Autoradiography of l–Methyl–4–phenyl–l,2,3,6–tetrahydropyridine (MPTP): Uptake in the Monoaminergic Pathways and in Melanin Containing Tissues

Abstract: A recently discovered neurotoxic compound, l–methyl–4–phenyl–l,2,3,6–tetrahydropyridine, has been found to cause a parkinsonian–like syndrome in man and monkey, but not in laboratory animals such as rat, mouse and guinea pig. MPTP seems to selectively destroy the melanin containing dopaminergic cells in pars compacta of substantia nigra. Lower mammalian species do not have melanin in these cells, which indicates that the presence of neuromelanin may be of importance for the development of MPTP–induced lesions. By means of whole–body autoradiography of ³H–MPTP in mice, accumulation and retention was observed in the dopaminergic pathways, in locus caeruleus and in structures in the medulla oblongata and spinal cord. A high uptake was also seen in melanin–containing tissues such as in the eyes of pigmented mice. MPTP has earlier been found to have high affinity in vitro for dopamine melanin, which is similar to the pigment in substantia nigra. The typical features of the MPTP–induced neurotoxicity with destruction of pigmented nerve cells and development of parkinsonism may be due to accumulation and retention of MPTP and its metabolites in these cells. In species with pigmented nerve cells, such as man and monkey, the accumulation may be much more pronounced because of the melanin affinity of MPTP and its metabolites     

Acacetin Protects Dopaminergic Cells against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Induced Neuroinflammation <i>in Vitro</i> and <i>in Vivo</i>

Acacetin (5,7-dihydroxy-4'-methoxyflavone), a constituent of flavone naturally present in plants, has anti-cancer and anti-inflammatory activities. Neuroinflammation is thought to be one of the major pathological mechanisms responsible for Parkinson's disease (PD), and has been a primary target in the development of treatment for PD. In the present study, we evaluated the neuroprotective effect of acacetin in PD induced by 1-methyl-4-phenylpyridine (MPP⁺)/or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and examined the related pathways in vitro and in vivo. In primary mesencephalic culture, acacetin protected dopaminergic (DA) cells and inhibited production of inflammatory factors such as nitric oxide, prostaglandin E2, and tumor necrosis factor-α against MPP⁺-induced toxicity in a dose-dependent manner. Then, we confirmed the effect of acacetin (10?mg/kg/d for 3?d, per os (p.o.)) in a mouse model of PD induced by MPTP (30?mg/kg/d for 5?d, intraperitoneally (i.p.)). In the behavioral test (pole test), the acacetin-treated mice showed decreased time of turning and locomotor activity, which were longer in MPTP-only treated mice. In addition, the acacetin-treated group inhibited degeneration of DA neurons and depletion of dopamine level induced by MPTP toxicity in the substantia nigra and striatum of the brain. Moreover, the acacetin-treated group inhibited microglia activation, accompanied by production of inducible nitric oxide synthases and cyclooxygenase-2. These results suggest that acacetin can protect DA neurons against the neurotoxicity involved in PD via its anti-inflammatory action.     

Beneficial effect of magnesium on the isolated perfused rat heart during reperfusion after ischaemia: Comparison between pre-ischaemic and post-ischaemic administration of magnesium

Summary The effect of high concentration of magnesium on both mechanical dysfunction and metabolic damage after ischaemia-reperfusion was studied in isolated rat hearts. The heart was perfused by the Langendorff's technique at a constant flow (10 ml/min) with modified Krebs-Henseleit solution and driven at 300 beats/min. The heart was made ischaemic by reducing the flow to 0 ml/min for 25 min, and then reperfused at the constant flow for 15 min. MgSO₄ was added to the perfusate for 5 min before the onset of ischaemia, or after the end of ischaemia (after the onset of reperfusion). Ischaemia-reperfusion produced both mechanical dysfunction (as evidenced by an increase in the left ventricular end diastolic pressure and a decrease in the left ventricular developed pressure) and metabolic damage [as evidenced by a decrease in the myocardial adenosine triphosphate (ATP)]. When 15 mmol/l MgSO₄ was given before ischaemia, there was no appreciable recovery of mechanical function, whereas when given after ischaemia (during reperfusion), there was a marked recovery of mechanical function. Lower concentrations (10 or 5 mmol/l) of MgSO₄ given after ischaemia recovered the mechanical function concentration-dependently. The beneficial effect of 15 mmol/l MgSO₄ was minimized by the coexistence of 4.5 mmol/l CaCl₂ in the reperfusion solution. The decrease in the myocardial level of ATP induced by ischaemia-reperfusion was attenuated by 15 mmol/l MgSO₄ given in the reperfusion solution. These results suggest that high Mg²⁺ is effective in attenuating both functional and metabolic damage of the post-ischaemic heart, provided it is given after ischaemia. Send offprint requests to Y. Abiko at the above address     

