Destruction Of Dopaminergic Neurons Research Articles

Alterations in descending brain-spinal pathways regulating colorectal motility in a rat model of Parkinson's disease.

Patients with Parkinson's disease (PD) often have constipation. It is assumed that a disorder of the regulatory mechanism of colorectal motility by the central nervous system is involved in the constipation, but this remains unclear. The aim of this study was to investigate whether central neural pathways can modulate colorectal motility in a rat model of PD. PD model rats were generated by injection of 6-hydroxydopamine into a unilateral medial forebrain bundle and destruction of dopaminergic neurons in the substantia nigra. Colorectal motility was measured in vivo in anesthetized rats. Intraluminal administration of capsaicin, as a noxious stimulus, induced colorectal motility in sham-operated rats but not in PD rats. Intrathecally administered dopamine (DA) and serotonin (5-HT), which mediate the prokinetic effect of capsaicin, at the L6-S1 levels enhanced colorectal motility in PD rats similarly to that in sham-operated rats. In PD rats, capsaicin enhanced colorectal motility only when a GABAA receptor antagonist was preadministered into the lumbosacral spinal cord. Capsaicin-induced colorectal motility was abolished by intrathecal administration of a D2-like receptor antagonist but not by administration of 5-HT2 and 5-HT3 receptor antagonists. These findings demonstrate that the inhibitory GABAergic component becomes operative and the stimulatory serotonergic component is suppressed in PD rats. The alteration of the central regulatory mechanism of colorectal motility is thought to be related to the occurrence of constipation in PD patients. Our findings provide a new insight into the pathogenesis of defecation disorders observed in PD.NEW & NOTEWORTHY In a rat model of Parkinson's disease, the component of descending brain-spinal pathways that regulate colorectal motility through a mediation of the lumbosacral defecation center was altered from stimulatory serotonergic neurons to inhibitory GABAergic neurons. Our findings suggest that chronic constipation in Parkinson's disease patients may be associated with alterations in central regulatory mechanisms of colorectal motility. The plasticity in the descending pathway regulating colorectal motility may contribute to other disease-related defecation abnormalities.

Interlinked role of ASN, TDP-43 and Miro1 with parkinopathy: Focus on targeted approach against neuropathy in parkinsonism.

Parkinsonism is a complex neurodegenerative disease that is difficult to differentiate because of its idiopathic and unknown origins. The hereditary parkinsonism known as autosomal recessive-juvenile parkinsonism (AR-JP) is marked by tremors, dyskinesias, dystonic characteristics, and manifestations that improve sleep but do not include dementia. This was caused by deletions and point mutations in PARK2 (chromosome 6q25.2-27). Diminished or unusual sensations (paresthesias), loss of neuron strength both in the CNS and peripheral nerves, and lack of motor coordination are the hallmarks of neuropathy in parkinsonism. The incidence of parkinsonism during oxidative stress and ageing is associated with parkinopathy. Parkinopathy is hypothesized to be triggered by mutation of the parkin (PRKN) gene and loss of normal physiological functions of PRKN proteins, which triggers their pathogenic aggregation due to conformational changes. Two important genes that control mitochondrial health are PRKN and phosphatase and tensin homologue deleted on chromosome 10-induced putative kinase 1 (PINK1). Overexpression of TAR DNA-binding protein-43 (TDP-43) increases the aggregation of insoluble PRKN proteins in OMM. Foreign α-synuclein (ASN)promotes parkinopathy via S-nitrosylation and hence has a neurotoxic effect on dopaminergic nerves. Miro1(Miro GTPase1), a member of the RAS superfamily, is expressed in nerve cells. Due to PINK1/PRKN and Miro1's functional relationship, an excess of mitochondrial calcium culminates in the destruction of dopaminergic neurons. An interlinked understanding of TDP-43, PINK1/PRKN, ASN, and Miro1 signalling in the communication among astrocytes, microglia, neurons, and immune cells within the brain explored the pathway of neuronal death and shed light on novel strategies for the diagnosis and treatment of parkinsonism.

