Decreased Dopamine Levels Research Articles

Propagated but topologically distributed forebrain neurons expressing alpha-synuclein in aged macaques

In neurodegenerative disorders, such as Parkinson's disease (PD), alpha-synuclein (α-syn) accumulates to induce cell death and/or form a cytoplasmic inclusion called Lewy body (LB). This α-syn-related pathology is termed synucleinopathy. It remains unclear how α-syn accumulation expands during the progress of synucleinopathy in the human brain. In our study, we investigated the patterns of distribution and propagation of forebrain neurons expressing α-syn in aged macaques. It was found that the occurrence of α-syn-positive neurons proceeded topologically based on the midbrain dopamine pathways arising from the substantia nigra and the ventral tegmental area where they were primarily observed. In the nigrostriatal or mesolimbic dopamine pathway, the age-dependent increase in α-syn-positive neurons was evident in the striatum or the nucleus accumbens, respectively. Concerning the nigrostriatal pathway, a mediolateral or rostrocaudal gradient was seen in the substantia nigra or the striatum, respectively, and a compensatory increase in dopamine transporter occurred in the striatum regardless of the decreased dopamine level. In the mesocortical dopamine pathway, α-syn-positive neurons appeared in the prefrontal and then motor areas of the frontal lobe. Given that neither LB formation nor clinical phenotype manifestation was detected in any of the monkeys examined in the present study, aged macaques may be useful as a potential presymptomatic model for PD and LB-related neuropsychiatric disorders.

Paraquat exposure-induced Parkinson’s disease-like symptoms and oxidative stress in Drosophila melanogaster: Neuroprotective effect of Bougainvillea glabra Choisy

Extracts from the leaves of Bougainvillea glabra Choisy are used in traditional medicines, but their actions on the central nervous system have not been studied. In the present study, we investigated the potential neuroprotective effects of Bougainvillea glabra Choisy leaf extract (BG extract) against paraquat (PQ)-induced neurotoxicity. Male adult wild-type flies (1- 4days old) were exposed to PQ (3.5mM) and/or BG extract (120μg/mL) through food for 4days. PQ-fed flies had decreased locomotor capacity in negative geotaxis and crossing number assays and had a higher incidence of mortality than the control group. PQ neurotoxicity was also associated with a marked decrease in dopamine levels and increase in acetylcholinesterase (AChE) activity, reactive oxygen species (ROS) production and lipid peroxidation. Co-exposure to BG extract prevented mortality, and dopamine depletion, improved locomotor performance and decreased AChE activity, ROS production and lipid peroxidation. GC–MS and HPLC analyses of BG extract revealed the presence of many antioxidant compounds such as phytol, α,γ-tocopherol, squalene, stigmasterol, geranylgeraniol, quercetin, and caffeic, vanillic, coumaric, ferulic acids. Our results showed neuroprotective effects of BG extract, reflecting the presence of antioxidant compounds. Thus, we suggested that B. glabra leaves could be considered an effective agent in the prevention of neurological disorders, where dopamine depletion and/or oxidative stress are involved, as in Parkinson’s disease (PD).

El tabaquismo: una adicción

El tabaquismo es factor de riesgo y a la vez una adicción compleja con componentes físicos, psicológicos y sociales. Adicción es la necesidad compulsiva de volver a consumir una droga para experimentar sus efectos, en el caso la nicotina, estimulación, euforia, placer, aumento de la atención concentración y memoria, además de disminución de la ansiedad, estrés y apetito. El Manual Diagnóstico y Estadístico de los Trastornos Mentales (DSM V) cataloga el tabaquismo como una adicción, la nicotina es una de las drogas más adictivas que existen, junto con la cocaína y la heroína, además demora 10 segundos en llegar al cerebro cuando se fuma. La nicotina se relaciona con distintos sistemas de neurotransmisión en el sistema nervioso central, es agonista de los receptores α4β2 de acetilcolina, siendo la unión receptor- neurotransmisor de alta sensibilidad. Las vías neurofisiológicas más importes implicadas en la dependencia por la nicotina son dopaminérgica (la más importante), noradrenérgica, GABA-érgica, glutamatérgica y endocanabinoide. El síndrome de abstinencia es una característica básica de la adicción, y es un conjunto de síntomas y signos, físicos y psíquicos que aparecen como consecuencia de la interrupción, reducción o abandono del tabaco. El síndrome de abstinencia se produce como consecuencia de varios factores: disminución de los niveles de cortisol plasmáticos, disminución de los niveles de noradrenalina en el Locus Coeruleous (LC) y principalmente disminución de los niveles de dopamina en el Núcleo Accumbens.

