacetic acid (DOPAC) and homovanillic acid (HVA), were assessed by HPLC-EC in the frontal cortex (FC) and caudate nucleus (CN). Increases of DA concentration were seen in both low and high dose groups in the CN after 1 and 3 months of dosing and in the FC after 2 months of exposure. An increase in DA turnover was observed in the CN of the high dose group following 2 months of dosing. Data suggest an activation of the dopaminergic system after long-term, intermittent exposure to 3-NPA. The production of radical oxygen species associated with DA metabolism may contribute to 3-NPA-induced neurotoxicity.

Animals↗

PubMed2000

Comparative neurobiological effects of ibogaine and MK-801 in rats.

Ibogaine is a plant-derived alkaloid with putative 'anti-addictive' properties. Although ibogaine binds to multiple targets in the brain, recent evidence suggests the drug acts as an N-methyl-D-aspartate (NMDA) antagonist similar to MK-801. The purpose of the present study was to compare neurochemical and neuroendocrine effects of ibogaine and MK-801 in vivo. Male rats received either i.p. saline, ibogaine (10 and 100 mg/kg), or MK-801 (0.1 and 1 mg/kg). Groups of rats (N=6-8/group) were decapitated 30 or 60 min after injection. Brains were harvested for analysis of dopamine (DA) and its metabolites, while trunk blood was collected for analysis of plasma corticosterone and prolactin. Ibogaine produced marked dose-dependent reductions in tissue DA with concurrent increases in the metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). This profile of ibogaine-induced effects on DA metabolism was consistently observed in the cortex, striatum, olfactory tubercle, and hypothalamus. MK-801, on the other hand, did not reduce DA levels in any brain region but did cause modest region-specific elevations in DA metabolites. Ibogaine and MK-801 caused comparable elevations in circulating corticosterone, but only ibogaine increased prolactin. The present findings show that the effects of ibogaine on DA neurotransmission and neuroendocrine secretion are not fully mimicked by MK-801. Thus, the wide spectrum of in vivo actions of ibogaine can probably not be explained simply on the basis of antagonism at NMDA receptors.

Animals↗

PubMed2000

Selenium, an antioxidant, attenuates methamphetamine-induced dopaminergic toxicity and peroxynitrite generation.

Methamphetamine (METH) has been known to produce neurotoxicity via generation of reactive oxygen and nitrogen species. Selenium, an antioxidant, was reported to protect against METH-induced dopaminergic neurotoxicity in mouse caudate nucleus. In the present study, the in vitro and in vivo efficacy of the supplementation of selenium was studied in METH-induced generation of peroxynitrite. PC12 cell cultures were exposed to 200 microM METH either with or without 10 microM and 20 microM selenium (30 min prior to METH exposure). After 24 h, METH exposure resulted in the significant depletion of dopamine, and its metabolites DOPAC and HVA, as well as the significant formation of 3-nitrotyrosine (3-NT), a marker of peroxynitrite generation, in PC12 cell cultures. Selenium supplementation attenuated the depletion of dopamine and its metabolites, DOPAC and HVA and the formation of 3-NT in PC12 cells. For in vivo studies, adult male mice were supplemented with selenium in drinking water, 1 week before and 1 week after the multiple injections of METH (4x10 mg/kg, i.p. at 2-h interval) or an equivalent volume of saline. The supplementation of Se attenuated the formation of 3-NT in the striatum resulting from METH treatment. These data suggest that METH-induced neurotoxicity is mediated by the production of peroxynitrite, and selenium plays a protective role in METH-induced neurotoxicity.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2000

A dose-response study of ibogaine-induced neuropathology in the rat cerebellum.

Ibogaine (IBO) is an indole alkaloid from the West African shrub, Tabernanthe iboga. It is structurally related to harmaline, and both these compounds are rigid analogs of melatonin. IBO has both psychoactive and stimulant properties. In single-blind trials with humans, it ameliorated withdrawal symptoms and interrupted the addiction process. However, IBO also produced neurodegeneration of Purkinje cells and gliosis of Bergmann astrocytes in the cerebella of rats given even a single dose (100 mg/kg, ip). Here, we treated rats (n = 6 per group) with either a single ip injection of saline or with 25 mg/kg, 50 mg/kg, 75 mg/kg, or 100 mg/kg of IBO. As biomarkers of cerebellar neurotoxicity, we specifically labeled degenerating neurons and axons with silver, astrocytes with antisera to glial fibrillary acidic protein (GFAP), and Purkinje neurons with antisera to calbindin. All rats of the 100-mg/kg group showed the same pattern of cerebellar damage previously described: multiple bands of degenerating Purkinje neurons. All rats of the 75-mg/ kg group had neurodegeneration similar to the 100-mg/kg group, but the bands appeared to be narrower. Only 2 of 6 rats that received 50 mg/kg were affected; despite few degenerating neuronal perikarya, cerebella from these rats did contain patches of astrocytosis similar to those observed with 75 or 100 mg/kg IBO. These observations affirm the usefulness of GFAP immunohistochemistry as a sensitive biomarker of neurotoxicity. None of the sections from the 25-mg/kg rats, however stained, were distinguishable from saline controls, indicating that this dose level may be considered as a no-observable-adverse-effect level (NOAEL).