Ukgansan Protects Dopaminergic Neurons against MPTP-Induced Neurotoxicity via the Nurr1 Signaling Pathway.

Nuclear receptor-related 1 protein (Nurr1) is a nuclear hormone receptor that protects dopaminergic neurons and is a promising therapeutic target for Parkinson's disease (PD). Parkinson's disease is a neurodegenerative disorder caused by the destruction of dopaminergic neurons in the substantia nigra pars compacta (SNpc), and the long-term use of conventional dopamine replacement therapies causes many side effects, highlighting the need for new treatments such as complementary and alternative medicine. Ukgansan has been used in East Asia to treat neurological disorders, including neurodegenerative diseases, and has been reported to have strong effects in treating patients with PD. In addition, recent studies have reported that Ukgansan has a neuroprotective potential. However, there are no detailed studies on the mechanism of action of Nurr1. Thus, unlike previous studies, we focused on the Nurr1 pathways. We confirmed neurotoxicity and apoptosis signaling in the differentiated PC12 cells. In addition, to confirm the protective effect of Ukgansan, we conducted behavioral tests (motor coordination and postural balance, and bradykinesia) and tyrosine hydroxylase immunohistochemistry in both the SNpc and striatum. Specifically, this study demonstrated the effect of Ukgansan in protecting dopaminergic neurons and increasing Nurr1 involved in maintaining dopamine levels by activating Nurr1 expression in MPTP-induced PC12 cells and a mouse model of PD. In this mechanism, the loss of dopaminergic neurons and dopamine depletion were suppressed, and motor impairment caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity was improved. These results provide evidence that Ukgansan ameliorates PD's motor symptoms and progression.

Caffeic Acid Phenethyl Ester With Mesenchymal Stem Cells Improves Behavioral and Histopathological Changes in the Rat Model of Parkinson Disease.

Parkinson disease (PD) results from the destruction of dopaminergic neurons in the brain. This study aimed to investigate the protective effects of natural antioxidants such as caffeic acid phenethyl ester (CAPE) to maintain these neurons. CAPE is one of the main ingredients of propolis. Intranasal administration of 1-methyl-4-phenyl-2;3;4;6-tetrahydropyridine (MPTP) was used to generate a PD model in rats. A total of 2×bone marrow stem cells (BMSCs) were injected from the tail vein. Behavioral tests, immunohistochemistry, DiI, cresyl fast violet, and TUNEL staining were used to evaluate the rats 2 weeks after treatment. In all treatment groups with stem cells, the DiI staining method revealed that the cells migrated to the substantia nigra pars compacta after injection. Treatment with CAPE significantly protects dopaminergic neurons from MPTP. The highest number of tyrosine hydroxylase (TH) positive neurons was seen in the pre-CAPE+PD+stem cell (administration of CAPE, then the creation of PD, finally injection of stem cells) group. The number of TH+cells in all groups that received CAPE was significant compared to groups that received the stem cells only (P<0.001). Intranasal administration of MPTP significantly increases the number of apoptotic cells. The lowest number of apoptotic cells was in the CAPE+PD+stem cell group. The results showed that the use of CAPE and stem cells in Parkinson rats caused a significant reduction in the apoptotic cells.

