Increased Tyrosine Hydroxylase Research Articles

Paracentrotus lividus sea urchin gonadal extract mitigates neurotoxicity and inflammatory signaling in a rat model of Parkinson's disease.

The present study investigates the neuroprotective effects of the sea urchin Paracentrotus lividus gonadal extract on rotenone-induced neurotoxicity in a Parkinson's disease (PD) rat model. Parkinson's disease, characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN), is exacerbated by oxidative stress and neuroinflammation. The study involved fifty Wistar rats divided into five groups: control, dimethyl sulfoxide (DMSO) control, Paracentrotus lividus gonadal extract-treated, rotenone-treated, and combined rotenone with Paracentrotus lividus gonadal extract-treated. Behavioral assessments included the rotarod and open field tests, while biochemical analyses measured oxidative stress markers (malondialdehyde (MDA), nitric oxide (NO), glutathione (GSH)), antioxidants (superoxide dismutase (SOD), catalase (CAT)), pro-inflammatory cytokines (interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α)), and neurotransmitters (dopamine (DA), levodopa (L-Dopa)). Histological and immunohistochemical analyses evaluated the neuronal integrity and tyrosine hydroxylase (TH) and alpha-synuclein expression. The results showed that Paracentrotus lividus gonadal extract significantly mitigated rotenone-induced motor deficits and improved locomotor activity. Biochemically, the extract reduced oxidative stress and inflammation markers while enhancing antioxidant levels. Histologically, it restored neuronal integrity and reduced alpha-synuclein accumulation. Molecularly, it increased tyrosine hydroxylase and dopa decarboxylase gene expression, essential for dopamine synthesis. These findings suggest that Paracentrotus lividus gonadal extract exerts neuroprotective effects by modulating oxidative stress, neuroinflammation, and dopaminergic neuron integrity, highlighting its potential as a therapeutic agent for Parkinson's disease.

Abstract 4125419: Very-Low-Density Lipoprotein Induces Neuronal Growth with Increased Tyrosine Hydroxylase Expression through Cardiomyocyte-Secreted Exosomes in Metabolic Syndrome

Introduction: Metabolic syndrome (MS) is an important predisposing factor for atrial fibrillation, and is highly related to the autonomic nervous system. Triglyceride-rich very-low-density lipoprotein (VLDL) has specific VLDL receptors (VLDLR), which are abundantly expressed in cardiomyocytes. Hypothesis: VLDL affects neuronal growth through cardiomyocyte-secreted exosomes in metabolic syndrome. Goals/Aims: To determine whether exosomes from VLDL-incubated cardiomyocytes can alter neuronal proliferation. Methods/ Approach: HL-1 cardiomyocytes were incubated with VLDL isolated from human subjects with MS, and exosomes were extracted at the end of the incubation period. VLDLR knockdown HL-1 cells were used to determine the role of VLDLR in exosome secretion. The molecular contents of exosomes were determined by mass spectrometry, which identified neurotropic proteins only detected in the exosomes of MS VLDL-incubated cardiomyocytes. We selected transmembrane protein 14B (TMEM14B) to investigate its effect on neuronal proliferation in P19 cells. Results: Regardless of the knockdown or overexpression of VLDLR in HL-1 cardiomyocytes, exosomes isolated from after VLDL incubation were shown to cause 2.062-fold and 2.084-fold expression of tyrosine hydroxylase (TH) in P19 cells, relative to P19 cells induced by non-VLDL-treated HL-1 cardiomyocyte-secreted exosomes. A similar trend could be seen with HL-1 cardiomyocytes without VLDLR editing, as VLDL-incubated HL-1 cardiomyocytes produced exosomes that could cause 1.926-fold increase in P19 TH expression, relative to treatment by exosomes from HL-1 cardiomyocytes without VLDL-incubation. The P19 cells incubated with TMEM14B demonstrated increased neurite length, with an average of 2.342-fold neurite length when compared with that of control cells. Conclusions: VLDL in MS induced HL-1 cardiomyocytes to secrete exosomes containing neurotrophic molecules and increased dendritic growth of neuronal cells. This effect was VLDLR-independent and was partially caused by TMEM14B in the exosomes.