Differential effects of neonatal SSRI treatments on hypoxia-induced behavioral changes in male and female offspring

Prenatal hypoxia induced by transient intrauterine ischemia is a serious clinical problem, and at present, effective treatments are lacking. Currently, it is unknown how prenatal hypoxia affects behaviors in adulthood. Therefore, we developed a mouse model that mimics prenatal hypoxia in humans using uterine artery occlusion in late gestation. We examined whether prenatal hypoxia induces behavioral changes in adult male and female offspring by conducting a series of behavioral tests. In adulthood, longer immobility was observed in the forced swim test in males, whereas females showed decreased inhibition in the prepulse inhibition test. We then investigated the effects of two different selective serotonin reuptake inhibitors (SSRIs), fluoxetine (FLX) and escitalopram (ESC), on these behavioral changes. These drugs affect the neurodevelopmental process and have long-term neurological consequences. FLX treatment from postnatal day 3 (P3) to P21 ameliorated the behavioral changes in both male and female mice. In comparison, ESC treatment ameliorated the behavioral changes only in female mice. Neurochemical analysis revealed that dopamine was increased in the female hippocampus, but not in males. Thus, neonatal SSRI treatment decreases dopamine levels in the hippocampus in females selectively. Our findings suggest that prenatal hypoxia is a risk factor for behavioral abnormalities in adulthood, and that neonatal SSRI treatment might have clinical potential for alleviating these long-term behavioral deficits.

Developmental neurotoxic effects of graphene oxide exposure in zebrafish larvae (Danio rerio)

Although graphene oxide (GO), a nanomaterial with hexagonal planar layer, has been widely studied due to its applications in neurobiology that include drug delivery and tissue engineering, additional studies to assess its potential toxic effects are still needed. Thus, this study evaluated the effects of GO exposure (at 5, 10, 50 or 100mg/L) during six consecutive days on mortality, hatching, spontaneous movement, heart rate, morphology, locomotion behavior, acetylcholinesterase (AChE) activity, dopamine levels and relative gene expression of developmental neurology-related genes using zebrafish larvae. In the 5mg/L dose, synapsin IIa expression up-regulation was seen concomitantly with down-regulation of dat expression, showing a potential compensatory mechanism. Moreover, the 10mg/L exposure caused an increase in heart rate, in absolute turn angle, brain cell damage and a decrease in dopamine levels. These alterations may be associated with autophagosome formation found in GO-exposed larval brain. No changes were observed on higher doses of GO exposure, probably due to nanomaterial agglomeration. Taken together, these results show that toxic effects of GO exposure are not dose-dependent, and are preeminent in lower concentrations. Additional studies are needed to deepen the specific mechanisms of GO neurotoxicity and are required to elucidate its potential biomedical use.

Identification of potential therapeutic compounds for Parkinson's disease using Drosophila and human cell models

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. It is caused by a loss of dopaminergic neurons in the substantia nigra pars compacta, leading to a decrease in dopamine levels in the striatum and thus producing movement impairment. Major physiological causes of neurodegeneration in PD are oxidative stress (OS) and mitochondrial dysfunction; these pathophysiological changes can be caused by both genetic and environmental factors. Although most PD cases are sporadic, it has been shown that 5–10% of them are familial forms caused by mutations in certain genes. One of these genes is the DJ-1 oncogene, which is involved in an early-onset recessive PD form. Currently, PD is an incurable disease for which existing therapies are not sufficiently effective to counteract or delay the progression of the disease. Therefore, the discovery of alternative drugs for the treatment of PD is essential. In this study we used a Drosophila PD model to identify candidate compounds with therapeutic potential for this disease. These flies carry a loss-of-function mutation in the DJ-1β gene, the Drosophila ortholog of human DJ-1, and show locomotor defects reflected by a reduced climbing ability. A pilot modifier chemical screen was performed, and several candidate compounds were identified based on their ability to improve locomotor activity of PD model flies. We demonstrated that some of them were also able to reduce OS levels in these flies. To validate the compounds identified in the Drosophila screen, a human cell PD model was generated by knocking down DJ-1 function in SH-SY5Y neuroblastoma cells. Our results showed that some of the compounds were also able to increase the viability of the DJ-1-deficient cells subjected to OS, thus supporting the use of Drosophila for PD drug discovery. Interestingly, some of them have been previously proposed as alternative therapies for PD or tested in clinical trials and others are first suggested in this study as potential drugs for the treatment of this disease.