Hydroxychloroquine attenuated motor impairment and oxidative stress in a rat 6-hydroxydopamine model of Parkinson’s disease

Purpose Parkinson’s disease (PD) is associated with the destruction of dopaminergic neurons in the substantia nigra (SN). Hydroxychloroquine (HCQ) has the capability to cross the blood–brain barrier and promote a neuroprotective potential. This study evaluated the effects of HCQ on the 6-hydroxydopamine (6-OHDA)-induced PD model in rats. Methods Wistar rats were randomly divided into sham, PD, PD + levodopa and PD + HCQ groups. The PD model was induced by a stereotactic administration of 6-OHDA into the left SN pars compacta (SNpc) and confirmed by rotation and the Murprogo’s tests. HCQ (100 mg/kg, p.o.) and levodopa (12 mg/kg, p.o.) were administered once a day for 21 days. Three weeks after surgery, the behavioral tests were performed. Brain lipid peroxidation index (MDA), glutathione peroxidase activity (GPx), total antioxidant capacity (TAC) levels and α-synuclein protein expression in the SN were also measured. Results The behavioral tests demonstrated that induction of PD increased the muscle rigidity and the number of rotations, which were reversed by HCQ treatment. Also, induction of PD was associated with an increase in α-synuclein protein levels and MDA and decreased TAC levels and GPx activity. However, HCQ decreased α-synuclein and MDA levels while increased TAC levels and GPx activity. In addition, histopathological data showed that HCQ protects dopaminergic neurons against 6-OHDA-induced toxicity. Conclusion According to the results, HCQ has a beneficial effect in improving PD-related pathophysiology, in part, by mitigating oxidative stress and protecting the dopaminergic neurons in the SN.

Calpain activation and progression of inflammatory cycles in Parkinson's disease.

Parkinson's disease (PD) is a progressive, neurodegenerative condition of the central nervous system (CNS) affecting 6.3 million people worldwide with no curative treatments. Current therapies aim to mitigate PD's effects and offer symptomatic relief for patients. Multiple pathways are involved in the pathogenesis of PD, leading to neuroinflammation and the destruction of dopaminergic neurons in the CNS. This review focuses on PD pathology and the role of calpain, a neutral protease, as a regulator of various immune cells such as T-cells, microglia and astrocytes which lead to persistent neuroinflammatory responses and neuronal loss in both the brain and spinal cord (SC). Calpain plays a significant role in the cleavage and aggregation of toxic α-synuclein (α-syn), a presynaptic neural protein, and other organelles, contributing to mitochondrial dysfunction and oxidative stress. α-Syn aggregation results in the formation of Lewy bodies (LB) that further contribute to neuronal damage through lipid bilayer penetration, calcium ion (Ca2+) influx, oxidative stress and damage to the blood brain barrier (BBB). Dysfunctional mitochondria destabilize cytosolic Ca2+ concentrations, raising intracellular Ca2+; this leads to excessive calpain activation and persistent inflammatory responses. α-Syn aggregation also results in the disruption of dopamine synthesis through phosphorylation of tyrosine hydroxylase (TH), a key enzyme involved in the conversion of tyrosine to levodopa (L-DOPA), the amino acid precursor to dopamine. Decreased dopamine levels result in altered dopamine receptor (DR) signaling, ultimately activating pro-inflammatory T-cells to further contribute to the inflammatory response. All of these processes, together, result in neuroinflammation, degeneration and ultimately neuronal death seen in PD. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP-a prodrug to the neurotoxin 1-methyl-4-phenylpyridinium (MPP+)), rotenone (an environmental neurotoxin), and 6-hydroxydopamine (6-OHDA - a neurotoxic synthetic organic compound) induce PD-like conditions when injected into rodents. All three agents work through similar mechanisms and lead to degeneration of dopaminergic neurons in the substantia nigra (SN) and more recently discovered in motor neurons of the spinal cord (SC). These neurotoxins also increase calpain activity, furthering the neuroinflammatory response. Hence, calpain inhibitors have been posited as potential therapeutics for PD to prevent calpain-related inflammation and neurodegenerative responses in not only the SN but the SC as well.

Triadin Decrease Impairs the Expression of E-C Coupling Related Proteins in Muscles of MPTP-Induced Parkinson's Disease Mice.

