Synergistic Effects of Levodopa, Benserazide, and Nortriptyline on Behavioral Impairments and Brain Pathology in an Experimental Rat Model of Parkinson’s Disease

Proteasome dysfunction has been demonstrated in Parkinson disease (PD), and proteasome inhibitors have been shown to induce degeneration of dopaminergic neurons in vitro and in vivo. The mechanism whereby proteasome dysfunction leads to dopaminergic cell death, however, is unknown. In this study, we show that proteasome inhibition in both PC12 cells and dopaminergic neurons derived from embryonic stem cells is associated with mitochondrial membrane permeabilization, activation of caspase-3, and nuclear changes consistent with apoptosis. Prior to the emergence of apoptotic features, we found that proteasome inhibition induced increased levels of phosphorylated p53. Inhibition of p53 by pifithrin-alpha or by RNA interference prevented mitochondrial membrane permeabilization and cytotoxicity. There was no increase in p53 mRNA in proteasome-inhibited cells, suggesting that p53 was increased in a transcription-independent manner. Further, there was no increase in Puma or Bax mRNA and p53 co-immunoprecipitated with Bcl-xL and Mdm2. These findings suggest that p53 mediates cell death by way of a direct mitochondrial effect in this model. We also observed increased levels of phosphorylated p53 in dopamine neurons of the substantia nigra pars compacta of mice following systemic administration of a proteasome inhibitor. These changes preceded degeneration of dopaminergic neurons. Increased phosphorylated p53 was also demonstrated in the substantia nigra pars compacta of post-mortem PD brains. These results suggest that abnormalities in p53 signaling play a role in dopaminergic cell death induced by proteasome inhibition and may be relevant to neurodegeneration in PD.

Lesion of substantia nigra pars compacta by the GluR5 agonist ATPA

Background: Parkinson’s disease (PD) is one of the most common neurodegenerative movement-related disturbance characterized by the degeneration of dopaminergic neurons with uncertain underlying mechanisms, which can be modeled by the rotenone (ROT). Neuroinflammation and oxidative stress (OS) are the most possible hypotheses to create this condition. Objectives: The aim of this study was to evaluate the effects of celecoxib (CLX) on ROT-induced rat model of PD. To this aim, the suppression of neuroinflammation and oxidative stress-mediated apoptosis was surveyed. Methods: In this experimental study, thirty-two male Sprague-Dawley rats randomly classified into 4 groups (n = 8 rats/group) in the following order: control, sham, PD (2.5 mg/kg/48 hours ROT subcutaneously), CLX + PD (20 mg/kg/24 daily orally CLX + 2.5 mg/kg/48 hours ROT). After 28 days of the experiment, the rats were sacrificed and their brain was removed. Then histological (Nissl staining) and biochemical assessments (total antioxidant capacity (TAC) were carried out and malondialdehyde (MDA) levels were measured. The data were analyzed by ANOVA test. Results: The biochemical assessments showed TAC was significantly increased in CLX + PD group compared with PD group, whereas MDA was decreased in CLX + PD group compared with PD group (P < 0.01). We found a significant decrease in the number of dopaminergic cells in substantia nigra pars compacta (SNc) in PD group (P < 0.001), and treatment with CLX markedly increased dopaminergic neurons in CLX + PD compare to PD group (P < 0.01). Conclusions: The findings of this study revealed that CLX treatment can effectively improve the antioxidant defense system and attenuates striatum insults on ROT-induced rat model of PD. These findings suggest that CLX plays a neuroprotective role in the inhibition of oxidative stress and neuroinflammation.

High frequency stimulation of the subthalamic nucleus improves speed of locomotion but impairs forelimb movement in Parkinsonian rats

Parkinson's disease (PD) is a progressive neurodegenerative disease as a result of the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The fundamental features of PD are motor and non-motor symptoms. PD symptoms develop due to the disruption of dopaminergic neurotransmitters and other neurotransmitters such as γ-aminobutyric acid (GABA). The potential role of GABA in PD neuropathology concerning the motor and non-motor symptoms of PD was not precisely discussed. Therefore, this review intended to illustrate the possible role of GABA in PD neuropathology regarding motor and non-motor symptoms. The GABA pathway is essential in regulating the inhibitory tone to prevent excessive stimulation of the cerebral cortex. Degeneration of dopaminergic neurons in PD is linked with reducing GABAergic neurotransmission. Decreasing GABA activity promotes mitochondrial dysfunction and oxidative stress, which are highly related to PD neuropathology. Hence, restoring GABA activity by GABA agonists may attenuate the progression of PD motor symptoms. Therefore, dysregulation of GABAergic neurons in the SNpc contributes to developing PD motor symptoms. Besides, PD non-motor symptoms are also related to the dysfunction of the GABAergic pathway, and amelioration of this pathway may reduce PD non-motor symptoms. In conclusion, the deregulation of the GABAergic pathway in PD might be intricate in developing motor and non-motor symptoms. Improving this pathway might be a novel, beneficial approach to control PD symptoms.