Investigating the effects of norepinephrine α1 receptor blockade on dopamine levels: A pilot PET study with [11 C]-(+)-PHNO in controls.

Interest in a role for norepinephrine (NE) in substance use disorders has increased over recent years. In particular, its interaction with dopamine (DA) is of importance. In this study, positron emission tomography (PET) was used to explore the impact of prazosin (an alpha 1 NE antagonist) on DA levels. Healthy volunteers were administered prazosin for approximately 4 weeks at the daily dose of 15 mg to reach steady state. Participants were scanned with PET imaging and the [11 C]-(+)-PHNO tracer at baseline (before prazosin), at steady state, and after a wash out period. Prazosin administration was associated with an increase of [11 C]-(+)-PHNO binding potential in the dorsal caudate relative to baseline, which corresponds to a decrease in DA levels. This study is the first to demonstrate interactions between DA and NE in healthy humans.

Dopamine modulates astroglial and microglial activity via glial renin-angiotensin system in cultures

Dopamine is an immunomodulatory molecule that acts on immune effector cells both in the CNS and peripheral tissues. However, the role of changes in dopamine levels in the neuroinflammatory response is controversial. The local/paracrine renin-angiotensin system (RAS) plays a major role in inflammatory processes in peripheral tissues and brain. In the present study, we investigated the possible role of the brain RAS in the effects of dopamine on the glial inflammatory responses. Astrocytes are the major source of the precursor protein angiotensinogen and angiotensin II (AII) in the brain. Neurotoxins such as MPP+ (1-methyl-4-phenylpyridinium) can act directly on astrocytes to increase levels of angiotensinogen and AII. Conversely, dopamine, via type-2 (D2) receptors, inhibited production of angiotensinogen, decreased expression of angiotensin type-1 (AT1) receptors and increased expression of AT2 receptors. In microglia, dopamine and dopamine agonists also regulated RAS activity. First, indirectly, via downregulation of the astrocyte-derived AII. Second, via dopamine-induced regulation of microglial angiotensin receptors. Dopamine decreased the microglial AT1/AT2 ratio leading to inhibition of the pro-inflammatory AT1/NADPH-oxidase/superoxide axis. D2 receptors were particularly responsible for microglial RAS inhibition in basal culture conditions. However, both D1 and D2 agonists inhibited the AT1/NADPH-oxidase axis in lipopolysaccharide-treated (LPS; i.e. activated) microglia. The results indicate that the decrease in dopamine levels observed in early stages of Parkinson’s disease and aging may promote neuroinflammation and disease progression via glial RAS exacerbation.

Western Diet Chow Consumption in Rats Induces Striatal Neuronal Activation While Reducing Dopamine Levels without Affecting Spatial Memory in the Radial Arm Maze.

Rats fed high fat diets have been shown to be impaired in hippocampal-dependent behavioral tasks, such as spatial recognition in the Y-maze and reference memory in the Morris water maze (MWM). It is clear from previous studies, however, that motivation and reward factor into the memory deficits associated with obesity and high-fat diet consumption, and that the prefrontal cortex and striatum and neurotransmitter dopamine play important roles in cognitive performance. In this series of studies we extend our research to investigate the effect of a high fat diet on striatal neurochemistry and performance in the delayed spatial win-shift radial arm maze task, a paradigm highly reliant on dopamine-rich brain regions, such as the striatum after high fat diet consumption. Memory performance, neuronal activation and brain dopaminergic levels were compared in rats fed a “Western” (21% fat, 0.15% cholesterol) chow diet compared to normal diet (6% fat, 0.15% cholesterol)-fed controls. Twelve weeks of dietary manipulation produced an increase in weight in western diet-fed rats, but did not affect learning and performance in the delayed spatial win-shift radial arm maze task. Concurrently, there was an observed decrease in dopamine levels in the striatum and a reduction of dopamine turnover in the hippocampus in western diet-fed rats. In a separate cohort of rats Fos levels were measured after rats had been placed in a novel arena and allowed to explore freely. In normal rats, this exposure to a unique environment did not affect neuronal activation. In contrast, rats fed a western diet were found to have significantly increased Fos expression in the striatum, but not prefrontal cortex or hippocampus. Our study demonstrates that while western diet consumption in rats produces weight gain and brain neuronal and neurotransmitter changes, it did not affect performance in the delayed spatial win-shift paradigm in the radial arm maze. We conclude that modeling the cognitive decline-obesity relationship is complex with considerations, of type of memory, behavioral task and dietary intervention (fat, fat and sugar, sugar, and cafeteria diets) all adding to our overall understanding.