Parkinson’s disease (PD), caused by destruction of dopaminergic neurons in the brain, leads to motor symptoms like bradykinesia, tremor, and walking impairments. While most research effort focuses on changes in neuronal pathology we examined how muscle proteins were altered in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. A Ca2+ release channel complex, consisting of ryanodine receptors (RYR), triadin (TRDN), and calsequestrin (CSQ1), is important for excitation-contraction coupling in the sarcoplasmic reticulum membrane in muscles. Thus, we investigated changes in the RYR Ca2+ release channel components in PD mice model. Based on a report that TRDN deletion impairs skeletal muscle function, we also investigated how the knock-down of TRDN affects other components of the RYR channel in the PD model. In this study, the expression levels of the components of RYR channels decreased in the quadriceps femoris muscle of MPTP-induced PD mice and in C2C12 cells treated with 1-methyl-4-phenylpyridinium. We show that decreased TRDN levels decrease RYR and CSQ1 levels. These results suggest that the levels of proteins related to Ca2+ channel function decreased in this model, which could impair muscle function. We conclude that muscle function alterations could add to the bradykinesia and tremor in this model of PD.

The protective effect of Lavandula officinalis extract on 6-hydroxydopamine-induced reactive oxygen species and apoptosis in PC12 cells

IntroductionParkinson's disease (PD) is a neurodegenerative desease marked by destruction of dopaminergic neurons. Lavandula officinalis (Lavender) has been widely used in traditional medicine to relieve CNS diseases and mental disorders. In the present study, protective effect of L. officinalis was studied against the 6-hydroxydopamine (6-OHDA) in PC12 cell line as a model of PD neural injury. MethodsPC12 cells were treated with methanol extract of L. officinalis for 24 h, then they were treated with 6-OHDA (200 μM) for 24 h. The cell viability, the rate of apoptosis, intracellular reactive oxygen species (ROS), and proteins involved in apoptosis were quantified using western blots analysis. ResultsWhile 6-OHDA significantly increased cytotoxicity (p<0.001), ROS (p<0.001) and apoptosis, the extract of L. officinalis significantly reduced ROS (p<0.05) and cell apoptosis at concentrations of 2.5 and 5 μg/ml. L. officinalis also significantly reduced Bax/Bcl-2 (p<0.001) and pERK/ERK ratio (p<0.001). ConclusionsL. officinalis significantly reduced ROS, cell apoptosis (0.5–5 μg/ml) and Bax/Bcl-2 and pERK/ERK ratio which supports its neuroprotective activities. Therefore, L. officinalis may exert beneficial effect in minimizing the cell injury occurs in neurodegenerative diseases, including PD. Further studies will be required to detect the most potent active neuroprotective components of the extract.

Parkinson's Disease: A Comprehensive Analysis of Fungi and Bacteria in Brain Tissue.

Parkinson's disease (PD) is characterized by motor disorders and the destruction of dopaminergic neurons in the substantia nigra pars compacta. In addition to motor disability, many patients with PD present a spectrum of clinical symptoms, including cognitive decline, psychiatric alterations, loss of smell and bladder dysfunction, among others. Neuroinflammation is one of the most salient features of PD, but the nature of the trigger remains unknown. A plausible mechanism to explain inflammation and the range of clinical symptoms in these patients is the presence of systemic microbial infection. Accordingly, the present study provides extensive evidence for the existence of mixed microbial infections in the central nervous system (CNS) of patients with PD. Assessment of CNS sections by immunohistochemistry using specific antibodies revealed the presence of both fungi and bacteria. Moreover, different regions of the CNS were positive for a variety of microbial morphologies, suggesting infection by a number of microorganisms. Identification of specific fungal and bacterial species in different CNS regions from six PD patients was accomplished using nested PCR analysis and next-generation sequencing, providing compelling evidence of polymicrobial infections in the CNS of PD. Most of the fungal species identified belong to the genera Botrytis, Candida, Fusarium and Malassezia. Some relevant bacterial genera were Streptococcus and Pseudomonas, with most bacterial species belonging to the phyla Actinobacteria and Proteobacteria. Interestingly, we noted similarities and differences between the microbiota present in the CNS of patients with PD and that in other neurodegenerative diseases. Overall, our observations lend strong support to the concept that mixed microbial infections contribute to or are a risk factor for the neuropathology of PD. Importantly, these results provide the basis for effective treatments of this disease using already approved and safe antimicrobial therapeutics.

