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Ultrasound in Medicine & Biology Apr 2024Neonatal hypoxic-ischemic brain damage (HIBD) can have long-term implications on patients' physical and mental health, yet the available treatment options are limited....
OBJECTIVE
Neonatal hypoxic-ischemic brain damage (HIBD) can have long-term implications on patients' physical and mental health, yet the available treatment options are limited. Recent research has shown that low-intensity pulsed ultrasound (LIPUS) holds promise for treating neurodegenerative diseases and traumatic brain injuries. Our objective was to explore the therapeutic potential of LIPUS for HIBD.
METHODS
Due to the lack of a suitable animal model for neonatal HIBD, we will initially simulate the therapeutic effects of LIPUS on neuronal cells under oxidative stress and neuroinflammation using cell experiments. Previous studies have investigated the biologic responses following intracranial injection of 6-hydroxydopamine (6-OHDA). In this experiment, we will focus on the biologic effects produced by LIPUS treatment on neuronal cells (specifically, SH-SY5Y cells) without the presence of other neuroglial cell assistance after stimulation with 6-OHDA.
RESULTS
We found that (i) pulsed ultrasound exposure, specifically three-intermittent sonication at intensities ranging from 0.1 to 0.5 W/cm², did not lead to a significant decrease in viability among SH-SY5Y cells; (ii) LIPUS treatment exhibited a positive effect on cell viability, accompanied by an increase in glial cell-derived neurotrophic factor (GDNF) levels and a decrease in caspase three levels; (iii) the administration of 6-OHDA had a significant impact on cell viability, resulting in a decrease in both brain cell-derived neurotrophic factor (BDNF) and GDNF levels, while concurrently elevating caspase three and matrix metalloproteinase-9 (MMP-9) levels; and (iv) LIPUS treatment demonstrated its potential to alleviate the changes induced by 6-OHDA, particularly in the levels of BDNF, GDNF, and tyrosine hydroxylase (TH).
CONCLUSION
LIPUS treatment may possess partial therapeutic capabilities for SH-SY5Y cells damaged by 6-OHDA neurotoxicity. Our findings enhance our understanding of the effects of LIPUS treatment on cell viability and its modulation of key factors involved in the pathophysiology of HIBD and show the promising potential of LIPUS as an alternative therapeutic approach for neonates with HIBD.
Topics: Animals; Infant, Newborn; Humans; Brain-Derived Neurotrophic Factor; Oxidopamine; Glial Cell Line-Derived Neurotrophic Factor; Neuroblastoma; Ultrasonic Waves; Caspases; Biological Products
PubMed: 38290910
DOI: 10.1016/j.ultrasmedbio.2024.01.004 -
ACS Chemical Neuroscience Feb 2024Abnormal glutamate signaling is implicated in the heightened vulnerability of dopaminergic neurons in Parkinson's disease (PD). NMDA receptors are ion-gated glutamate...
Abnormal glutamate signaling is implicated in the heightened vulnerability of dopaminergic neurons in Parkinson's disease (PD). NMDA receptors are ion-gated glutamate receptors with high calcium permeability, and their GluN2D subunits are prominently distributed in the basal ganglia and brainstem nuclei. Previous studies have reported that dopamine depletion led to the dysfunctions of GluN2D-containing NMDA receptors in PD animal models. However, it remains unknown whether selective modulation of GluN2D could protect dopaminergic neurons against neurotoxicity in PD. In this study, we found that allosteric activation of GluN2D-containing NMDA receptors decreased the cell viability of MES23.5 dopaminergic cells and the GluN2D inhibitor, QNZ46, showed antioxidant effects and significantly relieved apoptosis in 6-OHDA-treated cells. Meanwhile, we demonstrated that QNZ46 might act via activation of the ERK/NRF2/HO-1 pathway. We also verified that QNZ46 could rescue abnormal behaviors and attenuate dopaminergic cell loss in a 6-OHDA-lesioned rat model of PD. Although the precise mechanisms underlying the efficacy of QNZ46 remain elusive, the inhibition of the GluN2D subunit should be a considerable way to treat PD. More GluN2D-selective drugs, which present minimal side effects and broad therapeutic windows, need to be developed for PD treatment in future studies.
Topics: Rats; Animals; Oxidopamine; Dopaminergic Neurons; Receptors, N-Methyl-D-Aspartate; NF-E2-Related Factor 2; Signal Transduction; Neurotoxicity Syndromes; Parkinson Disease
PubMed: 38277219
DOI: 10.1021/acschemneuro.3c00608 -
Behavioural Brain Research Mar 2024Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the Substantia nigra pars compacta...
Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the Substantia nigra pars compacta (SNpc), which leads to motor and non-motor symptoms (NMS). NMS can appear many years before the classical motor symptoms and are associated with the neurodegeneration of several nuclei; in this work, we highlight the neurodegeneration of Locus coeruleus (LC) in PD. The aim was to investigate the effects of depleting SNpc and LC catecholaminergic neurons on behavioral and neurobiological endpoints. Here we used 6-hydroxydopamine (6-OHDA) in order to induced neurotoxic damage in three independent experimental groups: SNpc lesion group, which 6-OHDA was injected into CPu (CPu-6-OHDA), LC lesion group, which 6-OHDA was injected directly on LC to selectively caused a damage on this nucleus (LC-6-OHDA), and the combined SNpc and LC lesion group (CL-6-OHDA). Next, the behavioral studies were performed using the Morris water maze (MWM), open field (OF), and elevated plus maze (EPM). After stereotaxic surgeries, the animals showed a loss of 67% and 77% of Tyrosine hydroxylase (TH) reactive neurons in the SNpc and LC, respectively. The behavioral analysis showed the anxiety-like behavior in CL-6-OHDA group in the EPM test; in the MWM test, the combined lesions (CL-6-OHDA) showed an impairment in memory acquisition and spatial memory; and no changes were observed in locomotor activity in all the tests. Furthermore, our investigation demonstrating the effects of depleting SN and LC catecholaminergic neurons on behavioral and neurobiological parameters. All these data together lead us to believe that a bilateral PD model including a LC bilateral degeneration is potentially a more accurate model to evaluate the NMS in the pathological development of the disease in rodents.
Topics: Animals; Oxidopamine; Parkinson Disease; Rodentia; Locus Coeruleus; Dopaminergic Neurons; Substantia Nigra; Disease Models, Animal
PubMed: 38266776
DOI: 10.1016/j.bbr.2024.114873 -
European Journal of Pharmaceutical... Mar 2024Parkinson's disease is the second most prevalent age-related neurodegenerative disease and disrupts the lives of people aged >60 years. Meanwhile, single-target drugs...
Parkinson's disease is the second most prevalent age-related neurodegenerative disease and disrupts the lives of people aged >60 years. Meanwhile, single-target drugs becoming inapplicable as PD pathogenesis diversifies. Mitochondrial dysfunction and neurotoxicity have been shown to be relevant to the pathogenesis of PD. The novel synthetic compound J24335 (11-Hydroxy-1-(8-methoxy-5-(trifluoromethyl)quinolin-2-yl)undecan-1-one oxime), which has been researched similarly to J2326, has the potential to be a multi-targeted drug and alleviate these lesions. Therefore, we investigated the mechanism of action and potential neuroprotective function of J24335 against 6-OHDA-induced neurotoxicity in mice, and in PC12 cell models. The key target of action of J24335 was also screened. MTT assay, LDH assay, flow cytometry, RT-PCR, LC-MS, OCR and ECAR detection, and Western Blot analysis were performed to characterize the neuroprotective effects of J24335 on PC12 cells and its potential mechanism. Behavioral tests and immunohistochemistry were used to evaluate behavioral changes and brain lesions in mice. Moreover, bioinformatics was employed to assess the drug-likeness of J24335 and screen its potential targets. J24335 attenuated the degradation of mitochondrial membrane potential and enhanced glucose metabolism and mitochondrial biosynthesis to ameliorate 6-OHDA-induced mitochondrial dysfunction. Animal behavioral tests demonstrated that J24335 markedly improved motor function and loss of TH-positive neurons and dopaminergic nerve fibers, and contributed to an increase in the levels of dopamine and its metabolites in brain tissue. The activation of both the CREB/PGC-1α/NRF-1/TFAM and PKA/Akt/GSK-3β pathways was a major contributor to the neuroprotective effects of J24335. Furthermore, bioinformatics predictions revealed that J24335 is a low toxicity and highly BBB permeable compound targeting 8 key genes (SRC, EGFR, ERBB2, SYK, MAPK14, LYN, NTRK1 and PTPN1). Molecular docking suggested a strong and stable binding between J24335 and the 8 core targets. Taken together, our results indicated that J24335, as a multi-targeted neuroprotective agent with promising therapeutic potential for PD, could protect against 6-OHDA-induced neurotoxicity via two potential pathways in mice and PC12 cells.