Mechanical acupuncture at HT7 attenuates alcohol self-administration in rats by modulating neuroinflammation and altering mPFC-habenula-VTA circuit activity.

Alcohol use disorder is a chronic disorder with significant limitations in pharmacological treatments, necessitating the exploration of non-pharmacological interventions. We used a model of alcohol self-administration (10% v/v) to analyze behavioral, neurochemical, and signaling mechanisms. Our findings demonstrate that stimulation of the HT7 acupuncture point significantly decreased the frequency of active lever presses in rats self-administering alcohol (p < 0.05). Alcohol self-administration increased microglial activity and sigma 1 receptor expression in the habenula (Hb), while HT7 stimulation mitigated these effects, decreasing microglial activity and sigma 1 receptor levels (p < 0.05). Additionally, alcohol self-administration reduced brain-derived neurotrophic factor (BDNF) expression in the medial prefrontal cortex (mPFC) and increased tyrosine hydroxylase (TH) levels in the ventral tegmental area (VTA) (p < 0.05). HT7 stimulation reversed these alterations by increasing BDNF expression in the mPFC and decreasing TH levels in the VTA (p < 0.05). Further investigation revealed that BDNF microinjection into the mPFC inhibited sigma 1 receptor activity in the Hb, while microglial inhibition in the Hb decreased TH expression in the VTA (p < 0.05). The administration of the microglial inhibitor MINO to the Hb also reduced alcohol self-administration (p < 0.05). These results suggest that HT7 stimulation regulates the mPFC-Hb-VTA circuit, leading to decreased alcohol-seeking behavior. Our study demonstrates that HT7 acupuncture can modulate the mPFC-Hb-VTA circuit, providing a potential non-pharmacological treatment for alcohol-seeking behavior by influencing microglial activity, sigma 1 receptor expression, and TH levels. These findings contribute to a deeper understanding of the neural mechanisms underlying acupuncture's therapeutic effects on alcohol use disorder.

Unveiling the Therapeutic Potential of Small Molecule of SVAK-12: A Comprehensive In Silico, In Vitro, and In Vivo Studies on its Neuroprotective Effects and Molecular Interactions in Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder associated with a progressive loss of dopaminergic cells and as of now, there is no established definitive treatment available for this condition. In this study, the focus was on investigating the impact of SVAK-12, a small molecule that can cross the blood-brain barrier and remain stable without structural changes. The effect of SVAK-12 was investigated in vitro on neurotoxicity, in vivo model of Parkinson's Diseases and in silico. Through in vitro and in vivo experiments, as well as molecular docking simulations, it was found that SVAK-12 (375 ng.ml) led to increased cell viability, reduced cellular damage, and decreased production of NO and ROS. Additionally, it boosted levels of important neurotrophic factors like BDNF (130.49%) and GDNF (116.38%), potentially aiding in alleviating motor disability and depression. The study also highlighted SVAK-12's potential as a therapeutic candidate for neurological disorders due to its ability to increase tyrosine hydroxylase expression and dopamine levels (4.84 times). While it did not significantly improve motor symptoms in vivo, it did enhance motor asymmetry in the forelimbs and gene expression related to brain regions. Besides, it induced significant BMP-2 gene expression in substantial nigra regions without significant changes in GDNF and Nurr1 gene expression in the striatum expression. The docking of SVAK-12, Levodopa, Amantadine, Biperiden, Selegiline, and Rasagiline to the binding site of GFRα1, sortilin, and TrkB showed that SVAK-12 had greater MolDock score than Selegiline and Amantadine for GFRα1 and greater than amantadine for Sortilin and TrKB. Overall, the study suggests that SVAK-12's neuro-biocompatibility, ability to reduce free radicals, and enhanced neurotrophic factors make it a promising candidate as a neuroprotective drug.

Ecklonia cava Polyphenols Have a Preventive Effect on Parkinson's Disease through the Activation of the Nrf2-ARE Pathway.