Recombinant AAV8-mediated intrastriatal gene delivery of CDNF protects rats against methamphetamine neurotoxicity

Methamphetamine (METH) exerts significant neurotoxicity in experimental animals and humans when taken at high doses or abused chronically. Long-term abusers have decreased dopamine levels, and they are more likely to develop Parkinson's disease (PD). To date, few medications are available to treat the METH-induced damage of neurons. Glial cell line-derived neurotrophic factor (GDNF) has been previously shown to reduce the dopamine-depleting effects of neurotoxic doses of METH. However, the effect of cerebral dopamine neurotrophic factor (CDNF), which has been reported to be more specific and efficient than GDNF in protecting dopaminergic neurons against 6-OHDA toxicity, in attenuating METH neurotoxicity has not been determined. Thus, the present study aimed to evaluate the neuroprotective effect of CDNF against METH-induced damage to the dopaminergic system in vitro and in vivo. In vitro, CDNF protein increased the survival rate and reduced the tyrosine hydroxylase (TH) loss of METH-treated PC12 cells. In vivo, METH was administered to rats following human CDNF overexpression mediated by the recombinant adeno-associated virus. Results demonstrated that CDNF overexpression in the brain could attenuate the METH-induced dopamine and TH loss in the striatum but could not lower METH-induced hyperthermia.

Effects of Tramadol Addiction on Brain of Adult Male Albino Rats and Role of lofexidine during Withdrawal Period: A Biochemical, Histopathological and Immunohistochemical Study

Background: Tramadol is a synthetic opioid analgesic commonly prescribed for moderate to severe pain, becoming abused more popular among teens in most countries. In addition to the euphoric and mood-enhancing effects sought by tramadol abusers, taking this drug for nonmedical purposes, abusing tramadol can lead to tolerance and dependence. Abusers who continue to take tramadol long enough and at high enough doses will eventually develop a physical dependence on the drug and experience unpleasant, or even dangerous, symptoms of withdrawal if they stop taking the medication. Objective: To study the biochemical, histopathological and immunohistochemical changes of repeated administration of tramadol on the brain cells of male albino rats and role of duration of addiction in the damaging effects produced, and to prove if there is a role for lofexidine in the treatment of tramadol addiction in withdrawal period and detect the changes after recovery period and withdrawal of tramadol .Materials and methods: 100 adult male albino rats were randomly divided into equal 5groups: Group I: (20 rats) Control group: including those given normal feeding. Group II: (20 rats) Tramadol treated group for one month. Group III: (20 rats) Tramadol treated group for 2 months. Group IV: (20 rats) Tramadol treated for one month then given lofexidine for another month during withdrawal. Group V: (20 rats) Tramadol treated for one month and left for another month for recovery. Animals were observed for any behavioral changes throughout the research and recorded. At the end of the experiment animals were scarified by cervical dislocation under inhalation anesthesia, autopsy was done and the brain specimens were obtained, prepared for biochemical study for dopamine level and others preserved for histopathological and immunohistochemical study with their specific procedures. Results: Repeated Tramadol administration resulted in rats behavioral changes( restlessness, irritability defensive aggressive reactions) and produced decreased dopamine levels and significant brain damage in the histopathological and immunohistochemical study that increased with increased period of intake (The maximum damage was recorded in group III with two months tramadol administration, varying degrees of recovery after stoppage of intake were noted in Group V and more improvement by Lofexidine treatment in Group IV). Conclusions: Repeated Tramadol administration causes degenerative changes on the rat brain which increased with increasing the period of this administration. Some improvement was detected after stoppage and more improvement with Lofexidine treatment in withdrawal period.

Examination of the Role of NMDA and GABAA Receptors in the Effects of Hyperbaric Oxygen on Striatal Dopamine Levels in Rats.