Inhaled fluoride, magnesium salt and L-arginine reverse bronchospasma

In vitro studies showed that fluoride and magnesium salts relax bronchial smooth muscle cells. Their combined administration could have potential interest. Magnesium fluoride salt (MgF₂) is nearly insoluble. A soluble derivate can be obtained by introducing L‐arginineinine (L‐arginine) between the ions. L‐arginine, being the substrate leading to the release of NO, might add another relaxing effect to this derivate. Relaxing effects of NaF, MgSO₄, L‐arginine, NaF+MgSO₄ and MgF₂+L‐arginine given via the inhaled route were studied on rats challenged with acetylmethylcholine (ACMCH) following eight successive doses. Tested salts were given at the fourth dose of ACMCH. Changes in bronchial resistances (R) were measured and compared to results obtained in a control group, receiving ACMCH alone. NaF, MgSO₄, and L‐arginine led to significant bronchorelaxing effects (p < 0.05). The association NaF+MgSO₄ gave a greater decrease in bronchial resistance compared to that obtained with each salt (fluoride and magnesium) separately. (MgF₂, 2L‐arginine) induced a significant fall in R at the fourth dose of ACMCH just after its inhalation. R values obtained with (MgF₂, 2L‐arginine) were significantly lower than L‐arginine alone at the sixth dose of ACMCH (p < 0.05). (MgF₂, 2L‐arginine) is a triple combination able to induce a significant and constant bronchodilating effect through three different pathways. The effect looked partly additive. Copyright © 2010 John Wiley & Sons, Ltd.     

1‐Methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine Pretreatment Attenuates Methamphetamine‐Induced Dopamine Toxicity

Abstract: The effects of pretreatment with MPTP (1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine) on the acute and long‐term effects of methamphetamine on striatal dopamine were evaluated in BALB/c mice. Four subcutaneous injections of a non‐toxic dose of MPTP (8 mg/kg, at 2 hr intervals) were followed three days later by a toxic regimen of methamphetamine (four injections of 4 mg/kg, at 2 hr intervals) and mice were sacrificed immediately or three days later. Control mice received saline in place of the MPTP or methamphetamine and mice were observed for acute changes in body temperature, self‐injurious behaviour, and striatal dopamine metabolites, or long‐term changes in striatal dopamine levels, tyrosine hydroxylase immunoreactivity and glial fibrillary acidic protein. It was observed that pretreatment with MPTP protected mice against the acute increase in body temperature caused by the methamphetamine but, at the same time, delayed the occurrence of self‐injurious behaviour following the repeated injections of methamphetamine. Likewise, pretreatment with MPTP attenuated the long‐term depletion of striatal dopamine induced by the methamphetamine as well as the large increase in glial fibrillary acidic protein and the reduction in tyrosine hydroxylase immunoreactivity. The MPTP‐treatment itself did not alter any of these neurotoxic markers. Finally, the acute decrease in 3,4‐dihydroxyphenyacetic acid levels and increased ratio of 3‐methoxytyramine/dopamine observed 60 min. after a single injection of methamphetamine (4 mg/kg) were also attenuated in MPTP‐treated mice. These results are discussed in the context of the hypothesis that the low‐dose treatment with MPTP may modify exchange diffusion across the striatal cell membrane thereby altering the acute and long‐lasting effects of methamphetamine.     