The effect of titanium dioxide nanoparticles on mice midbrain substantia nigra.

Objective(s):Widely used Titanium dioxide nanoparticles (TiO2) enter into the body and cause various organ damages. Therefore, we aimed to study the effect of TiO2 on the substantia nigra of midbrain.Materials and Methods:40 male BALB/c mice were randomly divided into five groups: three groups received TiO2 at doses of 10, 25, and 50 mg/kg, the fourth group received normal saline for 45 days by gavage, and control group (without intervention). Then, Motor tests including pole and hanging tests were done to investigate motor disorders. The animal brain was removed for histological purposes. Accordingly, immunohistochemistry was performed to detect tyrosine hydroxylase positive cells, and then toluidine blue staining was done to identify dark neurons in the substantia nigra. Eventually, the total number of these neurons were counted using stereological methods in different groups.Results:The results showed that the time recorded for mice to turn completely downward on the pole in the TiO2-50 group increased and also the time recorded for animals to hang on the wire in the hanging test significantly decreased (P<0.05) in comparison with other groups. Also, the average number of tyrosine hydroxylase positive neurons in TiO2-25 and TiO2-50 groups significantly decreased as compared to the TiO2-10 and control groups (P<0.05). The total number of dark neurons in the TiO2-25 and TiO2-50 groups was substantially higher than the TiO2-10, control and normal saline groups (P<0.05).Conclusion:Our findings indicated that TiO2, depending on dose, can cause the destruction of dopaminergic neurons and consequently increase the risk of Parkinson’s disease.

Effects of Mitochondrial Antioxidant SkQ1 on Biochemical and Behavioral Parameters in a Parkinsonism Model in Mice.

According to one hypothesis, Parkinson's disease pathogenesis is largely caused by dopamine catabolism that is catalyzed on mitochondrial membranes by monoamine oxidase. Reactive oxygen species are formed as a byproduct of these reactions, which can lead to mitochondrial damage followed by cell degeneration and death. In this study, we investigated the effects of administration of the mitochondrial antioxidant SkQ1 on biochemical, immunohistochemical, and behavioral parameters in a Parkinson-like condition caused by protoxin MPTP injections in C57BL/6 mice. SkQ1 administration increased dopamine quantity and decreased signs of sensory-motor deficiency as well as destruction of dopaminergic neurons in the substantia nigra and ventral tegmental area in mice with the Parkinson-like condition.

Effects of Propofol on the Liver Oxidative-Antioxidant Balance in a Rat Model of Parkinson's Disease.

Parkinson's disease is caused by the destruction of dopaminergic neurons in the substantia nigra of the midbrain. One of the possible factors involved in the pathogenesis of Parkinson's disease is impaired oxidativeantioxidative balance. The present study aimed to evaluate selected parameters of the liver oxidative-antioxidative system in a Wistar rat model with Parkinson's disease treated with propofol. Experiments were performed on 32 rats divided into 4 groups: 1 - control, 2 - Parkinson's disease, 3 - control with propofol, 4 - Parkinson's disease with propofol. The rats were decapitated at 8 weeks of age and their livers were collected. In the liver, the activities of catalase (CAT), glutathione peroxidase (GPx), glutathione transferase (GST), glutathione reductase (GR) and the concentrations of: Malondialdehyde (MDA), total antioxidant capacity (TAC), total oxidant status (TOS) were assessed. The study demonstrated a decrease in CAT activity and an increase in MDA, TOS concentrations in group 2 compared to that of group 1. Administration of propofol in rats of group 4 caused an increase in CAT activity and a decrease in MDA concentration compared to that of group 2 and an increase in TAC, CAT, GR levels, decrease in MDA levels compared to that of group 1. There was also an increase in GR and TAC in group 3 compared to that of group 1. Propofol in Parkinson's disease stimulates the production of antioxidant enzymes in the liver, simultaneously decreasing oxidative stress, which has a beneficial effect on the oxidative-antioxidative balance.