Hyperbaric oxygen induced in rats a decrease in striatal dopamine levels. Such decrease could be a result of changes in glutamatergic and GABAergic controls of the dopaminergic neurons into the Substantia Nigra Pars Compacta. The aim of this study was to determine the role of gluatamatergic and Gama-Amino-Butyric-Acid neurotransmissions in this alteration. Dopamine-sensitive electrodes were implanted into the striatum under general anesthesia. After one week rest, awaked rats were exposed to oxygen-nitrogen mixture at a partial pressure of oxygen of 3 absolute atmospheres. Dopamine level was monitored continuously (every 3min) by in vivo voltammetry with multifiber carbon electrodes before and during hyperbaric oxygen exposure. Hyperbaric oxygen induced a decrease in dopamine level in relationship with the increase in partial pressure of oxygen (-40% at 3 ATA). The used of N-Methyl-D-Aspartate, agonist of glutamatergic N-Methyl-D-Aspartate receptors did not improve considerably this change and gabazine antagonist of Gama-Amino-Butyric-Acid-a receptors induced some little alteration of this change. These results suggest the involvement of other mechanisms.

Propagated but Topologically Distributed Forebrain Neurons Expressing Alpha-Synuclein in Aged Macaques.

In neurodegenerative disorders, such as Parkinson's disease (PD), alpha-synuclein (α-syn) accumulates to induce cell death and/or form a cytoplasmic inclusion called Lewy body (LB). This α-syn-related pathology is termed synucleinopathy. It remains unclear how α-syn accumulation expands during the progress of synucleinopathy in the human brain. In our study, we investigated the patterns of distribution and propagation of forebrain neurons expressing α-syn in aged macaques. It was found that the occurrence of α-syn-positive neurons proceeded topologically based on the midbrain dopamine pathways arising from the substantia nigra and the ventral tegmental area where they were primarily observed. In the nigrostriatal or mesolimbic dopamine pathway, the age-dependent increase in α-syn-positive neurons was evident in the striatum or the nucleus accumbens, respectively. Concerning the nigrostriatal pathway, a mediolateral or rostrocaudal gradient was seen in the substantia nigra or the striatum, respectively, and a compensatory increase in dopamine transporter occurred in the striatum regardless of the decreased dopamine level. In the mesocortical dopamine pathway, α-syn-positive neurons appeared in the prefrontal and then motor areas of the frontal lobe. Given that neither LB formation nor clinical phenotype manifestation was detected in any of the monkeys examined in the present study, aged macaques may be useful as a potential presymptomatic model for PD and LB-related neuropsychiatric disorders.

Activation and blockade of serotonin6 receptors in the dorsal hippocampus enhance T maze and hole-board performance in a unilateral 6-hydroxydopamine rat model of Parkinson's disease

The role of dorsal hippocampus (DH) serotonin6 (5-HT6) receptors in memory is unknown, particularly in memory impairment of Parkinson's disease. We tested here effects of activation and blockade of DH 5-HT6 receptors on working and hippocampus-dependent memories in rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle. The lesion induced working and hippocampus-dependent memory impairments as measured by the T-maze rewarded alternation and hole-board tests, and decreased dopamine (DA) levels in the striatum, medial prefrontal cortex (mPFC), DH and amygdala. Intra-DH injection of 5-HT6 receptor agonist WAY208466 (1.5, 3 and 6µg/rat) did not change choice accuracy and the number of head-dippings when re-exposure to hole-board in sham-operated rats, while 5-HT6 receptor antagonist SB258585 (4µg/rat) increased choice accuracy and decreased the number of head-dippings. In the lesioned rats, both WAY208466 (3 and 6µg/rat) and SB258585 (2 and 4µg/rat) increased choice accuracy and decreased the number of head-dippings. Neurochemical results showed that intra-DH injection of WAY208466 or SB258585 produced significant effects on DA and noradrenaline (NA) levels in the mPFC (WAY208466: sham-operated, NA −44%; lesioned, DA 522%, NA −47%; SB258585: sham-operated, DA 72%, NA 85%; lesioned, DA −68%), DH (WAY208466: lesioned, DA 427%; SB258585: sham-operated, DA 119%, NA 206%) and amygdala (WAY208466: sham-operated, NA −28%; lesioned, DA 302%; SB258585: sham-operated, NA 183%); however, 5-HT levels in these brain regions were not changed. These findings suggest DA depletion plays a key role in working and hippocampus-dependent memory impairments, and 5-HT6 receptors in the DH are involved in the regulation of the memories.