SEA0400, a specific Na+/Ca2+ exchange inhibitor, prevents dopaminergic neurotoxicity in an MPTP mouse model of Parkinson's disease

We have recently shown that the Na⁺/Ca²⁺ exchanger (NCX) is involved in nitric oxide (NO)-induced cytotoxicity in cultured astrocytes and neurons. However, there is no in vivo evidence suggesting the role of NCX in neurodegenerative disorders associated with NO. NO is implicated in the pathogenesis of neurodegenerative disorders such as Parkinson’s disease. This study examined the effect of SEA0400, the specific NCX inhibitor, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity, a model of Parkinson’s disease, in C57BL/6J mice. MPTP treatment (10 mg/kg, four times at 2-h intervals) decreased dopamine levels in the midbrain and impaired motor coordination, and these effects were counteracted by S-methylthiocitrulline, a selective neuronal NO synthase inhibitor. SEA0400 protected against the dopaminergic neurotoxicity (determined by dopamine levels in the midbrain and striatum, tyrosine hydroxylase immunoreactivity in the substantia nigra and striatum, striatal dopamine release, and motor deficits) in MPTP-treated mice. SEA0400 had no radical-scavenging activity. SEA0400 did not affect MPTP metabolism and MPTP-induced NO production and microglial activation, while it attenuated MPTP-induced increases in extracellular signal-regulated kinase (ERK) phosphorylation and lipid peroxidation product, thiobarbituric acid reactive substance. These findings suggest that SEA0400 protects against MPTP-induced neurotoxicity probably by blocking ERK phosphorylation and lipid peroxidation which are downstream of NCX-mediated Ca²⁺ influx.     

Nullification of a positive correlation between urinary contents of α1-microglobulin and ulinastatin with intracerebroventricularly administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (MPP+) in mice

Striatal dopamine contents in C57BL/6J mice were reduced at 24 h after intracerebroventricular (ICV) administration of 1-methyl-4-phenyl-1,2, 3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP⁺) in a dose-dependent manner. A dose of 1.8 μg MPP⁺ significantly (P < 0.05) suppressed the dopamine contents, whereas a similar dose of MPTP did not. A definite positive correlation between urinary contents of α₁-microglobulin (α₁M) and ulinastatin (UT) existed in normal mice. However, this correlation was nullified by ICV administration of 18 and 36 μg MPTP or 1.8 and 18 μg MPP⁺. With 1.8 μg MPTP, a positive correlation between urinary contents of α₁M and UT was displayed. The urine volume, creatinine content, glomerular filtration rate, α₁M and UT contents, and α₁M/UT ratio of urine collected for 24 h post-ICV administration of MPTP or MPP⁺, were not statistically different from those of control mice. Our findings suggest that the central effects of MPP⁺, a neurotoxic metabolite of MPTP, nullify the positive correlation between urinary contents of α₁M and UT without affecting renal functions. Received: 23 July 1997/Final version: 24 October 1997     

硫酸镁联合依达拉奉治疗急性脑梗死的疗效观察

目的:探讨依达拉奉联合应用硫酸镁静脉给药治疗急性脑梗死的疗效和最佳剂量.方法:联合治疗组患者在依达拉奉治疗的基础上给以3种负荷量的硫酸镁(0mL,10mL,20mL)加24h内60mL硫酸镁维持以及每日20mL,14d的硫酸镁维持治疗,监测患者的血压、腱反射等镁的副作用,动态观察了血清镁浓度,在30d和90d对患者进行ESS评分.结果:10mL 、20mL硫酸镁联合治疗组患者的血清镁能够迅速提升,明显增加患者远期的ESS评分,其中20mL组更为有效.未见明显的不能耐受的不良反应.结论:依达拉奉联合应用硫酸镁,负荷应用硫酸镁10mL、20mL对脑梗死患者具有良好的治疗作用,其中20mL负荷量效果最佳.     

