Tyrosine Hydroxylase Research Articles

Transient receptor potential vanilloid 2 (TRPV2) channels modulate the nigrostriatal dopaminergic activity in rats.

Neuroprotective effects of Lactiplantibacillus plantarum and Pediococcus pentosaceus strains against oxidative stress via modulation of Nrf2-mediated antioxidation and anti-apoptosis.

Recombinant IL-1β induces striatal dopamine depletion in aged rats: Involvement of histamine H1 receptors.

Parkinson's disease (PD) is a multifaceted disease that is influenced by both genetic and environmental parameters. Non-coding RNAs have been shown to be ideal biomarkers for several diseases, including PD. This study was conducted to evaluate the expression levels of NEAT1, hsa-let-7a-5p, and miR-506-3p in individuals with PD to assess their efficacy for early-stage PD diagnosis. Twenty-four patients with PD and 29 healthy individuals participated in this study. The IntaRNA tool was used to predict potential base pairings between NEAT1 and let-7a-5p, and NEAT1 and miR-506-3p. RT-qPCR was employed to measure the relative expression of tyrosine hydroxylase (TH), as well as nuclear enriched abundant transcript 1 (NEAT1), hsa-let-7a-5p, and miR-506-3p levels in both groups. The area under the receiver operating characteristic curve (AUC) was calculated to evaluate the diagnostic value. The PD group exhibited significantly elevated NEAT1 expression levels compared to the healthy control group. While the PD group exhibited an insignificant decreased TH expression level relative to the healthy group. Furthermore, the levels of hsa-let-7a-5p and miR-506-3p expression were seen to be decreased in patients with PD in comparison to the control group. Integration of NEAT1, hsa-let-7a-5p, and miR-506-3p levels significantly enhanced diagnostic capabilities and increased the AUC to 0.9501 (95% confidence interval: 0.8978-1.000, p < .0001). The elevated NEAT1 expression and the decreased expression of hsalet- 7a-5p and miR-506-3p in PD patients indicate that these factors might contribute to the disease's pathogenesis. Combining the ROC curves of NEAT1 and hsa-let-7a-5p with miR-506-3p showed improved sensitivity and specificity, facilitating more accurate PD diagnosis. More importantly, they may contribute as promising non-invasive biomarkers for PD diagnosis.

To investigate the underlying mechanisms through which electroacupuncture (EA) at the Guanyuan (CV4) acupoint inhibits sympathetic activity and neurogenic inflammatory responses to relieve pain in rats with pelvic inflammatory disease (PID). Escherichia coli and Staphylococcus aureus were used to establish a PID rat model. EA was evaluated at frequencies of 2, 100, and 2/100 Hz, and 2/100 Hz was selected for subsequent investigation. The rats were randomly divided into the control, model, EA-guanyuan (2/100 Hz), and EA-nonsensitized groups (n = 6). Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were assessed using von Frey filaments. Hematoxylin and eosin staining was performed to evaluate the histopathology. The tyrosine hydroxylase (TH) expression was analyzed using immunofluorescence (IF) staining. The levels of tumor necrosis factor-α (TNF-α), interleukin-2 (IL-2), transforming growth factor-β1 (TGF-β1), intercellular cell adhesion molecule-1 (ICAM-1), 5-hydroxytryptamine receptor 3 (5-HT3R), substance P (SP), hyaluronic acid (HA), and bradykinin (BK) were measured using an enzyme-linked immunosorbent assay (ELISA). Western blot analysis was performed to measure the expression of 5-HT3R, calcitonin gene-related peptide (CGRP), HA, Kininogen 1 (KNG1), prostaglandin I2 (PGI2), and trefoil factor 2 (TFF2). Transmission electron microscopy (TEM) was used to observe synaptic connections. EA at CV4 reduced the behavioral pain score (p < 0.05), increased MWT and TWL, and alleviated uterine tissue pathological damage in rats. EA at CV4 reduced the levels of 5-HT3R, CGRP, BK, HA, KNG1, PGI2SP, TGF-β1, ICAM-1, and TNF-α, and increased IL-2 levels (p < 0.05). Furthermore, EA at CV4 inhibited sympathetic activity by decreasing TH expression (p < 0.05). Additionally, EA at CV4 restored the synaptic connections between the pelvic nerves of the dorsal commissural neuron (DCN). EA at CV4 alleviated the pathological damage and pain sensitization of uterine tissue in rats with PID by inhibiting sympathetic activity and neurogenic inflammatory response.