Effects of neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment on ovarian development of the sapphire devil, Chrysiptera cyanea.

In the neuroendocrine system controlling fish reproduction, dopamine (DA) acts as a gonadotropin inhibitory factor and plays a role in regulating gonadal development of certain species. The present study examined the effects of chemical destruction of dopaminergic neurons in the brain on DA production and ovarian development in the sapphire devil Chrysiptera cyanea, a reef-associated damselfish. The avidin-biotin-peroxidase complex method using an antibody against tyrosine hydroxylase (TH), a critical enzyme in the DA synthesis pathway, identified a population of dopaminergic neurons with somata in the anteroventral preoptic nucleus of the diencephalon and fibers terminating in the proximal pars distalis of the pituitary. Maintaining fish in seawater containing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at 0.02 and 0.2 µg/mL for 2 days resulted in decreases in DA, 3,4-dihydroxyphenylacetic acid (DOPAC; DA metabolite), and DA metabolic rate in the whole brain. The number of TH-positive neurons in the diencephalon decreased after 0.02 µg/mL MPTP treatment for 2 days. These results suggest that MPTP treatment destroys TH-positive neurons in the diencephalon, thereby decreasing the synthesis and release of DA from the brain. This treatment rescued ovarian development in fish with artificially retracted ovaries during the spawning season. The gonadosomatic index of MPTP-treated fish 5 and 7 days after treatment was significantly higher than that of control fish. Oocytes in the vitellogenic stages were observed in the ovaries of MPTP-treated fish, but not in control fish. These results suggest that DA in the brain drives ovarian development in the sapphire devil.

Proposed Motor Scoring System in a Porcine Model of Parkinson's Disease induced by Chronic Subcutaneous Injection of MPTP.

Destruction of dopaminergic neurons in the substantia nigra pars compacta (SNpc) is a common pathophysiology of Parkinson's disease (PD). Characteristics of PD patients include bradykinesia, muscle rigidity, tremor at rest and disturbances in balance. For about four decades, PD animal models have been produced by toxin-induced or gene-modified techniques. However, in mice, none of the gene-modified models showed all 4 major criteria of PD. Moreover, distinguishing between PD model pigs and normal pigs has not been well established. Therefore, we planned to produce a pig model for PD by chronic subcutaneous administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), neurotoxin. Changes in behavioral patterns of pigs were thoroughly evaluated and a new motor scoring system was established for this porcine model that was based on the Unified Parkinson's Disease Rating Scale (UPDRS) in human PD patients. In summary, this motor scoring system could be helpful to analyze the porcine PD model and to confirm the pathology prior to further examinations, such as positron emission tomography-computed tomography (PET-CT), which is expensive, and invasive immunohistochemistry (IHC) of the brain.

Analysis of single nucleotide polymorphism rs415430 in the WNT3 gene in Parkinson’s disease in Russian population

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disease that arises as a result of the destruction of dopaminergic neurons. Reasons for the development of PD are not completely clarified and, at present, a number of genes involved in the development of both familial and sporadic PD forms have been detected. According to recent data from genome-wide association studies, single nucleotide polymorphisms (SNPs) in these genes (including the MAPT locus) can play a significant role in the development of PD. In connection with the above, we analyzed the distribution of genotype frequencies of SNP rs415430 in WNT3 gene in Russian patients with sporadic PD and in Russian population controls (OR = 0.84, Confidence Interval (95% CI) 0.58–1.23, p = 0.39). We conclude that the WNT3 gene rs415430 SNP does not influence the risk of the development of PD in the Russian population.

