Intracerebroventricular Injection Of 6-OHDA Research Articles

Fabrication of solid lipid nanoparticles containing vitexin protects dopaminergic neurons against 6-hydroxydopamine induced Parkinson's disease model via altered the genetic backgrounds

Vitexin is a flavonoid which obtained from Crataegus pinnatifida Bunge. Further, its neuroprotective effects are examined in PD model. The motive of the current study was to fabricate vitexin loaded solid lipid nanoparticles and evaluate the effect against 6- hidroxidopamine (6-OHDA) induced parkinson's disease animal model. Intracerebroventricular injection of 6-OHDA was used for induction the PD and mice were treated with the said drug loaded nanocarrier for 28 days. In our study, hot melt emulsification and ultrasonication method was employed for the preparation of Vitexin loaded nanolipoidal carrier. Further, the enzymatic activities incudes Catalase (CAT), superoxide dismutase (SOD), glutathione (GSH) glutathione peroxidase (GPx), glutathione S-transferase (GST), level of reactive oxygen species, total reactive antioxidant dopamine and its metabolite homovanilic and 3, 4-dihydroxyphenylacetic acid, were determined in the striatum. Furthermore, the behavioural parameters including locomotor, memory and depressive were estimated. The Vitexin loaded solid lipid nanoparticles therapeutics in 6-OHDA induced Parkinson's, results clearly showed improvement in total reactive antioxidant, CAT, GPx, Dopamine and its metabolite level in striatum of mice. We also observed that reactive oxygen species in the striatum were diminished by solid lipid nanoparticles of Vitexin. Furthermore, the said formulation is well efficient in averting the memory destruction in Morris water maze test as well as depressive like behaviour in tail suspension test. Vitexin loaded solid lipid nanoparticles founds protective effects in neurodegeneration on 6-OHDA induced neurotoxicity in mice. In features, this could be alternative effective therapeutic approach for the management of PD.

Gelatin nanoparticle-mediated intranasal delivery of substance P protects against 6-hydroxydopamine-induced apoptosis: an in vitro and in vivo study.

BackgroundThe aim of this study was to investigate the protective role of intranasally administered substance P-loaded gelatin nanoparticles (SP-GNPs) against 6-hydroxydopamine (6-OHDA)-induced apoptosis in vitro and in vivo, and to provide a new strategy for treating brain pathology, such as Parkinson’s disease.MethodsSP-GNPs were prepared by a water-in-water emulsion method, and their stability, encapsulating efficiency, and loading capacity were evaluated. PC-12 cells were used to examine the enhancement of growth and inhibition of apoptosis by SP-GNPs in vitro using MTT assays. In the in vivo study, hemiparkinsonian rats were created by intracerebroventricular injection of 6-OHDA. The rats then received intranasal SP-GNPs daily for 2 weeks. Functional improvement was assessed by quantifying rotational behavior, and the degree of apoptosis was assessed by immunohistochemical staining for caspase-3 in the substantia nigra region.ResultsPC-12 cells with 6-OHDA-induced disease treated with SP-GNPs showed higher cell viability than their untreated counterparts, and cell viability increased as the concentration of substance P (SP) increased, indicating that SP could enhance cell growth and inhibit the cell apoptosis induced by 6-OHDA. Rats with 6-OHDA-induced hemiparkinsonism treated with SP-GNPs made fewer rotations and showed less staining for caspase-3 than their counterparts not treated with SP, indicating that SP protects rats with 6-OHDA-induced hemiparkinsonism from apoptosis and therefore demonstrates their functional improvement.ConclusionIntranasal delivery of SP-GNPs protects against 6-OHDA-induced apoptosis both in vitro and in vivo.

Protective effect of hesperidin in a model of Parkinson's disease induced by 6-hydroxydopamine in aged mice

ObjectiveParkinson's disease (PD) may be caused by the interaction of a number of factors, including genetics, toxins, oxidative stress, mitochondrial abnormalities, and aging. Studies have shown that consumption of an antioxidant-rich diet may reduce the incidence of neurodegenerative diseases. The aim of this study was to evaluate the role of the flavonoid hesperidin in an animal model of PD induced by 6-hidroxidopamine (6-OHDA).Methods: Aged mice were treated with hesperidin (50 mg/kg) during 28 d after an intracerebroventricular injection of 6-OHDA. The enzymatic activities of superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase, and glutathione S-transferase, the levels of glutathione, reactive oxygen species, total reactive antioxidant potential, dopamine and its levels of metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid, was analyzed in the striatum. The behavioral parameters (depressive-like, memory, and locomotor) were measured. ResultsThis study demonstrated that hesperidin (50 mg/kg) treatment was effective in preventing memory impairment in the Morris water maze test, as well as, depressive-like behavior in the tail suspension test. Hesperidin attenuated the 6-OHDA-induced reduction in glutathione peroxidase and catalase activity, total reactive antioxidant potential and the dopamine and its metabolite levels in the striatum of aged mice. 6-OHDA increased reactive oxygen species levels and glutathione reductase activity in the striatum, and these alterations were mitigated by chronic administration of hesperidin. ConclusionThis study demonstrated a protective effect of hesperidin on the neurotoxicity induced by 6-OHDA in aged mice, indicating that it could be useful as a therapy for the treatment of PD.