Simultaneous visual sustained attention-discrimination and goal-directed search are associated with excretion of catecholaminergic metabolites in children with attention-deficit/hyperactivity disorder

The relationship between visual sustained attention-discrimination and goal-directed search was evaluated using a visual discrimination and exploration (goal-directed search) paradigm and urinary excretion of catecholaminergic metabolites [dopamine (DA) and norepinephrine (NE)] in 6–12 year-old children ( n = 31) strictly selected and diagnosed with attention-deficit/hyperactivity disorder (ADHD) using diagnostic criteria and other objective indices. The Structured Clinical Interview (SCID) (DSM-IV) was used to formally diagnose ADHD in children. A cognitive laboratory test was used to assess visual sustained attention-discrimination and goal-directed search (Children Color Trails Test 1 and 2). Urinary excretion of DA and NE metabolites was measured via reversed high-pressure liquid chromatography (HPLC). Pearson product-moment correlations were used to investigate the relationship between visual sustained attention and goal-directed search and urinary catecholamine metabolites of DA and NE. The present findings revealed a positive and moderately significant relationship between visual sustained attention and visual exploration and catecholaminergic metabolite levels of NE and DA, according to expectation. Decreased visual sustained attention and goal-directed search was associated with decreased DA and NE metabolite levels. The present results are consistent with past research with children with ADHD and studies with primates examining the intricate and respective interaction between the Locus Coeruleus and visual sustained attention-discrimination and the Ventral Tegmental Area and goal-directed search (visual exploration) respectively modulated through NE and DA. Applied and theoretical issues associated with the present findings also are discussed addressing recent computer-generated analogues of action selection models within the context of the extant findings.

Switch from excitatory to inhibitory actions of ethanol on dopamine levels after chronic exposure: Role of kappa opioid receptors

Acute ethanol exposure is known to stimulate the dopamine system; however, chronic exposure has been shown to downregulate the dopamine system. In rodents, chronic intermittent exposure (CIE) to ethanol also increases negative affect during withdrawal, such as, increases in anxiety- and depressive-like behavior. Moreover, CIE exposure results in increased ethanol drinking and preference during withdrawal. Previous literature documents reductions in CIE-induced anxiety-, depressive-like behaviors and ethanol intake in response to kappa opioid receptor (KOR) blockade. KORs are located on presynaptic dopamine terminals in the nucleus accumbens (NAc) and inhibit release, an effect which has been linked to negative affective behaviors. Previous reports show an upregulation in KOR function following extended CIE exposure; however it is not clear whether there is a direct link between KOR upregulation and dopamine downregulation during withdrawal from CIE. This study aimed to examine the effects of KOR modulation on dopamine responses to ethanol of behaving mice exposed to air or ethanol vapor in a repeated intermittent pattern. First, we showed that KORs have a greater response to an agonist after moderate CIE compared to air exposed mice using ex vivo fast scan cyclic voltammetry. Second, using in vivo microdialysis, we showed that, in contrast to the expected increase in extracellular levels of dopamine following an acute ethanol challenge in air exposed mice, CIE exposed mice exhibited a robust decrease in dopamine levels. Third, we showed that blockade of KORs reversed the aberrant inhibitory dopamine response to ethanol in CIE exposed mice while not affecting the air exposed mice demonstrating that inhibition of KORs “rescued” dopamine responses in CIE exposed mice. Taken together, these findings indicate that augmentation of dynorphin/KOR system activity drives the reduction in stimulated (electrical and ethanol) dopamine release in the NAc. Thus, blockade of KORs is a promising avenue for developing pharmacotherapies for alcoholism.

Efecto neuroprotector de fitoquímicos en cultivo de neuronas dopaminérgicas

IntroductionParkinson's disease is a progressive neurodegenerative disorder characterised by a loss of dopaminergic neurons in the substantia nigra pars compacta, which results in a significant decrease in dopamine levels and consequent functional motor impairment. DevelopmentAlthough its aetiology is not fully understood, several pathogenic mechanisms, including oxidative stress, have been proposed. Current therapeutic approaches are based on dopamine replacement drugs; these agents, however, are not able to stop or even slow disease progression. Novel therapeutic approaches aimed at acting on the pathways leading to neuronal dysfunction and death are under investigation. ConclusionsIn recent years, such natural molecules as polyphenols, alkaloids, and saponins have been shown to have a neuroprotective effect due to their antioxidant and anti-inflammatory properties. The aim of our review is to analyse the most relevant studies worldwide addressing the benefits of some phytochemicals used in in vitro models of Parkinson's disease.