MCH11, a new monoacylglycerol lipase inhibitor, reduces ethanol consumption and motivation to drink in mice, with sex-dependent differences.

Remote ischemic conditioning as a potential therapy for Parkinson's Disease: Inhibiting TLR4-Driven neuroinflammation and oxidative damage.

Sinapic acid attenuates PERK-dependent ER stress signaling and resolves α-synuclein pathology in rotenone-induced Parkinson's disease rat model.

Persistent COX-2 upregulation in L-DOPA-induced dyskinesia is unaffected by inhibition with celecoxib.

Differential effects of acute and chronic fluoxetine on c-Fos expression in specific subpopulations of midbrain dopaminergic neurons.

From rodents to humans: Conserved codistribution of dopaminergic with serotonergic neurons in the dorsal raphe nucleus and their molecular characterization.

Metabolic engineering of Pichia pastoris as an industrial chassis enables biosynthesis of dopamine from methanol.

A myeloid Tet2-IL-1β axis modulates intestinal inflammation by restricting catecholaminergic stimulation of enterochromaffin cell differentiation.

Memantine modulates neuroinflammation and motor coordination in a Parkinson's disease model.

Parkinson’s disease (PD) is a neurodegenerative disorder associated with neuroinflammation and gut dysfunction. The G protein-coupled estrogen receptor (GPER) has showed therapeutic potential in inflammatory bowel diseases (IBD), yet its role and underlying mechanisms in PD remain unclear. Here, we aimed to investigate the role and mechanisms of GPER in protecting PD. Female mice underwent bilateral ovariectomies (OVX) and were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce PD, followed by administration of GPER agonist G1. The expressions of tyrosine hydroxylase (TH) and α-synuclein (α-syn), as well as activations of inflammatory cells and NLRP3 inflammasome in the brain and ileum were evaluated. BV2 cells were pretreated with G1 and/or the antagonist G15, then treated with LPS and ATP to activate NLRP3 inflammasome. Activation of NLRP3 inflammasome in BV2 cells was assessed. Results demonstrated that G1 treatment increased TH expression, reduced α-syn expression, and suppressed inflammation and NLRP3 inflammasome in both the midbrain and ileum of MPTP-treated OVX mice. Pretreatment with G1 suppressed the activation of NLRP3 inflammasome in BV2 cells, while the effect was reversed by G15. These findings indicate that GPER activation exerts a protective effect in MPTP-induced OVX mice by modulating NLRP3 inflammasome in both brain and gut, which might provide novel insights into the pathogenesis and therapy of PD.

Abstract Previous research revealed a reduction in the VGF immunoreactivity within the substantia nigra (SN) of rats with a 60–90% dopaminergic neuron loss and in the plasma of newly diagnosed Parkinson’s disease (PD) patients. Hence, our aim was to explore whether central and peripheral proVGF changes occur during early dopaminergic dysfunction. To investigate this, we employed a rat model mimicking early-stage PD by injecting the SN unilaterally with an adeno-associated virus (AAV) carrying either the human α-synuclein (α-syn; n = 19) or green fluorescent protein (GFP; n = 18) gene. After conducting motor assessments and sacrificing the animals, brain and blood samples were collected. Tyrosine hydroxylase (TH)-, glutamic acid decarboxylase (GAD)-, and phosphorylated (p)-α-syn antibodies were used for immunohistochemistry (IHC), while an antibody targeting the C-terminus of proVGF was employed for IHC, western blot (WB), and enzyme linked immunosorbent asssay (ELISA). The α-syn overexpression caused a modest (~ 30%) reduction in TH immunoreactivity within the SN—without affecting the striatum—and did so without producing overt motor symptoms, effectively modeling a pre-symptomatic PD stage. This early dopaminergic dysfunction was accompanied by decreased immunostaining for both proVGF C-trerminus and GAD in the SN, but not the striatum. Reduction in plasma proVGF levels were also observed, indicating systemic changes during initial dopaminergic impairment. Analysis using WB confirmed a decrease in a 70 kDa band consistent with proVGF in both SN and plasma. These findings suggest proVGF as a promising early biomarker for PD, opening new avenues for intervention before the onset of clinical symptoms.

