-
Brain Research Bulletin Jan 2022Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic (DAergic) neurons of the substantia nigra pars compacta (SNc) by neurodegeneration.... (Review)
Review
Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic (DAergic) neurons of the substantia nigra pars compacta (SNc) by neurodegeneration. Recent findings in animal models of PD propose tonic inhibition of the remaining DA neurons through GABA release from reactive glial cells. Movement dysfunctions could be ameliorated by promotion of activity in dormant DA cells. The endocannabinoid system (ECS) is extensively present in basal ganglia (BG) and is known as an indirect modulator of DAergic neurotransmission, thus drugs designed to target this system have shown promising therapeutic potential in PD patients. Interestingly, down/up-regulation of cannabinoid receptors (CBRs) varies across the different stages of PD, suggesting that some of the motor/ non-motor deficits may be related to changes in CBRs. Determination of the profile of changes of these receptors across the different stages of PD as well as their neural distribution within the BG could improve understanding of PD and identify pathways important in disease pathobiology. In this review, we focus on temporal and spatial alterations of CBRs during PD in the BG. At present, as inconclusive, but suggestive results have been obtained, future investigations should be conducted to extend preclinical studies examining CBRs changes within each stage in controlled clinical trials in order to determine the potential of targeting CBRs in management of PD.
Topics: Basal Ganglia; Cannabinoid Receptor Antagonists; Endocannabinoids; Humans; Parkinson Disease
PubMed: 34808322
DOI: 10.1016/j.brainresbull.2021.11.009 -
Methods in Molecular Biology (Clifton,... 2022Neuron death is a key feature of neurological disorders like Alzheimer's or Parkinson's disease (PD). As a result, analysis of neurodegeneration is often considered a...
Neuron death is a key feature of neurological disorders like Alzheimer's or Parkinson's disease (PD). As a result, analysis of neurodegeneration is often considered a central experiment in the postmortem characterization of preclinical PD animal models. Stereology provides a precise estimate of particles, like neurons, in three-dimensional objects, like the brain, and is the gold standard quantification approach for the assessment of neuron survival in neurodegenerative disease research. Here, we provide a detailed step-by-step guide for the quantification of dopaminergic neurons in the substantia nigra pars compacta, a brain area prone to neuron loss in PD. In addition, we outline the protocol for the analysis of the dopaminergic terminals in the striatum, the projection area of midbrain dopaminergic neurons, as a readout for the integrity of the nigrostriatal projections.
Topics: Animals; Corpus Striatum; Dopamine; Dopaminergic Neurons; Mice; Neostriatum; Neurodegenerative Diseases; Parkinson Disease
PubMed: 35776351
DOI: 10.1007/978-1-0716-2409-8_10 -
Journal of Enzyme Inhibition and... Dec 2023Parkinson's disease (PD) is characterised by progressive death of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc) and pathological accumulation of... (Review)
Review
Parkinson's disease (PD) is characterised by progressive death of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc) and pathological accumulation of α-synuclein fibrils, as well as central nervous system inflammation. Elevated levels of central inflammatory factors in PD disrupt the kynurenine pathway (KP) and favour the activation of excitotoxic branches, leading to a significant reduction in the neuroprotective metabolite kynurenic acid (KYNA) and a significant increase in the neurotoxic metabolite quinolinic acid (QUIN), which exacerbates excitotoxicity and amplifies the inflammatory response, closely related to the occurrence and development of PD. KYNA analogs, precursor drugs, and KP enzyme modulators may represent a new therapeutic strategy for PD. This article reviews the role of KP in the neurodegenerative pathology of PD and its prevention and treatment, aiming to provide necessary theoretical basis and new ideas for the study of the neurobiological mechanisms underlying PD-related behavioural dysfunction and targeted interventions.