Parkinson's disease (PD) is a degenerative neurological disorder defined by the deterioration and loss of dopamine-producing neurons in the substantia nigra, leading to a range of motor impairments and non-motor symptoms. The underlying mechanism of this neurodegeneration remains unclear. This research examined the neuroprotective properties of Ecklonia cava polyphenols (ECPs) in mitigating neuronal damage induced by rotenone via the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway. Using human neuroblastoma SH-SY5Y cells and PD model mice, we found that ECP, rich in the antioxidant polyphenol phlorotannin, boosted the gene expression and functionality of the antioxidant enzyme NAD(P)H quinone oxidoreductase-1. ECP also promoted Nrf2 nuclear translocation and increased p62 expression, suggesting that p62 helps sustain Nrf2 activation via a positive feedback loop. The neuroprotective effect of ECP was significantly reduced by Compound C (CC), an AMP-activated protein kinase (AMPK) inhibitor, which also suppressed Nrf2 nuclear translocation. In PD model mice, ECPs improved motor functions impaired by rotenone, as assessed by the pole test and wire-hanging test, and restored intestinal motor function and colon tissue morphology. Additionally, ECPs increased tyrosine hydroxylase expression in the substantia nigra, indicating a protective effect on dopaminergic neurons. These findings suggest that ECP has a preventative effect on PD.

Unveiling the therapeutic prospects of EGFR inhibition in rotenone-mediated parkinsonism in rats: Modulation of dopamine D3 receptor

Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. The dopamine D3 receptor (D3R) plays a significant role in the pathogenesis and treatment of PD. Activation of receptor tyrosine kinases (RTKs) inhibits signaling mediated by G protein-coupled receptor (GPCR). Epidermal growth factor receptors (EGFRs) and dopamine D3 receptors in the brain are directly associated with PD, both in terms of its development and potential treatment. Therefore, we investigated the impact of modulating the EGFR, a member of the RTKs family, and the dopamine D3R, a member of the GPCR family. In the present study, 100 mg/kg of lapatinib (LAP) was administered to rotenone-intoxicated rats for three weeks. Our findings indicate that LAP effectively alleviated motor impairment, improved histopathological abnormalities, and restored dopaminergic neurons in the substantia nigra. This restoration was achieved through the upregulation of dopamine D3R and increase of tyrosine hydroxylase (TH) expression, as well as boosting dopamine levels. Furthermore, LAP inhibited the activity of p-EGFR, GRK2, and SCR. Additionally, LAP exhibited antioxidant properties by inhibiting the 4-hydroxynonenal (4-HNE) and PLCγ/PKCβII pathway, while enhancing the antioxidant defense mechanism by increasing GSH-GPX4 pathway. The current study offers insights into the potential repositioning of LAP as a disease-modifying drug for PD. This could be achieved by modulating the dopaminergic system and curbing oxidative stress.

Salidroside Mediated the Nrf2/GPX4 Pathway to Attenuates Ferroptosis in Parkinson's Disease.

Parkinson's Disease (PD) is characterized by the loss of dopaminergic neurons, with ferroptosis playing a significant role. Salidroside (SAL) has shown neuroprotective potential, this study aims to explore its capacity to mitigate ferroptosis in PD, focusing on the modulation of the Nuclear Factor E2-Related Factor 2 (Nrf2)/ Glutathione Peroxidase 4 (GPX4) pathway. Male C57BL/6 mice were subjected to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce PD-like symptoms, followed by SAL and Nrf2 inhibitor administration. Then behavioral tests, immunohistochemical staining, transmission electron microscopy, and Western blot analysis were conducted to assess motor functions, pathological changes, ferroptosis, and related protein expressions. In vitro, SH-SY5Y cells were treated with erastin to induce ferroptosis to assess the protective effects of SAL. Additionally, A53T-α-synuclein (α-syn) was used to stimulate the PD model, SAL and a Nrf2 inhibitor (ML385) was utilized to elucidate the role of the Nrf2/GPX4 pathway in mitigating ferroptosis in PD. In vivo, SAL significantly improved motor functions and reduced the expression of α-syn, while increasing tyrosine hydroxylase (TH) expression of PD mice. Additionally, SAL treatment notably enhanced the levels of antioxidants and reduced MDA and iron content in the substantia nigra of PD mice. In vitro, SAL treatment increased the TH, GPX4, Nrf2 expression, and mitochondrial membrane potential whereas alleviated ferroptosis through the Nrf2/GPX4 pathway, as evidenced in erastin-induced and α-syn overexpressing SH-SY5Y cells. While these effects were reversed upon Nrf2 inhibition. SAL demonstrates significant potential in mitigating PD pathology and ferroptosis, positioning the Nrf2/GPX4 pathway as a promising therapeutic target. However, future studies should focus on the long-term effects of SAL, its pharmacokinetics, addressing the multifactorial nature of PD pathogenesis.