Twelve-month-old male mice expressing the human A53T variant of α-synuclein (A53T) develop dopamine neuron degeneration, neuroinflammation, and motor deficits, along with dysfunctions of the mitochondrial Na+-Ca2+ exchanger (NCX) isoforms 1 (NCX1) and 3 (NCX3) in the nigrostriatal system. Since gender is thought to play a role in the etiology of Parkinson’s disease (PD), we characterized neurochemical and behavioral alterations in 12-month-old female A53T transgenic mice. We investigated the presence of dopaminergic degeneration, astrogliosis and microgliosis using immunohistochemistry for tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule-1 (IBA-1) in both the substantia nigra pars compacta (SNc) and striatum. In the same regions, we also evaluated the co-localization of NCX1 in cells positive for IBA-1 and the co-localization of NCX3 in TH-positive neurons and fibers. Furthermore, in both male and female mice, we performed motor (beam walking and pole tests) and memory [novel object recognition (NOR) and spontaneous alternation] tasks, together with tests to evaluate peripheral deficits (olfactory and stool collection tests). Female A53T transgenic mice displayed degeneration of nigral dopaminergic neurons, but neither microgliosis nor astrogliosis in the SNc and striatum. Moreover, female A53T transgenic mice displayed co-localization between NCX1 and IBA-1 positive cells in the striatum but not SNc, whereas NCX3 did not co-localize with either TH-positive terminals or neuronal bodies in the nigrostriatal system. Furthermore, female A53T transgenic mice showed increased crossing time in the beam walking test, but no impairments in the pole or memory tests, and in tests that evaluated peripheral deficits, whereas male A53T transgenic mice displayed motor, memory and peripheral deficits. Immunohistochemical and behavioral results obtained here in the female mice differ from those previously observed in males, and suggest a dissimilar influence of NCX1 and NCX3 on dopaminergic function in female and male A53T transgenic mice, strengthening the validity of these mice as a model for studying the etiological factors of PD.

Delayed Dominant-Negative TNF Gene Therapy Halts Progressive Loss of Nigral Dopaminergic Neurons in a Rat Model of Parkinson's Disease

Parkinson’s disease (PD) is a progressive widespread neurodegenerative disorder affecting the brain. It is characterized by dopaminergic neuron degeneration in the substantia nigra pars compacta (SNpc). Current therapeutic options ease the symptoms of PD; however, they have multiple undesirable effects and do not slow the disease progression. Exercise by itself has many positive impacts on general health. In this review, the positive impact of different forms of exercise were found to improve motor and non-motor symptoms in PD. Exercise effects is mediate by multiple mechanisms, including the upregulation of brain-derived neurotrophic factor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, and autophagy regulating proteins; and downregulates proinflammatory cytokines. In this review, the significance of exercise in PD, as well as in the prevention and maintenance of the disease was discussed. Many questions are left unanswered in this manuscript, including potential genetic factors underlying response to exercise. Therefore, further high-quality studies on humans are needed.

Parkinson's disease (PD) is a progressive neurodegenerative brain disease due to degeneration of dopaminergic neurons (DNs) presented with motor and non-motor symptoms. PD symptoms are developed in response to the disturbance of diverse neurotransmitters including γ-aminobutyric acid (GABA). GABA has a neuroprotective effect against PD neuropathology by protecting DNs in the substantia nigra pars compacta (SNpc). It has been shown that the degeneration of GABAergic neurons is linked with the degeneration of DNs and the progression of motor and non-motor PD symptoms. GABA neurotransmission is a necessary pathway for normal sleep patterns, thus deregulation of GABAergic neurotransmission in PD could be the potential cause of sleep disorders in PD. Sleep disorders affect GABA neurotransmission leading to memory and cognitive dysfunction in PD. For example, insomnia and short sleep duration are associated with a reduction of brain GABA levels. Moreover, PD-related disorders including rigidity and nocturia influence sleep patterns leading to fragmented sleep which may also affect PD neuropathology. However, the mechanistic role of GABA in PD neuropathology regarding motor and non-motor symptoms is not fully elucidated. Therefore, this narrative review aims to clarify the mechanistic role of GABA in PD neuropathology mainly in sleep disorders, and how good GABA improves PD. In addition, this review of published articles tries to elucidate how sleep disorders such as insomnia and REM sleep behavior disorder (RBD) affect PD neuropathology and severity. The present review has many limitations including the paucity of prospective studies and most findings are taken from observational and preclinical studies. GABA involvement in the pathogenesis of PD has been recently discussed by recent studies. Therefore, future prospective studies regarding the use of GABA agonists in the management of PD are suggested to observe their distinct effects on motor and non-motor symptoms. There is a bidirectional relationship between the pathogenesis of PD and sleep disorders which might be due to GABA deregulation.