Topics: Humans; Parkinson Disease; Kynurenine; Central Nervous System; Inflammation
PubMed: 37381707
DOI: 10.1080/14756366.2023.2225800 -
Brain Sciences Apr 2023Parkinson's disease (PD) is the second most common neurodegenerative disease, with symptoms such as tremor, bradykinesia with rigidity, and depression appearing in the... (Review)
Review
Parkinson's disease (PD) is the second most common neurodegenerative disease, with symptoms such as tremor, bradykinesia with rigidity, and depression appearing in the late stage of life. The key hallmark of PD is the loss or death of dopaminergic neurons in the region substantia nigra pars compacta. Neuroinflammation plays a key role in the etiology of PD, and the contribution of immunity-related events spurred the researchers to identify anti-inflammatory agents for the treatment of PD. Neuroinflammation-based biomarkers have been identified for diagnosing PD, and many cellular and animal models have been used to explain the underlying mechanism; however, the specific cause of neuroinflammation remains uncertain, and more research is underway. So far, microglia and astrocyte dysregulation has been reported in PD. Patients with PD develop neural toxicity, inflammation, and inclusion bodies due to activated microglia and a-synuclein-induced astrocyte conversion into A1 astrocytes. Major phenotypes of PD appear in the late stage of life, so there is a need to identify key early-stage biomarkers for proper management and diagnosis. Studies are under way to identify key neuroinflammation-based biomarkers for early detection of PD. This review uses a constructive analysis approach by studying and analyzing different research studies focused on the role of neuroinflammation in PD. The review summarizes microglia, astrocyte dysfunction, neuroinflammation, and key biomarkers in PD. An approach that incorporates multiple biomarkers could provide more reliable diagnosis of PD.
PubMed: 37190599
DOI: 10.3390/brainsci13040634 -
Neurologia 2023Parkinson's disease (PD) is the second most prevalent neurodegenerative disease among adults worldwide. It is characterised by the death of dopaminergic neurons in the... (Review)
Review
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease among adults worldwide. It is characterised by the death of dopaminergic neurons in the substantia nigra pars compacta and, in some cases, presence of intracytoplasmic inclusions of α-synuclein, called Lewy bodies, a pathognomonic sign of the disease. Clinical diagnosis of PD is based on the presence of motor alterations. The treatments currently available have no neuroprotective effect. The exact causes of PD are poorly understood. Therefore, more precise preclinical models have been developed in recent years that use induced pluripotent stem cells (iPSC). In vitro studies can provide new information on PD pathogenesis and may help to identify new therapeutic targets or to develop new drugs.
Topics: Adult; Humans; Parkinson Disease; Induced Pluripotent Stem Cells; Neurodegenerative Diseases; Dopaminergic Neurons; Neuroprotective Agents
PubMed: 37858889
DOI: 10.1016/j.nrleng.2023.10.004 -
International Journal of Molecular... May 2023Parkinson's disease (PD) is one of the most common neurodegenerative disorders, characterized by an initial and progressive loss of dopaminergic neurons of the via a... (Review)
Review
Parkinson's disease (PD) is one of the most common neurodegenerative disorders, characterized by an initial and progressive loss of dopaminergic neurons of the via a potentially substantial contribution from protein aggregates, the Lewy bodies, mainly composed of α-Synuclein among other factors. Distinguishing symptoms of PD are bradykinesia, muscular rigidity, unstable posture and gait, hypokinetic movement disorder and resting tremor. Currently, there is no cure for PD, and palliative treatments, such as Levodopa administration, are directed to relieve the motor symptoms but induce severe side effects over time. Therefore, there is an urgency for discovering new drugs in order to design more effective therapeutic approaches. The evidence of epigenetic alterations, such as the dysregulation of different miRNAs that may stimulate many aspects of PD pathogenesis, opened a new scenario in the research for a successful treatment. Along this line, a promising strategy for PD treatment comes from the potential exploitation of modified exosomes, which can be loaded with bioactive molecules, such as therapeutic compounds and RNAs, and can allow their delivery to the appropriate location in the brain, overcoming the blood-brain barrier. In this regard, the transfer of miRNAs within Mesenchymal stem cell (MSC)-derived exosomes has yet to demonstrate successful results both in vitro and in vivo. This review, besides providing a systematic overview of both the genetic and epigenetic basis of the disease, aims to explore the exosomes/miRNAs network and its clinical potential for PD treatment.