Neuroprotective Effect of <i>trans</i>-Cinnamaldehyde on the 6-Hydroxydopamine-Induced Dopaminergic Injury

The anti-inflammatory and neuroprotective effects of trans-cinnamaldehyde (TCA) were investigated on the inflammatory cells and the dopaminergic degeneration in mice. TCA inhibited the up-regulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in the lipopolysaccharide (LPS)-induced inflammatory BV2 microglial cells. To investigate the TCA efficacy on the 6-hydroxydopamine (6-OHDA)-induced dopaminergic degeneration in mice, an intracerebroventricular injection of 6-OHDA was given to the mice, and TCA (30 mg/kg) was intraperitoneally administered. At 7 d after the 6-OHDA injection, 6-OHDA led to a severe loss of tyrosine hydroxylase (TH)-positive dopaminergic neurons in the striatum and substantia nigra (SN). On the other hand, TCA dramatically maintained the number of TH-positive dopaminergic neurons in the striatum and SN regions of the 6-OHDA-treated mice, which indicates that TCA is able to inhibit the 6-OHDA-induced reduction of TH expression in the dopaminergic neurons in the striatum and SN regions. TCA also inhibited the induction of iNOS and COX-2 in the 6-OHDA model, similarly as shown in the LPS-induced inflammatory BV2 microglial cells. These results indicate that TCA has a neuroprotective effect on dopaminergic neurons and that this effect may be associated with the inhibition of inflammatory responses. These findings suggest that TCA may be a therapeutic candidate for the prevention of inflammation-mediated neurodegenerative diseases.

Feeding and Drinking Responses and Hypothalamic Monoamine Concentrations of Neonatal Chicks Following Intracerebroventricular Injection of 6-OHDA

Bungo, T., Tachibana, T., Sashihara, K., Kawakami, S.-I., Ohgushi A., Furuse, M. and Ueda, H. 2002. Feeding and drinking responses and hypothalamic monoamine concentrations of neonatal chicks following intracerebroventricular injection of 6-OHDA. J. Appl. Anim. Res., 22: 183–192. To clarify the involvement of catecholaminergic systems in the regulation of food and water intake in the neonatal chick, 6-hydroxydopamine (6-OHDA) or fusaric acid (FA) was administered intracerebroventricularly ICV) and the concentrations of monoamine in the hypothalamus were determined. We found that food intake was significantly increased by ICV injection of 6-OHDA (25, 50 and 100 μg) until 60 min after injection, but the effect disappeared at 120 min. Although both 6-OHDA and FA had no significant effect on water intake, the water consumption in chicks treated with FA tended to be higher than that with saline (control). Norepinephrine (NE) in the hypothalamus was reduced in chicks treated with 6-OHDA (P<0.05). These results indicate that changes in NE concentration of the hypothalamus mainly influence food intake in chicks.

Levodopa and dopamine agonists in the treatment of Parkinson's disease: advantages and disadvantages.

Recent studies have suggested that free radicals play a key role in the progression of Parkinson's disease (PD). Although levodopa is the most effective therapeutic agent in the treatment of PD and has improved the quality of life and increased life expectancy, its beneficial effects are not permanent. Long-term treatment with levodopa produces a variety of side effects in patients with PD. We have previously reported that levodopa may accelerate the progression of PD in certain patients. To determine whether neuronal damage can be caused by levodopa overdoses, we estimated the effects of levodopa on free radical formation. Electron spin resonance spectrometry showed that levodopa oxidation produced levodopa radicals. Furthermore, chronic administration of levodopa increased thiobarbituric acid-reacting substances (TBARS) in various brain regions of 6-hydroxydopamine (6-OHDA; i.c.v.)-pretreated mice, although levodopa administration in control mice had no effect on TBARS. These results indicate that high dose levodopa accelerates neuronal degeneration in some parkinsonian brains. We then evaluated the protective effects of bromocriptine on striatal dopaminergic neurons, with determination of dopamine (DA) and its metabolites as markers. Pretreatment of bromocriptine completely protected mice against the decreases in striatal DA and its metabolites induced by intracerebroventricular injection of 6-OHDA, while levodopa/carbidopa had no protective effects. Furthermore, in an in vitro system that generated .OH from FeSO4-H2O2, bromocriptine dose-dependently scavenged .OH. These findings clearly indicate that bromocriptine has neuroprotective effects against neurotoxins such as 6-OHDA, probably due in part to its free redical scavenging activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Locus ceruleus modulates migrating myoelectric complex in rats.