Parkinson's Disease: Mitochondrial Molecular Pathology, Inflammation, Statins, and Therapeutic Neuroprotective Nutrition

Pathological hallmarks of Parkinson's disease are destruction of dopaminergic neurons in the basal ganglia, especially the substantia nigra, and the presence of Lewy bodies within nerve cells. Environmental toxins are associated with the disease and, in a minority of cases, genetic factors have been identified. Inflammation-with activation of phagocytic microglia, release of cytokines, invasion by T cells, and complement activation-plays a role in damaging these neurons. Excessive production of reactive oxygen species, mitochondrial dysfunction leading to apoptosis, accumulation and oligomerization of the protein alpha-synuclein, and defective protein disposal by the ubiquitin proteasome system are involved in the complex web of events mediating nigral cell demise. Two agents of current interest, coenzyme Q10 and creatine, may be disease modifying, and large studies are in progress. Related mechanisms of other substances, including omega-3 fatty acids and vitamin D, are included in this review. The association with serum cholesterol levels and the effects of statin drugs are uncertain but important.

Destruction of Dopaminergic Neurons in the Midbrain by 6-Hydroxydopamine Decreases Hippocampal Cell Proliferation in Rats: Reversal by Fluoxetine

BackgroundNon-motor symptoms (e.g., depression, anxiety, and cognitive deficits) in patients with Parkinson disease (PD) precede the onset of the motor symptoms. Although these symptoms do not respond to pharmacological dopamine replacement therapy, their precise pathological mechanisms are currently unclear. The present study was undertaken to examine whether the unilateral 6-hydroxydopamine (6-OHDA) lesion to the substantia nigra pars compacta (SNc), which represents a model of long-term dopaminergic neurotoxicity, could affect cell proliferation in the adult rat brain. Furthermore, we examined the effects of the selective serotonin reuptake inhibitor (SSRI) fluoxetine and the selective noradrenaline reuptake inhibitor maprotiline on the reduction in cell proliferation in the subgranular zone (SGZ) by the unilateral 6-OHDA lesion.Methodology/Principal FindingsA single unilateral injection of 6-OHDA into the rat SNc resulted in an almost complete loss of tyrosine hydroxylase (TH) immunoreactivity in the striatum and SNc, as well as in reductions of TH-positive cells and fibers in the ventral tegmental area (VTA). On the other hand, an injection of vehicle alone showed no overt change in TH immunoreactivity. A unilateral 6-OHDA lesion to SNc significantly decreased cell proliferation in the SGZ ipsilateral to the 6-OHDA lesion, but not in the contralateral SGZ or the subventricular zone (SVZ), of rats. Furthermore, subchronic (14 days) administration of fluoxetine (5 mg/kg/day), but not maprotiline significantly attenuated the reduction in cell proliferation in the SGZ by unilateral 6-OHDA lesion.Conclusions/SignificanceThe present study suggests that cell proliferation in the SGZ of the dentate gyrus might be, in part, under dopaminergic control by SNc and VTA, and that subchronic administration of fluoxetine reversed the reduction in cell proliferation in the SGZ by 6-OHDA. Therefore, SSRIs such as fluoxetine might be potential therapeutic drugs for non-motor symptoms as well as motor symptoms in patients with PD, which might be associated with the reduction in cell proliferation in the SGZ.