Topics: Humans; Parkinson Disease; MicroRNAs; Dopaminergic Neurons; Brain; Epigenesis, Genetic
PubMed: 37298496
DOI: 10.3390/ijms24119547 -
Frontiers in Aging Neuroscience 2023Parkinson's disease (PD) is the second-most common neurodegenerative disease and is largely caused by the death of dopaminergic (DA) cells. Dopamine loss occurs in the... (Review)
Review
Parkinson's disease (PD) is the second-most common neurodegenerative disease and is largely caused by the death of dopaminergic (DA) cells. Dopamine loss occurs in the substantia nigra pars compacta and leads to dysfunctions in motor functions. Death of DA cells can occur with oxidative stress and dysfunction of glial cells caused by Parkinson-related gene mutations. Lactoferrin (Lf) is a multifunctional glycoprotein that is usually known for its presence in milk, but recent research shows that Lf is also found in the brain regions. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a known mitochondrial toxin that disturbs the mitochondrial electron transport chain (ETC) system and increases the rate of reactive oxygen species. Lf's high affinity for metals decreases the required iron for the Fenton reaction, reduces the oxidative damage to DA cells caused by MPTP, and increases their surveillance rate. Several studies also investigated Lf's effect on neurons that are treated with MPTP. The results pointed out that Lf's protective effect can also be observed without the presence of oxidative stress; thus, several potential mechanisms are currently being researched, starting with a potential HSPG-Lf interaction in the cellular membrane of DA cells. The presence of Lf activity in the brain region also showed that lactoferrin initiates receptor-mediated transcytosis in the blood-brain barrier (BBB) with the existence of lactoferrin receptors in the endothelial cells. The existence of Lf receptors both in endothelial cells and DA cells created the idea of using Lf as a secondary molecule in the transport of therapeutic agents across the BBB, especially in nanoparticle development.
PubMed: 37731953
DOI: 10.3389/fnagi.2023.1204149 -
Neurotoxicity Research Feb 2022Rotenone (RO)-induced neurotoxicity exhibits pathophysiological features similar to those reported in patients with Parkinson's disease (PD), such as nitrosative and...
Rotenone (RO)-induced neurotoxicity exhibits pathophysiological features similar to those reported in patients with Parkinson's disease (PD), such as nitrosative and oxidative stress, mitochondrial dysfunction, and neural cytoarchitecture alterations in the substantia nigra pars compacta (SNpc)/striatum (ST), which has been used for decades as an animal model of PD in humans. -Theanine (LT), a major amino acid component of green tea, exhibits potent antioxidant and anti-inflammatory activities and protects against various neural injuries. We investigated the potential therapeutic effects of LT on RO-induced behavioral and neurochemical dysfunction in rats and the neuroprotective mechanisms underlying these effects. Unilateral stereotaxic intranigral infusion of RO into the SNpc to induce PD-like manifestations induced significant behavioral impairment as evaluated using an open field test, rotarod test, grip strength measurement, and beam-crossing task in rats. LT treatment (300 mg/kg i.p., 21 days) ameliorated most RO-induced behavioral impairments. In addition, LT treatment reduced nitric oxide level and lipid peroxidation production, increased mitochondrial function and integrity, as well as the activities of mitochondrial complexes I, II, IV, and V, and reduced the levels of neuroinflammatory and apoptotic markers in the SNpc and ameliorated the levels of catecholamines, GABA and glutamate in the ST induced by RO. These results demonstrate the possible therapeutic effects of LT against RO-induced behavioral impairments, including antioxidative effects, prevention of mitochondrial dysfunction, prevention of neurochemical deficiency, anti-neuroinflammatory effects, and anti-apoptotic effects. This is the first report on the neuroprotective effect of LT against RO-induced behavioral impairments, and the above evidence provides a potential clinically relevant role for LT in the management of human PD.
Topics: Animals; Disease Models, Animal; Glutamates; Humans; Neuroprotective Agents; Parkinsonian Disorders; Rats; Rotenone
PubMed: 34988886
DOI: 10.1007/s12640-021-00451-w -
The Journal of Physiology Nov 2023A monosynaptic pathway connects the substantia nigra pars compacta (SNpc) to neurons of the dorsal motor nucleus of the vagus (DMV). This monosynaptic pathway modulates...