Animals↗

PubMed2000

Acute effects of cocaine on play behaviour of rats.

Play behaviours are exhibited by many mammalian species. The similarity of such behaviour across children, non-human primates and rats makes it an especially appropriate target for the investigation of drug- or toxicant-induced disruption. In this study the acute effects of cocaine on play behaviour in male and female Sprague-Dawley rats was assessed. Same-sex dyads of rats (postnatal day 35-36) were separated 24 h prior to testing. On the following day, one or both rats of the dyad were injected with the same dose of cocaine (0, 2.5, 5.0 or 20.00 mg/kg). Thirty minutes later the rats were placed together and, after 5 min of habituation, the frequency of pins and crawl-overs were measured for each subject. In dyads in which both rats were treated, crawl-overs and pinning behaviour were decreased by 20 mg/kg cocaine. In dyads in which only one rat was treated, there was marginal effect of cocaine treatment on pinning frequency, while crawl-overs were unaffected. Pinning frequency was not sexually dimorphic in either type of dyad; however, crawl-overs were more frequently exhibited by females in dyads in which only one rat was treated. Thus, pinning behaviour in juvenile rats appears somewhat more sensitive to cocaine-induced disruption than crawl-over behaviours. Additionally, the presence of an untreated rat appears to attenuate the play-disrupting effects of cocaine on pinning frequency.

Animals↗

PubMed2000

Comparison between the role of the neuronal and inducible nitric oxide synthase in methamphetamine-induced neurotoxicity and sensitization.

The involvement of the neuronal and inducible nitric oxide synthase (nNOS and iNOS, respectively) in methamphetamine (METH)-induced dopaminergic neurotoxicity and behavioral sensitization was investigated. To determine METH-induced neurotoxicity, mice deficient in the nNOS and iNOS genes, nNOS(-/-) and iNOS(-/-) mice, and wild-type controls received either saline or METH (5 mg/kg x 3). After 72 h the level of striatal dopaminergic markers were measured. Administration of METH to nNOS(-/-) mice had no significant effect on the level of striatal dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), or dopamine transporter (DAT) binding sites. However, METH caused 25-40% depletion of dopaminergic markers in iNOS(-/-) mice and 63-69% depletion in the wild-type mice. METH-induced locomotor activity was measured following the administration of a low dose (1 mg/kg) on day 1. Subsequently animals received the high dose of METH (5 mg/kg x 3). On day 4, after a 68-72 h drug free period, animals were challenged with 1 mg/kg METH, and locomotor activity was recorded. The intensity of METH-induced locomotion in nNOS(-/-) mice on day 1 and 4 was similar, suggesting that locomotor sensitization did not develop. However, the intensity of METH-induced locomotion in the iNOS(-/-) and wild-type mice on day 4 was doubled compared to day 1, suggesting the development of sensitization. The present findings indicate that nNOS(-/-) mice are more resistant to METH-induced neurotoxicity and behavioral sensitization than iNOS(-/-) mice. These results suggest a major role for nNOS rather than iNOS in the effects of METH.

Analysis of Variance↗

PubMed2000

Prevention of dopaminergic neurotoxicity by targeting nitric oxide and peroxynitrite: implications for the prevention of methamphetamine-induced neurotoxic damage.

Methamphetamine (METH) is a neurotoxic psychostimulant that produces catecholaminergic brain damage by producing oxidative stress and free radical generation. The role of oxygen and nitrogen radicals is well documented as a cause of METH-induced neurotoxic damage. In this study, we have obtained evidence that METH-induced neurotoxicity is the resultant of interaction between oxygen and nitrogen radicals, and it is mediated by the production of peroxynitrite. We have also assessed the effects of inhibitors of neuronal nitric oxide synthase (nNOS) as well as scavenger of nitric oxide and a peroxynitrite decomposition catalyst. Significant protective effects were observed with the inhibitor of nNOS, 7-nitroindazole (7-NI), as well as by the selective peroxynitrite scavenger or decomposition catalyst, 5,10,15,20-tetrakis(2,4,6-trimethyl-3,5-sulfonatophenyl)porphyrinato iron III (FeTPPS). However, the use of a nitric oxide scavenger, 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO), did not provide any significant protection against METH-induced hyperthermia or peroxynitrite generation and the resulting dopaminergic neurotoxicity. In particular, treatment with FeTPPS completely prevented METH-induced hyperthermia, peroxynitrite production, and METH-induced dopaminergic depletion. Together, these data demonstrate that METH-induced dopaminergic neurotoxicity is mediated by the generation of peroxynitrite, which can be selectively protected by nNOS inhibitors or peroxynitrite scavenger or decomposition catalysts.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2000

Age as a susceptibility factor in the striatal dopaminergic neurotoxicity observed in the mouse following substituted amphetamine exposure.