Topics: Humans; Rats; Mice; Animals; Oxidopamine; Neuroprotective Agents; PC12 Cells; Neurodegenerative Diseases; Glycogen Synthase Kinase 3 beta; Molecular Docking Simulation; Dopamine; Mitochondrial Diseases; Dopaminergic Neurons
PubMed: 38199443
DOI: 10.1016/j.ejps.2024.106696 -
Journal of Molecular Neuroscience : MN Jan 2024The sympathetic nervous system (SNS) affects many functions of the body. SNS fibers regulate many aspects of liver function, repair, and regeneration. However, in the...
The sympathetic nervous system (SNS) affects many functions of the body. SNS fibers regulate many aspects of liver function, repair, and regeneration. However, in the model of bile duct ligation (BDL) in rats, the kind of impact caused by the regulation of liver SNS on liver fibrosis and liver regeneration is unclear. The main research objective of this experiment is to examine the effect of SNS on liver fibrosis and liver regeneration. Twenty-four male Sprague-Dawley (SD) rats were assigned randomly to four groups. These groups included the sham surgery group (sham), model group (BDL), 6-hydroxydopamine group (BDL+6-OHDA), and spinal cord injury group (BDL+SCI). In the sham group, only exploratory laparotomy was performed without BDL. In the 6-OHDA group, 6-OHDA was used to remove sympathetic nerves after BDL. In the spinal cord injury group, rats underwent simultaneous BDL and spinal cord injury. After 3 weeks of feeding, four groups of rats were euthanized using high-dose anesthesia without pain. Moreover, liver tissue and blood were taken to detect liver fibrosis and regeneration indicators. After intraperitoneal injection of 6-OHDA into BDL rats, liver fibrosis indicators decreased. The administration of the injection effectively alleviated liver fibrosis and inhibited liver regeneration. However, after SCI surgery in BDL rats, liver fibrosis indicators increased. This resulted in exacerbating liver fibrosis and activating liver regeneration. The SNS plays a role in contributing to the liver injury process in the rat BDL model. Therefore, regulating the SNS may become a novel method for liver injury treatment.
Topics: Animals; Male; Rats; Bile Ducts; Liver Cirrhosis; Oxidopamine; Rats, Sprague-Dawley; Spinal Cord Injuries; Sympathetic Nervous System
PubMed: 38183518
DOI: 10.1007/s12031-023-02176-1 -
Neurobiology of Disease Feb 2024Parkinson's disease (PD) is characterized by the progressive and asymmetrical degeneration of the nigrostriatal dopamine neurons and the unilateral presentation of the...
Parkinson's disease (PD) is characterized by the progressive and asymmetrical degeneration of the nigrostriatal dopamine neurons and the unilateral presentation of the motor symptoms at onset, contralateral to the most impaired hemisphere. We previously developed a rat PD model that mimics these typical features, based on unilateral injection of a substrate inhibitor of excitatory amino acid transporters, L-trans-pyrrolidine-2,4-dicarboxylate (PDC), in the substantia nigra (SN). Here, we used this progressive model in a multilevel study (behavioral testing, in vivo H-magnetic resonance spectroscopy, slice electrophysiology, immunocytochemistry and in situ hybridization) to characterize the functional changes occurring in the cortico-basal ganglia-cortical network in an evolving asymmetrical neurodegeneration context and their possible contribution to the cell death progression. We focused on the corticostriatal input and the subthalamic nucleus (STN), two glutamate components with major implications in PD pathophysiology. In the striatum, glutamate and glutamine levels increased from presymptomatic stages in the PDC-injected hemisphere only, which also showed enhanced glutamatergic transmission and loss of plasticity at corticostriatal synapses assessed at symptomatic stage. Surprisingly, the contralateral STN showed earlier and stronger reactivity than the ipsilateral side (increased intraneuronal cytochrome oxidase subunit I mRNA levels; enhanced glutamate and glutamine concentrations). Moreover, its lesion at early presymptomatic stage halted the ongoing neurodegeneration in the PDC-injected SN and prevented the expression of motor asymmetry. These findings reveal the existence of endogenous interhemispheric processes linking the primary injured SN and the contralateral STN that could sustain progressive dopamine neuron loss, opening new perspectives for disease-modifying treatment of PD.
Topics: Rats; Animals; Subthalamic Nucleus; Dopaminergic Neurons; Dopamine; Glutamine; Parkinsonian Disorders; Parkinson Disease; Substantia Nigra; Glutamates; Oxidopamine
PubMed: 38182075
DOI: 10.1016/j.nbd.2023.106398 -
Neuroscience Feb 2024Virgin and pups-naïve female and male adult mice display two opposite responses when they are exposed to pups for the first time. While females generally take care of...