Dietary administration of diquat for 13 weeks does not result in a loss of dopaminergic neurons in the substantia nigra of C57BL/6J mice

Male and female C57BL/6J mice were administered diquat dibromide (DQ∙Br₂) in their diets at concentrations of 0 (control), 12.5 and 62.5 ppm for 13 weeks to assess the potential effects of DQ on the nigrostriatal dopaminergic system. Achieved dose levels at 62.5 ppm were 6.4 and 7.6 mg DQ (ion)/kg bw/day for males and females, respectively. A separate group of mice was administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) ip as a positive control. The comparative effects of DQ and MPTP on the substantia nigra pars compacta (SNpc) and/or striatum were assessed using neurochemical, neuropathological and stereological endpoints. Morphological and stereological assessments were performed by investigators who were “blinded” to dose group. DQ had no effect on striatal dopamine concentration or dopamine turnover. There was no evidence of neuronal degeneration, astrocytic or microglial activation, or a reduction in the number of tyrosine hydroxylase positive (TH⁺) neurons in the SNpc or neuronal processes in the striatum of DQ-treated mice. These results are consistent with the rapid clearance of DQ from the brain following a single dose of radiolabeled DQ. In contrast, MPTP-treated mice exhibited decreased striatal dopamine concentration, reduced numbers of TH⁺ neurons in the SNpc, and neuropathological changes, including neuronal necrosis, as well as astrocytic and microglial activation in the striatum and SNpc.     

Comparison of Key Steps in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Neurotoxicity in Rodents

Abstract: Three steps in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity were compared with the neurodegenerative effects of the toxin in mice and rats. Firstly, we compared the neurotoxicity of MPTP, mediated by monoamine oxidase (MAO)-B, to that of 1-methyl-4-(2′-methylphenyl)-1,2,3,6-tetrahydropyridine (2′-CH₃-MPTP), an analogue oxidized by MAO-A and MAO-B. Both toxins caused degeneration of dopamine terminals in mice but not in rats. In NMRI mice noradrenaline terminals were also affected by both toxins. Pretreatment with deprenyl to prevent MAO-B-mediated oxidation in the capillary endothelium enhanced dopamine toxicity to 2′-CH₃-MPTP in nucleus accumbens but no potentiation was seen in striatum and the olfactory tubercle. Secondly, synaptosomal uptake of the 1-methyl-4-phenylpyridinium ion (MPP⁺) was studied. Uptake in rats was not significantly different from that in the two mice strains. Thirdly, no significant differences were found in MPP⁺-induced lactate production in striatal slices or synaptosomes. We conclude that the lack of effect of MPTP in rats is not due to mechanisms specific for MPTP but probably to the ability of rat catecholamine neurons to cope with, and survive, impaired energy metabolism.     

Prevention by a Ginkgo biloba extract (GBE 761) of the dopaminergic neurotoxicity of MPTP

In mice implanted subcutaneously with osmotic minipumps releasing the neurotoxic agent N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 7 days (105 micrograms h-1/mouse) (approximately 100 mg kg-1 day-1) a significant reduction (approximately 25%) in the striatal dopaminergic nerve endings was observed. This neurotoxic effect was prevented by the semi-chronic ingestion of a Ginkgo biloba extract for 17 days (GBE 761, approximately 100 mg kg-1 day-1). The high concentrations (approximately 1 g L-1) at which GBE 761 in-vitro either prevented the uptake of [3H]dopamine by synaptosomes prepared from striatum, or prevented the specific binding of the pure dopamine uptake inhibitor [3H]GBR 12783 to membranes prepared from striatum suggests that the prevention of the MPTP neurotoxicity does not depend on an inhibition of the MPTP uptake by dopamine neurons. This is also suggested by the lack of prevention of the in-vitro striatal binding of [3H]GBR 12783 administered i.v. at a tracer dose, in mice pretreated for 8 days with GBE 761 (100 mg kg-1 p.o.) and receiving a supplementary gastric administration of GBE 761 (100 mg kg-1) 1 h before testing. Similar treatment with GBE 761 did not modify the toxicity for dopamine neurons of 6-hydroxydopamine (20 micrograms) directly injected into the striatum of rats.     