A number of substituted amphetamines, including methamphetamine (METH) are considered dopaminergic neurotoxicants. METH causes long-term depletions of striatal dopamine (DA) and its metabolites (DOPAC and HVA) that are accompanied by other changes indicative of nerve terminal degeneration. These include argyrophilia as detected by silver degeneration stains and an elevation in glial fibrillary acidic protein (GFAP), a marker of reactive gliosis in response to injury, as well as a long-term decrease in tyrosine hydroxylase (TH) protein levels. The susceptibility to the dopaminergic neurotoxicity of METH and the other amphetamines can be affected by a number of factors including age, gender, stress, and environment. Many of these susceptibility factors have been extensively investigated in the rat but less so in the mouse. As the availability of genetically altered mice continues to expand, this species is increasingly selected for study. Thus, in previous work we determined that stress, gender, and the environment can significantly impact the neurotoxicity of the amphetamines. Here we determined how age affects the striatal DA depletion and GFAP elevation induced by d-METH in C57BL/6 mice. Age was a significant determinant of the ability of a known neurotoxic regimen of d-METH (10 mg/kg x 4) to produce striatal DA depletion with one-month-old C57BL16 mice displaying minimal and nonpersistent depletion of DA or its metabolites while mice 12 months of age displayed large and persistent depletions of DA (87%), DOPAC (71%), and HVA (94%). Large elevations in striatal GFAP were induced in mice 2-23 months of age by d-METH, with lower dosages of d-METH being effective in the older mice. In contrast, the usual neurotoxic regimen of d-METH was minimally effective in inducing GFAP elevations (49% over control) in one-month-old mice, despite elevations in body temperature equivalent to those observed in older mice. Although increasing the dosage of d-METH (20 to 80 mg/kg) did increase the GFAP response (100% over control), it was still well below that usually exhibited at the usual neurotoxic dosage (300-400% over control) in fully mature mice. These data suggest maturity of striatal dopamine systems may be an essential element in the striatal damage induced by the neurotoxic amphetamines.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2000

Calpain upregulation in spinal cords of mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a heroin analogue, is a neurotoxin that undergoes in vivo oxidation by monoamine oxidase-B (MAO-B) to 1-methyl-4-phenylpyridinium ion (MPP+) which preferentially exerts its toxic effects on the dopaminergic neurons of the substantia nigra in brain. Spinal interneuronal pathways are also likely to be affected in the course of MPP+ neurotoxicity. The primary effect of MPP+ is mediated by irreversible inhibition of mitochondrial complex I, releasing free radicals. MPP+ may also activate N-methyl-D-aspartate (NMDA) receptors, increasing the cytosolic concentration of free Ca2+. Intracellular free radicals indirectly and free Ca2+ directly can activate Ca2+-dependent proteases such as calpain. We investigated involvement of calpain in spinal cord degeneration due to neurotoxin by subjecting male C57BL/6N mice (17 months old) to MPTP administration (12.5 mg/kg for 0.5 h; 25 mg/kg for 0.25 h; and 50 mg/kg for 0.25, 0.5, 1, 2, and 24 h). RT-PCR and Western blot analysis were performed using the thoracic segment of spinal cords from control and MPTP-administered mice. The administration of MPTP caused calpain upregulation at the mRNA and protein levels to various extents, compared to control mice. Calpain activity was measured by 68 kDa neurofilament protein (NFP) degradation, which was increased in MPTP-induced PD mice. These results suggest that calpain may play a role in spinal cord degeneration in mice with MPTP-induced PD.

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

PubMed2000

Noribogaine (12-hydroxyibogamine): a biologically active metabolite of the antiaddictive drug ibogaine.

Ibogaine (IBO) is a plant-derived alkaloid that is being evaluated as a possible medication for substance use disorders. When administered peripherally to monkeys and humans, IBO is rapidly converted to an o-demethylated metabolite, 12-hydroxyibogamine (NORIBO). We have found in rats that peak blood levels of NORIBO can exceed those of the parent compound, and NORIBO persists in the bloodstream for at least 24 h. Surprisingly few studies have examined the in vivo biological activity of NORIBO. In the present series of experiments, we compared the effects of intravenous (i.v.) administration of IBO and NORIBO (1 and 10 mg/kg) on unconditioned behaviors, circulating stress hormones, and extracellular levels of dopamine (DA) and serotonin (5-HT) in the nucleus accumbens of male rats. IBO caused dose-related increases in tremors and forepaw treading, whereas NORIBO did not. Both IBO and NORIBO produced significant elevations in plasma corticosterone and prolactin, but IBO was more potent as a stimulator of corticosterone secretion. Neither drug affected extracellular DA levels in the nucleus accumbens. However, both IBO and NORIBO increased extracellular 5-HT levels, and NORIBO was more potent in this regard. The present data demonstrate that NORIBO is biologically active and undoubtedly contributes to the in vivo pharmacological profile of IBO in rats. Most importantly, NORIBO appears less likely to produce the adverse effects associated with IBO (i.e., tremors and stress-axis activation), suggesting that the metabolite may be a safer alternative for medication development.

Analysis of Variance↗