Antidepressant-like Effect of the Eburnamine-Type Molecule Vindeburnol in Rat and Mouse Models of Ultrasound-Induced Depression.

Vindeburnol (VIND, RU24722, BC19), a synthetic molecule derived from the eburnamine-vincamine alkaloid group, has many neuropsychopharmacological effects, but its antidepressant-like effects are poorly understood and have only been described in a few patents. To reliably estimate this effect, vindeburnol was studied in a model of long-term variable-frequency ultrasound (US) exposure at 20-45 kHz in male Wistar rats and BALB/c mice. Vindeburnol was administered chronically for 21 days against a background of simultaneous ultrasound exposure at a dose of 20 mg/kg intraperitoneally (IP). Using four behavioral tests, the sucrose preference test (SPT), the social interaction test (SIT), the open field test (OFT), and the forced swimming test (FST), we found that the treatment with the compound diminished depression-like symptoms in mice and rats. The compound restored the ultrasound-related reduced sucrose consumption to control levels and increased social interaction time in mice and rats compared with those in ultrasound-exposed animals. Vindeburnol showed contraversive results of horizontal and vertical activity in both species and generally did not increase locomotor activity. At the same time, the compound showed a specific effect in the FST, significantly reducing the immobility time. Moreover, we found an increase in norepinephrine, dopamine, and its metabolite levels in the brainstem, as well as an increase in dopamine, 3-methoxytyramine, and 3,4-dihydroxyphenylacetic acid levels in the striatum. We also observed a statistically significant increase in tyrosine hydroxylase (TH) levels in the region containing the locus coeruleus (LC). We suggest that using its distinct chemical structure and pharmacological activity as a starting point could boost antidepressant drug discovery.

Piezoelectric nanogenerators enabled neuromodulation rescued dopaminergic neuron loss in Parkinson’s disease

Parkinson’s disease (PD) is a neurodegenerative disease with dopaminergic neurons loss, which induces dopamine reduction and body motion disorder. Traditional deep brain stimulation (DBS), which involves the implanting metal electrodes into the subcortical nucleus of the brain, has a huge risk of invasive surgery and low resolution. Here we present that pomegranate-like piezoelectric nanogenerators are able to efficiently transduce ultrasonic wave into electric power generation under ultrasound stimulation, which modulates intracellular calcium signaling and tyrosine hydroxylase levels to activate the neuron activity and process of deep-brain tissue in vitro and in vivo. Strikingly, after one-week nanogenerator-mediated neuromodulation, the damaged dopaminergic neurons in PD-zebrafish and mice were reversed with a decrease in α-synuclein aggregates and an increase in tyrosine hydroxylase for neuronal recovery of PD. The behaviors of PD mice model also have a significant improvement, compared with untreated group. This approach provides a minimally invasive and high precision neurotechnology protect against neuronal death and loss of synapse in PD and other neurodegenerative diseases.