Introduction: Parkinson’s Disease (PD) is considered the second most frequent neurodegenerative disease in the world, affecting approximately 8.5 million people. Numerous efforts remain in the development of therapies that overcome the limitations of the treatments used for PD, Thus, gene therapy appears to be a promising technique for the treatment of this disease. Objective: To understand the most recent advances in the development of gene therapies for the treatment of PD. Method: The search was carried out in PubMed, Scopus and Cochrane databases using the terms “Genetic Therapy” AND “Parkinson Disease”. The inclusion criteria were complete, free and original articles (clinical trials, cohort, postmortem and in vitro studies) published between 2019 and 2024. Reviews, case series, case-reports, abstracts, letters to the editors, commentaries and animal studies were excluded. Results: neurturin infusion resulted in positive tyrosine hydroxylase staining, dopaminergic activity in substantia nigra and putamen and dopaminergic neuron survival. However, it shows limitations to the sites where it was injected and does not address underlying Lewy body accumulation and α-synuclein particles. Glia cell line-derived neurotrophic factor infusion increased tyrosine hydroxylase concentration and restored neural pathways. VY-AADC01 administration improved responses to levodopa therapy and lower dose requirements to control symptoms. Therapy on exon skipping the mutated PRKN2 gene can be used to maintain neuron function and avoid degradation, a potentially therapy for juvenile-onset PD. Conclusion: Gene therapy offers disease modifying and non-modifying approaches to PD treatment, showing significant advancements that may provide long-lasting treatment alternatives in the future.

Neurotrophins (BDNF, NGF, NT3, and NT4/5) acting through different receptors are able to impact numerous functions, including cell fate and morphological plasticity, an asset for the maturation and differentiation of cells from neurogenic niches. They bind to the neurotrophin receptor p75 (p75), which could either heterodimerize with Trk receptors or act on its own to relay the varied physiological functions of neurotrophins. Published data suggest a preponderant role of p75 for NGF stimulation of GnRH neurons in vitro. We therefore focused on this receptor and its relationships with neuronal populations involved in the central control of reproduction. Here we investigated the distribution and phenotype of p75 cells in the hypothalamus of ovariectomized estrogen-replaced mice using several combinations of immunohistochemical labeling. We found that p75 is expressed mainly in neurons of the organum vasculosum of the lamina terminalis (OVLT)-medial septum continuum and in the arcuate nucleus (ARC). In this latter region, p75 was also seen in tanycytic cells lining the third ventricle. Co-distribution of p75 with TrkA was only seen in the OVLT, an area in which p75 is present in 16% of nitric oxide synthase-expressing neurons. In the ARC, 33% of p75 neurons were colocalized with tyrosine hydroxylase, an enzyme essential for catecholamine production. Anatomical distribution and co-expression with neurotransmitters involved in reproduction control, together with data suggesting that β-NGF induced ovulation in camelidae, prompted us to perform immunohistochemical double labeling against p75 and kisspeptin or GnRH, two neuropeptides essential for the central control of ovulation. However, no colocalization of p75 with kisspeptin or GnRH neurons was seen. These results suggest that neurotrophins, acting via the p75 receptor, do not directly modulate GnRH or Kp neurons. On the other hand, they may influence dopamine and nitric oxide production, and possibly induce remodeling of tanycytic endfeet, ultimately impacting indirectly the central regulation of reproduction in mice.