Labedipinedilol‐A: A vanilloid‐based α/β‐adrenoceptor blocker with calcium entry blocking and long‐acting antihypertensive properties

The combination of β‐adrenoceptor blockade and vasodilator action have proved highly useful in antihypertensive therapy. Studies of the mechanisms of action of labedipinedilol‐A that combine these effects within a single molecule are described in this report. Intravenous labedipinedilol‐A (0.1–1.0 mg/kg) produced dose‐dependent hypotensive and bradycardia responses for above 1.0 h, significantly different from nifedipine (0.5 mg/kg, i.v.)‐induced hypotensive and reflex tachycardia activities in pentobarbital‐anesthetized Wistar rats. Pretreatment with labedipinedilol‐A also inhibited phenylephrine (20 μg/kg, i.v.)‐induced hypertensive and (‐)isoprenaline (0.5 μg/kg, i.v.)‐induced tachycardia effects. Oral administration of labedipinedilol‐A (5–50 mg/kg) in spontaneously hypertensive rats (SHR) reduced the blood pressure and heart rate for 24 h but did not increase heart rate. Labedipinedilol‐A (10^–7–10^–5 M) competitively antagonized (‐)isoprenaline (10^–10–10^–4M)‐induced positive chronotropic and inotropic effects of the isolated rat atria and tracheal relaxation responses of the isolated guinea pig tissues. Labedipinedilol‐A also prevented the rate‐increasing effects of increased extracellular Ca²⁺ (3.0–9.0 mM) in a concentration‐dependent manner. In the isolated rat aorta, labedipinedilol‐A competitively antagonized CaCl₂ and norepinephrine‐induced contractions with pKCa^–1 and pA₂ values of 8.46 ± 0.05 and 8.28 ± 0.03 and had a potent effect of inhibiting high K⁺‐induced vasocontraction. Furthermore, labedipinedilol‐A, in an equal antagonist activity, inhibited norepinephrine‐induced phasic and tonic contraction. In the cultured blood vessel smooth muscle cell (A7r5 cell line), KCl, norepinephrine, and Bay K 8644‐induced intracellular calcium changes were decreased after application of labedipinedilol‐A (10^–9–10^–6 M). The binding characteristics of labedipinedilol‐A were evaluated in [³H]CGP‐12177 binding to ventricle and lung and [³H]nitrendipine and [³H]prazosin binding to brain membranes in rats. The ‐logIC₅₀ values of labedipinedilol‐A for β₁‐, β₂‐, and α₁‐adrenoceptor and calcium channel, were 8.17 × 10^–7 M, 8.20 × 10^–7 M, 2.20 × 10^–8 M, and 2.46 × 10^–8 M, respectively. Labedipinedilol‐A‐induced sustained depressor effect was mainly attributed to its calcium entry and α‐adrenoceptor blocking activities in the blood vessel. Sustained bradycardia effect resulted from β‐adrenoceptor and calcium entry blocking, which deleted the sympathetic activation‐associated reflex tachycardia in the heart. Drug Dev. Res. 49:94–108, 2000. © 2000 Wiley‐Liss, Inc.     

Influence of α‐Adrenoceptor Agonists and Antagonists on Imipramine‐Induced Hypothermia in Mice

Abstract: Effects of adrenoceptor agonists and antagonists on imipramine‐induced hypothermia in mice were studied. Intraperitoneal injection of imipramine (10–40 mg kg^?1), α₂‐adrenoceptor agonist clonidine (0.05–0.1 mg kg^?1), α₁‐adrenoceptor agonist phenylephrine (6 mg kg^?1) and α₁‐adrenoceptor antagonist prazosin (1–4 mg kg^?1) but not α₂‐adrenoceptor antagonist yohimbine (1–4 mg kg^?1) induced significant hypothermia. The hypothermic response induced by imipramine (10–30 mg kg^?1) was not altered by clonidine (0.05–0.1 mg kg^?1) or phenylephrine (2–6 mg kg^?1). The response of imipramine (10–30 mg kg^?1) was reduced significantly by yohimbine (2 mg kg^?1) and was potentiated by prazosin (1 mg kg^?1). The hypothermic effect of clonidine (0.1 mg kg^?1) and imipramine (20 mg kg^?1) were also decreased significantly by different doses of yohimbine (1–4 mg kg^?1). The hypothermia induced by different doses of prazosin (1–4 mg kg^?1) was not altered by yohimbine (2 mg kg^?1) or by low dose of imipramine (10 mg kg^?1). It is concluded that α₂‐adrenoceptor mechanism may be involved in the hypothermic effect of imipramine.     