Regional Brain Stem Atrophy in Idiopathic Parkinson's Disease Detected by Anatomical MRI

Idiopathic Parkinson's disease (PD) is a neurodegenerative disorder characterized by the dysfunction of dopaminergic dependent cortico-basal ganglia loops and diagnosed on the basis of motor symptoms (tremors and/or rigidity and bradykinesia). Post-mortem studies tend to show that the destruction of dopaminergic neurons in the substantia nigra constitutes an intermediate step in a broader neurodegenerative process rather than a unique feature of Parkinson's disease, as a consistent pattern of progression would exist, originating from the medulla oblongata/pontine tegmentum. To date, neuroimaging techniques have been unable to characterize the pre-symptomatic stages of PD. However, if such a regular neurodegenerative pattern were to exist, consistent damages would be found in the brain stem, even at early stages of the disease. We recruited 23 PD patients at Hoenn and Yahr stages I to II of the disease and 18 healthy controls (HC) matched for age. T1-weighted anatomical scans were acquired (MPRAGE, 1 mm3 resolution) and analyzed using an optimized VBM protocol to detect white and grey matter volume reduction without spatial a priori. When the HC group was compared to the PD group, a single cluster exhibited statistical difference (p<0.05 corrected for false detection rate, 4287 mm3) in the brain stem, between the pons and the medulla oblongata. The present study provides in-vivo evidence that brain stem damage may be the first identifiable stage of PD neuropathology, and that the identification of this consistent damage along with other factors could help with earlier diagnosis in the future. This damage could also explain some non-motor symptoms in PD that often precede diagnosis, such as autonomic dysfunction and sleep disorders.

Weaver mutant mice exhibit long-term learning deficits under several measures of instrumental behavior

Homozygous weaver mutant mice (wv/wv) exhibit symptoms that parallel Parkinson's disease, including motor deficits and the destruction of dopaminergic neurons as well as degeneration in the cerebellum and hippocampus. To develop a more complete behavioral profile of these organisms, groups of wv/wv, wv/+ mice and C57BL/6 mice were observed on a within-subjects basis under a fixed-interval schedule of reinforcement, a differential-reinforcement-of-low-rate-of-responding schedule, and a discrimination task in which a saccharin solution and tap water were concurrently available from two food cups. Under both reinforcement schedules, the wv/wv mice responded as frequently as the comparison subjects, but they responded in a manner that was inappropriate to the contingencies. Rather than respond with increasing frequency as the upcoming reinforcer became temporally proximate, wv/wv mice responded with decreasing probability as a function of the time since the previous reinforcer. Under the discrimination task, the wv/wv mice, unlike the controls, obtained saccharin over tap water at the level of chance. The findings suggest that weaver mutant mice express learning deficits similar to those found in other dopamine-deficient organisms.

Destruction of midbrain dopaminergic neurons by using immunotoxin to dopamine transporter.

1. The ability to target specific neurons can be used to produce selective neural lesions and potentially to deliver therapeutically useful moieties for treatment of disease. In the present study, we sought to determine if a monoclonal antibody to the dopamine transporter (anti-DAT) could be used to target midbrain dopaminergic neurons. 2. The monoclonal antibody recognizes the second, large extracellular loop of DAT. The antibody was conjugated to the "ribosome-inactivating protein"; saporin, and stereotactically pressure microinjected into either the center of the striatum or the left lateral ventricle of adult, male Sprague-Dawley rats. 3. Local intrastriatal injections produced destruction of dopaminergic neurons in the ipsilateral substantia nigra consistent with suicide transport of the immunotoxin. Intraventricular injections (i.c.v.) produced significant loss of dopaminergic neurons in the substantia nigra and ventral tegmental area bilaterally without evident damage to any other aminergic structures such as the locus coeruleus and raphe nuclei. To confirm the anatomic findings, binding of [3-H]mazindol to DAT in the striatum and midbrain was assessed using densitometric analysis of autoradiograms. Anti-DAT-saporin injected i.c.v. at a dose of 21 microg, but not 8 microg, produced highly significant decreases in mazindol binding consistent with loss of the dopaminergic neurons. 4. These results show that anti-DAT can be used to target midbrain dopaminergic neurons and that anti-DAT-saporin may be useful for producing a lesion very similar to the naturally occurring neural degeneration seen in Parkinson's disease. Anti-DAT-saporin joins the growing list of neural lesioning agents based on targeted cytotoxins.