Cardiac autonomic pathways can be interrogated using optogenetics via selective expression of channelrhodopsin (ChR2) within intrinsic cardiac neurons. We tested the hypothesis that cholinergic activation via exogenous acetylcholine (ACh) would suppress the beta-adrenergic heart rate (HR) acceleration induced by tyrosine hydroxylase (TH) neuron stimulation. HR responses were measured for wild-type (WT) mice at increasing norepinephrine (NE) concentrations and for transgenic mice that expressed ChR2 in TH neurons while illuminating the right atrium using a 465nm microLED. Light pulse duty cycles (at 5Hz) increasing from 5-50% caused proportional increases in HR; however, HR was unstable at duty cycles >30%. At 20% duty cycle, HR increased 39.43±6.79%. HR increased for light pulse frequencies from 2.5-15Hz (30ms pulse width) but HR was unstable at 15Hz. HR increases for photostimulated TH hearts (TH) and WT hearts perfused with NE (1-800nM, WT+NE) had similar maxima but drastically different rise time constants (1.54±0.08 vs 18.04±3.87 sec, respectively). Increasing doses of ACh were added to the perfusate of WT+NE hearts and photostimulated TH hearts. High doses of ACh significantly diminished NE-induced and light-induced HR increases. Optogenetic activation of TH neurons caused rapid HR acceleration that was suppressed at higher ACh concentration than that required to suppress acceleration during NE perfusion. In WT+NE hearts this occurred at 400nM ACh and in TH hearts this did not occur until 1800nM ACh. AV block occurred more rapidly in TH hearts during photostimulation as ACh concentration increased, demonstrating a time-dependent element in the interaction of simultaneous cholinergic and adrenergic activation.

BackgroundParkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons, primarily due to mitochondrial dysfunction. Current treatments focus on managing symptoms but are unable to regenerate neurons. Human dental pulp stem cells (hDPSCs) offer a promising source for neurodegenerative therapy due to their accessibility and neuro-supportive properties. However, research on the mitochondrial characteristics of hDPSCs and their therapeutic potential remains limited. This study investigates the capacity of mitochondria isolated from hDPSCs to restore mitochondrial function and promote neuronal recovery and function in a PD cellular model.MethodshDPSCs were isolated and characterized for mesenchymal stem cell properties. Mitochondria were isolated, quantified, and assessed for viability and morphology using MitoTracker staining and transmission electron microscopy. Mitochondrial uptake and functional recovery were evaluated in a PD cellular model using MPP⁺-treated differentiated SH-SY5Y cells. Mitochondrial function was assessed by measuring Complex I activity, ATP production, and reactive oxygen species (ROS) levels. Neuroregeneration and synaptic function were analyzed through neurite length, growth-associated protein 43 (GAP43) and tyrosine hydroxylase (TH), Synaptophysin (SYP), dopamine transporter (DAT), calcium imaging, and mitochondrial dynamics.ResultsIsolated hDPSC-derived mitochondria were mostly viable, spherical, and displayed immature cristae. In MPP⁺-treated SH-SY5Y cells, mitochondrial transfer restored Complex I activity, elevated ATP production, and reduced ROS. Treated cells also showed significantly longer neurites and increased expression of GAP43, TH, SYP, and DAT. Calcium imaging revealed restored intracellular calcium responses upon stimulation. Mitochondria from hDPSCs localized in both cell bodies and neurites and remained distinct from damaged host mitochondria, supporting synaptic function.ConclusionsMitochondria derived from hDPSCs can restore bioenergetic function, reduce oxidative stress, and promote structural and functional recovery in a PD cellular model. These findings highlight the foundational therapeutic potential of hDPSC-derived mitochondria as a regenerative approach for neurodegenerative diseases.