Synthesis,characterization and biodistribution of 99mTc(CO)3–ABP and comparison with 99mTc–ABP

The (l‐hydroxy‐4‐amino‐butylidene‐l,l‐bisphosphate) (ABP) is a compound that inhibits bone resorption, and a highly effective drug in the treatment of metastatic bone disease. The fac‐[^99mTc(CO)₃(H₂O)₃]⁺ precursor was reacted with ABP in saline (pH=3–4) at 45°C for 15 min to produce the ^99mTc(CO)₃–ABP complex. The radiochemical purity (RCP) of the product was over 90% as measured by thin layer chromatography and high‐performance liquid chromatography. No decomposition of the complex at room temperature (25°C) was observed over a period of 6 h. Its partition coefficient indicated that it was a weak hydrophilic complex. The biodistribution in normal mice of ^99mTc(CO)₃–ABP complex differed greatly from that of ^99mTc–ABP, and the former had a lower bone uptake as compared with that of the latter. The experiment results showed that the incorporation of the [^99mTc(CO)₃]⁺ core into the ABP ligand may drastically change the characterization and biological features as compared with ^99mTc–ABP. Copyright © 2007 John Wiley & Sons, Ltd.     

The influence of dose and dosing interval on MPTP-induced dopaminergic neurotoxicity in mice

The effects of different dosing paradigms for the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were investigated in C57-black and CF-W albino mice. Several groups of mice received a total dose of 80 mg/kg of MPTP administered at different doses per injection and/or at different time intervals. In C57-black mice, the effects of MPTP administration on the neostriatal content of dopamine ranged from a 91% depletion (4 injections of 20 mg/kg per injection at 1 h intervals) to a non-significant effect (4 injections of 10 mg/kg per injection at 2 h intervals on each of 2 successive days). There was also considerable influence of the MPTP dose per injection and the dosing interval in CF-W mice, although the extent of neostriatal dopamine depletion in CF-W mice was not as great as that observed in C57-black mice. In addition, MPTP produced variable effects on neostriatal dopamine levels in different strains of mice as well as in Swiss-Webster mice obtained from different sources. Some of the strains were affected to a great extent while others were only marginally affected.     

Ferulic acid pretreatment mitigates MPTP-induced motor impairment and histopathological alterations in C57BL/6 mice

Abstract

Context: Ferulic acid (FA) is a potent ubiquitous plant antioxidant found in cereals such as brown rice, whole wheat, and oats. Phytochemical-based antioxidants are shown to be effective in neurodegenerative diseases. This study hypothesizes that supplementation of FA might combat oxidative stress-induced Parkinson’s disease (PD).

Objective: To explore the effect of FA on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced neurotoxicity.

Materials and methods: Mice were randomized into five groups: Group I mice served as control. Group II mice received 5?×?MPTP [25?mg/kg body weight (i.p.)] in saline 24?h apart starting from the 3rd day and continued till the last day of the experimental period of 7?d. In addition to MPTP injections, mice in Groups III, IV, and V were given FA at a dose of 20, 40, and 80?mg, respectively, for 7?d. Mice were subjected to a battery of behavioral tests along with histological investigations.

Results: Our histological findings revealed that MPTP administration enhanced Bax/Bcl2 ratio and microglial cells activation reflecting induction of apoptosis and inflammation, respectively. This dopaminergic neuronal loss caused impairment in motor balance and coordination in MPTP mice as assessed by various behavioral tests. FA at a dose of 40?mg/kg/d body weight effectively attenuated MPTP-induced neurotoxicity.

Discussion: Antioxidant, free-radical quenching, and anti-inflammatory activities of FA could contribute to its neuroprotective effect.

Conclusion: This study provides elementary evidence for the neuroprotective action of FA against MPTP-induced PD in mice and warrants further studies.     