A simple and fast densitometric method for the analysis of tyrosine hydroxylase immunoreactivity in the substantia nigra pars compacta and in the ventral tegmental area

Adenosine A(2A) receptor antagonists are one of the most attractive classes of drug for the treatment of Parkinson's disease (PD) as they are effective in counteracting motor dysfunctions and display neuroprotective and anti-inflammatory effects in animal models of PD. In this study, we evaluated the neuroprotective and anti-inflammatory properties of the adenosine A(2A) receptor antagonist ST1535 in a subchronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. C57BL/6J mice were repeatedly administered with vehicle, MPTP (20 mg/kg), or MPTP + ST1535 (2 mg/kg). Mice were sacrificed three days after the last administration of MPTP. Immunohistochemistry for tyrosine hydroxylase (TH) and cresyl violet staining were employed to evaluate dopaminergic neuron degeneration in the substantia nigra pars compacta (SNc) and caudate-putamen (CPu). CD11b and glial fibrillary acidic protein (GFAP) immunoreactivity were, respectively, evaluated as markers of microglial and astroglial response in the SNc and CPu. Stereological analysis for TH revealed a 32% loss of dopaminergic neurons in the SNc after repeated MPTP administration, which was completely prevented by ST1535 coadministration. Similarly, CPu decrease in TH (25%) was prevented by ST1535. MPTP treatment induced an intense gliosis in both the SNc and CPu. ST1535 totally prevented CD11b immunoreactivity in both analyzed areas, but only partially blocked GFAP increase in the SNc and CPu. A(2A) receptor antagonism is a new opportunity for improving symptomatic PD treatment. With its neuroprotective effect on dopaminergic neuron toxicity induced by MPTP and its antagonism on glial activation, ST1535 represents a new prospect for a disease-modifying drug.

Dopamine quinone toxicity has been implicated in the degeneration of nigral dopaminergic (DA) neurons in Parkinson’s disease (PD). NAD(P)H:quinone oxidoreductase (NQO1) may protect against this quinone toxicity. In Parkinsonian brains, levels of NQO1 are increased in reactive glia cells that are located around the remaining DA neurons in the substantia nigra pars compacta (SNc), suggesting a neuroprotective role of NQO1.It is not known at which stage of the disease process the upregulation of glial NQO1 starts. Furthermore, it is at present not clear whether NQO1 indeed plays a neuroprotective role in the disease process. As a first step to experimentally study a potential neuroprotective role of NQO1, it was examined whether activation of glia cells and changes in the distribution of NQO1-positive glia cells and the expression levels of glial NQO1, as seen in PD brains, also occurred in a 6-hydroxydopamine (6-OHDA) rat model of PD.Our results show that astroglia cells and microglia cells were activated. Furthermore, NQO1 was upregulated in astroglia cells in the SNc in those areas in which DA neurons degenerated. The time course and pattern of upregulation of NQO1 paralleled those of the degeneration of DA neurons. Activated microglia were seen at a later stage during the course of degeneration of DA neurons.In conclusion, in the present model, astroglia cells and microglia cells are activated in response to 6-OHDA-induced oxidative stress. Furthermore, levels of NQO1 are increased in astroglia cells. The findings in the present model are in line with the findings as seen in parkinsonian brains. The 6-OHDA rat model of PD is, therefore, suitable for further research to examine a potential neuroprotective role of NQO1.KeywordsTyrosine HydroxylaseAstroglia CellGlia CellGFAP ImmunoreactivityParkinsonian BrainThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Central amygdala-substantia nigra pars compacta circuit mediates anxiety- and depression-like behaviors in MPTP-treated mice.

Non motor symptoms (NMS) of PD are a key determinant of health, quality of life and societal cost of PD. Contrary to common perception, many NMS of PD occur early in PD and some may even predate the diagnosis of PD which is based on motor signs. These include olfactory deficit, sleep problems such as REM behaviour disorder, contipation and the more recently described male erectile dysfunction. The non motor quesionnaire (NMSQuest) and the recently validated NMS scale allow falgging and quantification of NMS of PD and therefore are important tools to comprehensively assess symptom load in PD.

<h3>Objectives</h3> Degeneration of dopaminergic neurons in the substantia nigra (SN) pars compacta is the primary cause of idiopathic Parkinson9s disease (iPD). In early stages of disease in particular, presentation of...