The role of the locus ceruleus (LC) in the control of migrating myoelectric complex (MMC) was investigated in rats with lesions induced by injections of 6-hydroxydopamine (6-OHDA). Control animals received the vehicle alone. MMC was recorded in conscious rats chronically fitted with electrodes. After 6-OHDA was injected into the LC, lesions of the LC were total, partial (mostly rostral), or ineffective. The MMC period was significantly longer in animals with a total or partial lesion but was unchanged in animals with an ineffective lesion. No lesion of other brain noradrenergic nuclei was observed. The longer MMC period is comparable to that obtained after intracerebroventricular injection of 6-OHDA, which is responsible for a more diffuse destruction of brain noradrenergic systems, including LC itself. Bilateral lesions of the central tegmental tract, which carries ascending noradrenergic axons from the medullary and pontine cell groups outside the LC, do not alter the MMC cycle. Consequently, the LC is most likely the major brain noradrenergic candidate for modulating the MMC pattern in rats.

The Iron Chelator Desferrioxamine (Desferal) Retards 6‐Hydroxydopamine‐Induced Degeneration of Nigrostriatal Dopamine Neurons

A selective increase in content of iron in the pars compacta of the substantia nigra has been implicated in the biochemical pathology of Parkinson's disease. Iron is thought to induce oxidative stress by liberation of oxygen free radicals from H2O2. Because 6-hydroxydopamine (6-OHDA) is thought to induce nigrostriatal dopaminergic neuronal lesions via metal-catalyzed free radical formation, the effect of the iron chelator desferrioxamine was investigated on 6-OHDA-induced dopaminergic neuron degeneration in the rat. Intracerebroventricular injection of 6-OHDA (250 micrograms) caused a 88, 79, and 70% reduction in striatal tissue content of dopamine (DA), 3,4-dihydroxyphenylacetic acid, and homovanillic acid (HVA), respectively, and a 2.5-fold increase in DA release as indicated by the HVA/DA ratio. Prior injection of desferrioxamine (130 ng i.c.v.) resulted in a significant protection (approximately 60%) against the 6-OHDA-induced reduction in striatal DA content and a normalization of DA release. Dopaminergic-related behavioral responses, such as spontaneous movements in a novel environment and rearing, were significantly impaired in the 6-OHDA-treated group. By contrast, the desferrioxamine-pretreated rats exhibited almost normal behavioral responses. The ability of iron chelators to retard dopaminergic neurodegeneration in the substantia nigra may indicate a new therapeutic strategy in the treatment of Parkinson's disease.

Use of 6-hydroxydopamine to deplete brain catecholamines in the rhesus monkey: effects on urinary catecholamine metabolites and behavior.

The purpose of this study was to determine: 1) whether 6-hydroxydopamine (6-OHDA), previously shown to deplete brain catecholamines (CA) in rodents, depletes brain CA in rhesus monkeys; 2) whether depletion of brain CA produces changes in behavior; and, 3) whether urinary output of 3-methoxy-4-hydroxyphenylglycol (MHPG) reflects brain norepinephrine (NE) depletions. Repeated intracerebroventricular (ICV) injection of 6-OHDA (N = 20; 15.5-73.3 mg/subject) produced chronic changes in social behavior and, at higher dosages, reduced output of urinary MHPG. However, 4 weeks after the last ICV 6-OHDA injection, urinary MHPG excretion returned to baseline values and whole brain CA content was not reliably different from control. A single treatment with 6-OHDA microinjected into the substantia nigra (SN) (N = 12; 120-240 microgram/subject) produced chronic whole brain depletions of brain CA without depleting serotonin. Reductions in brain CA were associated with a specific set of motor behaviors, aphagia, and adipsia. SN 6-OHDA produced greater brain NE depletions than ICV 6-OHDA, but urinary MHPG output was not reduced. SN 6-OHDA treated subjects showed chronic changes in social behavior and were more sensitive to the operant response rate decreasing effects of alpha-methyl-para-tyrosine (AMPT) than control subjects. Subjects with the largest depletions of brain dopamine (DA) (greater than 90%) were hypokinetic, rigid, and had a distal limb tremor. These results show that SN but not ICV injection of 6-OHDA can deplete brain CA in the rhesus monkey. The most prominent behavioral changes were characterized by disturbances in motor function. Urinary MPHG output does not reflect depletions of brain NE in this species.