Virgin and pups-naïve female and male adult mice display two opposite responses when they are exposed to pups for the first time. While females generally take care of the pups, males attack them. Since the nucleus accumbens (NA), and its dopaminergic modulation, is critical in integrating information and processing reward and aversion, we investigated if NMDA- and 6-OHDA-induced lesions, damaging mostly NA output and dopaminergic inputs respectively, affected female maternal behavior (MB) or male infanticidal behavior (IB) in mice. Our results revealed minor or no effects of both smaller and larger NMDA-induced lesions in MB and IB. On the other hand, while 6-OHDA-induced lesions in females reduced the incidence of full MB (12.5% 6-OHDA vs. 85.7% SHAM) increasing the latency to retrieve the pups, those lesions did not affect IB in males. There were no differences in locomotor and exploratory activity between the lesioned- and SHAM- females. Despite those lesions did not induce any major effect on IB, NMDA-lesioned males spent less time in the central area of an open field, while dopaminergic-lesioned males showed reduced number of rearing and peripheral crosses. The current study shows that an intact NA is not necessary for the expression of MB and IB. However, dopaminergic inputs to NA play different role in MB and IB. While damaging dopaminergic terminals into the NA did not affect IB, it clearly delayed the more flexible and rewarding expression of parental behavior.
Topics: Mice; Animals; Female; Male; Humans; Nucleus Accumbens; Oxidopamine; N-Methylaspartate; Dopamine; Maternal Behavior
PubMed: 38176609
DOI: 10.1016/j.neuroscience.2023.12.009 -
Acta Neuropathologica Communications Jan 2024Parthanatos represents a critical molecular aspect of Parkinson's disease, wherein AIMP2 aberrantly activates PARP-1 through direct physical interaction. Although AIMP2...
BACKGROUND
Parthanatos represents a critical molecular aspect of Parkinson's disease, wherein AIMP2 aberrantly activates PARP-1 through direct physical interaction. Although AIMP2 ought to be a therapeutic target for the disease, regrettably, it is deemed undruggable due to its non-enzymatic nature and predominant localization within the tRNA synthetase multi-complex. Instead, AIMP2 possesses an antagonistic splice variant, designated DX2, which counteracts AIMP2-induced apoptosis in the p53 or inflammatory pathway. Consequently, we examined whether DX2 competes with AIMP2 for PARP-1 activation and is therapeutically effective in Parkinson's disease.
METHODS
The binding affinity of AIMP2 and DX2 to PARP-1 was contrasted through immunoprecipitation. The efficacy of DX2 in neuronal cell death was assessed under 6-OHDA and H2O2 in vitro conditions. Additionally, endosomal and exosomal activity of synaptic vesicles was gauged in AIMP2 or DX2 overexpressed hippocampal primary neurons utilizing optical live imaging with VAMP-vGlut1 probes. To ascertain the role of DX2 in vivo, rotenone-induced behavioral alterations were compared between wild-type and DX2 transgenic animals. A DX2-encoding self-complementary adeno-associated virus (scAAV) was intracranially injected into 6-OHDA induced in vivo animal models, and their mobility was examined. Subsequently, the isolated brain tissues were analyzed.
RESULTS
DX2 translocates into the nucleus upon ROS stress more rapidly than AIMP2. The binding affinity of DX2 to PARP-1 appeared to be more robust compared to that of AIMP2, resulting in the inhibition of PARP-1 induced neuronal cell death. DX2 transgenic animals exhibited neuroprotective behavior in rotenone-induced neuronal damage conditions. Following a single intracranial injection of AAV-DX2, both behavior and mobility were consistently ameliorated in neurodegenerative animal models induced by 6-OHDA.
CONCLUSION
AIMP2 and DX2 are proposed to engage in bidirectional regulation of parthanatos. They physically interact with PARP-1. Notably, DX2's cell survival properties manifest exclusively in the context of abnormal AIMP2 accumulation, devoid of any tumorigenic effects. This suggests that DX2 could represent a distinctive therapeutic target for addressing Parkinson's disease in patients.
Topics: Animals; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Nuclear Proteins; Hydrogen Peroxide; Oxidopamine; Parkinson Disease; Parthanatos; Rotenone; Cell Line, Tumor
PubMed: 38172953
DOI: 10.1186/s40478-023-01697-5 -
Journal of Ethnopharmacology Mar 2024Piper longum L., a medicinal and food homologous herb, has a traditional history of use in treating gastrointestinal and neurological disorders. Piperine (PIP) the main...