Multifunction of Chrysin in Parkinson's Model: Anti-Neuronal Apoptosis, Neuroprotection via Activation of MEF2D, and Inhibition of Monoamine Oxidase-B.

Chrysin, a flavonoid compound existing in several plants, is applied as a dietary supplement because of its beneficial effects on general human health and alleviation of neurological disorders. However, mechanisms underlying neuroprotection of chrysin has not been fully elucidated, and the effects of chrysin on the Parkinson's disease (PD) model in vivo have not been investigated. It is here shown that chrysin protects primary granular neurons against 1-methyl-4-phenylpyridinium ion insult via antiapoptosis by reversing the dysregulated expression of Bcl-2, Bax, and caspase 3. The mechanisms also involved activating transcriptional factor myocyte enhancer factor 2D (MEF2D) via regulation of AKT-GSK3β signaling. In this in vivo model of PD, chrysin rescued the dopaminergic neurons loss and alleviated the decrease in dopamine level induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice. Moreover, chrysin markedly inhibited monoamine oxidase-B activity in vitro and in vivo. In conclusion, chrysin exerts beneficial effects to PD, possibly through multitarget mechanisms including antineuronal apoptosis, activation of the AKT-GSK3β/MEF2D pathway, and inhibition of the MAO-B activity.

Current treatments in Parkinson's including the proposal of an innovative dopamine microimplant

Parkinson's disease is a chronic, debilitating, progressive neurological disorder of multifactorial origin. It affects between 0.3% and 2% of the over-65 population worldwide, with a predilection for men, and is characterised by bradykinesia, muscular rigidity, resting tremor and postural instability. Parkinson's is caused by decreased dopamine levels due to the loss of dopaminergic neurons in the substantia nigra. Because dopamine is a highly oxidisable molecule, precursors such as levodopa, together with catechol-O-methyltransferase and monoamine oxidase inhibitors to prevent degradation, are used in the treatment of this disease. These therapies, however, are not without their adverse effects. Surgical treatments for Parkinson's include pallidotomy, therapy deep brain stimulation, and stem cells. A more recent development involves a titanium dioxide micro-implant containing nanopores that stabilise the dopamine for continuous release. When inserted into the caudate nucleus, this micro-implant was found to counteract 85% of symptoms in hemiparkinsonian rats, and is a promising therapy for patients with Parkinson's disease.

Adaptation within mitochondrial oxidative phosphorylation supercomplexes and membrane viscosity during degeneration of dopaminergic neurons in an animal model of early Parkinson's disease

In Parkinson's disease (PD) motor symptoms are not observed until loss of 70% of dopaminergic neurons in substantia nigra (SN), preventing early diagnosis. Mitochondrial dysfunction was indicated in neuropathological process already at early PD stages. Aging and oxidative stress, the main factors in PD pathogenesis, cause membrane stiffening, which could influence functioning of membrane-bound oxidative phosphorylation (OxPhos) complexes (Cxs) in mitochondria.In 6-OHDA rat model, medium-sized dopaminergic lesion was used to study mitochondrial membrane viscosity and changes at the level of OxPhos Cxs and their higher assembled states—supercomplexes (SCxs), during the early degeneration processes and after it.We observed loss of dopaminergic phenotype in SN and decreased dopamine level in striatum (STR) before actual death of neurons in SN. Behavioural deficits induced by lesion were reversed despite progressing neurodegeneration. Along with degeneration process in STR, mitochondrial Cx I performance and amount decreased in almost all forms of SCxs. Also, progressing decrease of Cx IV performance in SCxs (I1III2IV3–1, I1IV2–1) in STR was observed during degeneration. In SN, SCxs containing Cx I increased protein amount and a shifted individual Cx I1 into superassembled states. Importantly, mitochondrial membrane viscosity changed in parallel with altered SCxs performance.We show for the first time changes at the level of mitochondrial membrane viscosity influencing SCxs function after dopaminergic system degeneration. It implicates that altered mitochondrial membrane viscosity could play an important role in regulation of mitochondria functioning and pathomechanisms of PD. The data obtained are also discussed in relation to compensatory processes observed.