A monosynaptic pathway connects the substantia nigra pars compacta (SNpc) to neurons of the dorsal motor nucleus of the vagus (DMV). This monosynaptic pathway modulates the vagal control of gastric motility. It is not known, however, whether this nigro-vagal pathway also modulates the tone and motility of the proximal colon. In rats, microinjection of retrograde tracers in the proximal colon and of anterograde tracers in SNpc showed that bilaterally labelled colonic-projecting neurons in the DMV received inputs from SNpc neurons. Microinjections of the ionotropic glutamate receptor agonist, NMDA, in the SNpc increased proximal colonic motility and tone, as measured via a strain gauge aligned with the colonic circular smooth muscle; the motility increase was inhibited by acute subdiaphragmatic vagotomy. Upon transfection of SNpc with pAAV-hSyn-hM3D(Gq)-mCherry, chemogenetic activation of nigro-vagal nerve terminals by brainstem application of clozapine-N-oxide increased the firing rate of DMV neurons and proximal colon motility; both responses were abolished by brainstem pretreatment with the dopaminergic D1-like antagonist SCH23390. Chemogenetic inhibition of nigro-vagal nerve terminals following SNpc transfection with pAAV-hSyn-hM4D(Gi)-mCherry decreased the firing rate of DMV neurons and inhibited proximal colon motility. These data suggest that a nigro-vagal pathway modulates activity of the proximal colon motility tonically via a discrete dopaminergic synapse in a manner dependent on vagal efferent nerve activity. Impairment of this nigro-vagal pathway may contribute to the severely reduced colonic transit and prominent constipation observed in both patients and animal models of parkinsonism. KEY POINTS: Substantia nigra pars compacta (SNpc) neurons are connected to the dorsal motor nucleus of the vagus (DMV) neurons via a presumed direct pathway. Brainstem neurons in the lateral DMV innervate the proximal colon. Colonic-projecting DMV neurons receive inputs from neurons of the SNpc. The nigro-vagal pathway modulates tone and motility of the proximal colon via D1-like receptors in the DMV. The present study provides the mechanistic basis for explaining how SNpc alterations may lead to a high rate of constipation in patients with Parkinson's Disease.
Topics: Humans; Rats; Animals; Stomach; Rats, Sprague-Dawley; Substantia Nigra; Vagus Nerve; Gastrointestinal Motility; Colon; Constipation
PubMed: 37772988
DOI: 10.1113/JP284238 -
Metabolism Open Mar 2023Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease (AD). The pathologic hallmarks of the disease are the loss of...
Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease (AD). The pathologic hallmarks of the disease are the loss of dopaminergic neurons of substantia nigra pars compacta and the presence of intraneuronal alpha synuclein (a-syn) aggregates. Clinical features of PD include motor symptoms such as bradykinesia, rigidity, tremors, postural instability, and gait impairment, and non-motor symptoms such as constipation, orthostatic hypotension, REM sleep disorder, depression and dementia. Currently, there is no disease-modifying therapy for PD. Several human studies have shown that exercise reduces progression of motor symptoms, improves performance on cognitive tasks, and slows functional deterioration. However, regular exercise may not always be feasible in PD patients. Irisin is an exercise-induced myokine involved in metabolism modulation and body fat reduction, but it also crosses the blood-brain barrier and may mediate some of the benefits of exercise in brain function. Recent evidence has shown that irisin could be therapeutically promising in PD as an "exercise-mimicking" intervention. Exogenous irisin administration decreases brain a-syn pathology and loss of dopaminergic neurons, while it improves motor outcomes in preclinical models. Several other neurodegenerative disorders such as AD share common underlying pathogenetic mechanisms with PD such as protein misfolding and aggregation, neuroinflammation, brain metabolic abnormalities, and neuronal loss. Therefore, investigation of irisin as a disease-modifying therapy could be promising for PD and other neurodegenerative disorders including AD.
PubMed: 36785617
DOI: 10.1016/j.metop.2023.100233