ETHNOPHARMACOLOGICAL RELEVANCE
Piper longum L., a medicinal and food homologous herb, has a traditional history of use in treating gastrointestinal and neurological disorders. Piperine (PIP) the main alkaloid of P. longum, exists neuroprotective effects on various animal models of Parkinson's disease (PD). Nevertheless, the underlying mechanism, particularly the role of PIP in promoting gut-brain autophagy for α-Synuclein (α-Syn) degradation in PD, remains incompletely understood.
AIM OF THE STUDY
To explore the role of PIP in regulating the gut-brain autophagy signaling pathway to reduce α-Syn levels in both the colon and substantia nigra (SN) of PD model rats.
MATERIALS AND METHODS
Behavioral experiments were conducted to assess the impact of PIP on 6-hydroxydopamine (6-OHDA)-induced PD rats. The intestinal microbiome composition and intestinal metabolites were analyzed by metagenomics and GC-MS/MS. The auto-phagosomes were visualized by transmission electron microscopy. Immunohistochemistry, immunofluorescence, and western blotting were performed to assess the levels of tyrosine hydroxylase (TH), α-Syn, LC3II/LC3I, p62, and the PI3K/AKT/mTOR pathway in both the SN and colon of the rats. The pathway-related inhibitor and agonist were used to verify the autophagy mechanism in the SH-SY5Y cells overexpressing A53T mutant α-Syn (A53T-α-Syn).
RESULTS
PIP improved autonomic movement and gastrointestinal dysfunctions, reduced α-Syn aggregation and attenuated the loss of dopaminergic neurons in 6-OHDA-induced PD rats. After oral administration of PIP, the radio of LC3II/LC3I increased and the expression of p62 was degraded, as well as the phosphorylation levels of PI3K, AKT and mTOR decreased in the SN and colon of rats. The effect of PIP on reducing A53T-α-Syn through the activation of the PI3K/AKT/mTOR-mediated autophagy pathway was further confirmed in A53T-α-Syn transgenic SH-SY5Y cells. This effect could be inhibited by the autophagy inhibitor bafilomycin A1 and the PI3K agonist 740 Y-P.
CONCLUSIONS
Our findings suggested that PIP could protect neurons by activating autophagy to degrade α-Syn in the SN and colon, which were related to the suppression of PIP on the activation of PI3K/AKT/mTOR signaling pathway.
Topics: Rats; Humans; Animals; Parkinson Disease; alpha-Synuclein; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Oxidopamine; Tandem Mass Spectrometry; Neuroblastoma; Alkaloids; TOR Serine-Threonine Kinases; Brain; Autophagy; Piperidines; Benzodioxoles; Polyunsaturated Alkamides
PubMed: 38158101
DOI: 10.1016/j.jep.2023.117628 -
Brain Stimulation 2024This study aims to investigate the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on the development of systemic lupus erythematosus (SLE) in...
Locus coeruleus tyrosine hydroxylase positive neurons mediated the peripheral and central therapeutic effects of transcutaneous auricular vagus nerve stimulation (taVNS) in MRL/lpr mice.
OBJECTIVE
This study aims to investigate the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on the development of systemic lupus erythematosus (SLE) in MRL/lpr mice.
METHODS
MRL/lpr mice were treated with taVNS for ten weeks. Locus coeruleus (LC) tyrosine hydroxylase positive (TH) neurons were selectively lesioned by stereotactic injection of 6-hydroxydopamine (6-OHDA) or selectively activated by chemogenetic methods. Sympathetic denervation was conducted by intraperitoneal injection of 6-OHDA.
RESULTS
TaVNS activated the TH neurons in LC. TaVNS produced central therapeutic effects by reducing the number of hippocampal microglia, and increasing the number of surviving LC TH neurons in MRL/lpr mice. TaVNS also retarded the development of lymphadenectasis and splenomegaly, decreased the proportion of double-negative T (DNT) cells, and alleviated nephritis in MRL/lpr mice. The lesion of LC TH neurons eliminated both these central and peripheral therapeutic effects of taVNS, while chemogenetic activation of LC TH neurons mimicked most central and peripheral protective effects of taVNS in MRL/lpr mice. Furthermore, taVNS regulated the autonomic nervous system in MRL/lpr mice.
CONCLUSION
This study provides direct evidence that taVNS can retard the development of peripheral and central symptoms of SLE, which is mediated by the LC TH neurons.
Topics: Mice; Animals; Locus Coeruleus; Tyrosine 3-Monooxygenase; Vagus Nerve Stimulation; Mice, Inbred MRL lpr; Oxidopamine; Transcutaneous Electric Nerve Stimulation; Lupus Erythematosus, Systemic; Neurons; Vagus Nerve
PubMed: 38145753
DOI: 10.1016/j.brs.2023.12.008