Natriuretic peptide clearance receptor ligand (C‐ANP4–23) attenuates angiogenesis in a murine sponge implant model

Natriuretic peptide receptor‐C activation by the synthetic ligand C‐ANP‐_4–23, a specific agonist for this receptor, has been shown to inhibit key events of the angiogenic cascade, such as migration, proliferation and vascular endothelial growth factor (VEGF) production. In the present study we investigated whether C‐ANP_4–23 could also inhibit angiogenesis in the sponge model in vivo. To this end, we evaluated the effects of C‐ANP_4–23 on inflammatory and angiogenic components of the fibrovascular tissue induced by polyether polyurethane sponge implants in mice. Measurements of the haemoglobin content (μg/mg wet tissue) and blood flow (laser Doppler perfusion imaging) of the implants, used as an index of vascularization, revealed that single (200 ng) or multiple (200 ng/day, 5 days) doses of C‐ANP_4–23 reduced angiogenesis in the implants relative to the phosphate‐buffered saline‐treated group. The peptide exerted an inhibitory effect on nitric oxide production (nitrite levels) and had a dual effect on VEGF levels, depending on the number of doses (i.e. stimulation at 4 days after one dose; inhibition at 7 days after five doses). Histological analysis corroborated the biochemical and functional parameters indicative of inhibition of neovascularization (decreased vessel number) by C‐ANP_4–23. The peptide failed to modulate inflammation in our system. The inhibitory effect of C‐ANP_4–23 on the angiogenic component of the fibrovascular tissue induced by the synthetic matrix extends the range of the its actions and may indicate its therapeutic potential in controlling angiogenesis in fibroproliferative diseases.     

Effects of Colistin on the Sensory Nerve Conduction Velocity and F‐wave in Mice

The aim of this study was to examine the changes of sensory nerve conduction velocity (SNCV) and F‐wave for colistin‐induced peripheral neurotoxicity using a mouse model. Mice were administered with colistin 5, 7.5 and 15 mg/kg/day via a 3‐min. intravenous infusion. The sensory nerve conduction velocity (SNCV) and F‐wave were measured using the bipolar recording electrodes. The SNCV and F‐wave latency changed in a dose‐ and time‐dependent manner. The significant increase of F‐wave latency and significant decrease of SNCV appeared on day 3 (p < 0.05 and 0.01, respectively) in the 15 mg/kg/day group, and they were markedly changed on day 7 in the 7.5 mg/kg/day (p < 0.01 and 0.05, respectively) and 15 mg/kg/day groups (both p < 0.01). In addition, F‐wave latency also significantly increased on day 7 in the 5 mg/kg/day group (p < 0.05) without any clinical signs. These results indicate that SNCV and F‐wave latency were more sensitive in colistin‐induced neurotoxicity in mice, which highlights the early monitoring tool of polymyxins neurotoxicity in the clinic.     

Studies on the interactions of copper and cannabis

The action of copper (CuSO₄, 5mg/kg, oral) on selected neuropharmacological actions of cannabis resin (CI, oral) was studied on albino rats and mice. Copper potentiated the barbiturate hypnosispotentiating activity of CI in albino rats and mice and had no effect on hypothermic activity in albino rats.Single doses of copper partially inhibited tolerance to barbiturate hypnosis-potentiation activity and markedly delayed the development of tolerance to hypothermic activity of CI. Oral as well as i.c.v. copper (CuSO₄, 0.1 g) in single dose antagonised the tolerance to hypothermic activity of cannabis or THC for to two weeks. Copper-CI interaction could be antagonised by penicillamine. Zinc (ZnSO₄, 5 mg/kg, oral) had an action similar to that of copper in antagonising the development of tolerance to the hypothermic activity of CI, but magnesium (MgSO₄, 5 mg/kg, i.p.) was devoid of any such action.Studies indicate that, although copper has no significant neuropharmacological action, it interacts with CI activity, especially in tolerant rats, in effects on hypothermia. The site of action of copper is possibly the hypothalamus, where it inhibits the processes of tolerance development to CI on the noradrenergic neurone.     

Chronic administration of nicotine fails to alter the MPTP-induced neurotoxicity in mice

1. The effects of chronic (14 day) administration of nicotine on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (15 mg/kg, s.c.)-induced neurotoxicity in C57BL/6 mice were examined. 2. Nicotine pretreatment failed to alter the deficit in locomotor activity and the reduction in striatal levels of dopamine produced by MPTP. 3. Our results do not support a therapeutic action of nicotine in a Parkinsonian animal model.