Co-exposure to sodium hypochlorite and cadmium induced locomotor behavior disorder by influencing neurotransmitter secretion and cardiac function in larval zebrafish

Sodium hypochlorite (NaClO) and cadmium (Cd) are widely co-occurring in natural aquatic environment; however, no study has been conducted on effects of their combined exposure on aquatic organisms. To assess effects of exposure to NaClO and Cd in zebrafish larvae, we designed six treatment groups, as follows: control group, NaClO group (300 μg/L), 1/100 Cd group (48 μg/L), 1/30 Cd group (160 μg/L), NaClO+1/100 Cd group, and NaClO+1/30 Cd group analyzed behavior, neurological function and cardiac function. Results revealed that exposure to 1/30 Cd and NaClO+1/30 Cd caused abnormal embryonic development in larvae by altering body morphology and physiological indicators. Combined exposure to NaClO and 1/30 Cd affected the free-swimming activity and behavior of larvae in response to light-dark transition stimuli. Moreover, exposure to 1/30 Cd or NaClO+1/30 Cd resulted in a significant increase in tyrosine hydroxylase and acetylcholinesterase activities, as well as significant changes of various neurotransmitters. Lastly, exposure to 1/30 Cd or NaClO+1/30 Cd influenced the transcription of cardiac myosin-related genes and disturbed the myocardial contractile function. Altogether, our results suggested that combined exposure to NaClO and Cd induced oxidative damage in larvae, resulting in detrimental effects on nervous system and cardiac function, thus altering their swimming behavior.

RETRACTED: Aqueous leaf extract of Phyllanthus amarus protects against oxidative stress and misfiring of dopaminergic neurons in Paraquat-induced Parkinson's disease-like model of adult Wistar rats

Background of the studyPhyllanthus amarus has high nutritional value and is beneficial in managing and treating diverse ailments. This study assessed the role of aqueous leaf extract of Phyllanthus amarus on Paraquat (PQ) induced neurotoxicity in the substantia nigra of Wistar rats. Materials and methodsThe role of aqueous leaves extract of Phyllanthus amarus was assessed using an open field test (OFT) for motor activity, oxidative stress biomarkers [Catalase (CAT), and Superoxide Dismutase (SOD)], histological examination (H and E stained) for cytoarchitectural changes and immunohistochemical studies using tyrosine hydroxylase (TH) as a marker for dopaminergic neurons. Forty-two (42) rats were categorized into six groups (n = 7); group 1: control was administered 0.5 ml/kg distilled water, group 2: received 10 mg/kg PQ + 10 mg/kg L-dopa as reference drug, group 3; received 10 mg/kg PQ, while group 4: received 10 mg/kg PQ + 200 mg/kg P. amarus, group 5: received 10 mg/kg PQ + 300 mg/kg P. amarus, and group 6: received 10 mg/kg PQ + 400 mg/kg P. amarus respectively, for 14 days. All administrations were done orally; a significant difference was set at p < 0.05. Results and discussionThe study's open field test (OFT) revealed no motor activity deficit with Paraquat (PQ) exposure. Also, cytoarchitectural distortions were not observed with Paraquat (PQ) only treatment group compared to the control and other groups pretreated with P. amarus and L-dopa. Moreover, the Paraquat (PQ) only treatment group showed oxidative stress by significantly decreasing the antioxidant enzyme (SOD) compared to the control and L-dopa pretreated group. A significant decrease in tyrosine hydroxylase (TH) expressing dopaminergic neurons was also observed in Paraquat (PQ) only treatment. However, P. amarus treatment showed therapeutic properties by significantly increasing tyrosine hydroxylase (TH) expressing dopaminergic neuron levels relative to control. ConclusionAqueous leaf extract of Phyllanthus amarus possesses therapeutic properties against Paraquat (PQ) induced changes in the substantia nigra of Wistar rats.

Amelioration of rotenone-induced Parkinson's disease; comparing therapeutic role of erythropoietin versus low-level laser activation of mesenchymal stem cells (an in-vivo and in-vitro study)

ABSTRACT Parkinson's disease (PD), the second common neurodegenerative disease, is characterized by the loss of the dopaminergic neurons in the substantia nigra (SN). Because of L-dopa's side effects, new therapeutic methods were considered such as stem cells for PD treatment. The major challenge facing stem cell therapy following transplantations is their peripheral sequestration and decreased survival. Thus, the ability of erythropoietin (EPO) and low-level laser therapy (LLLT) to enhance mesenchymal stem cell (MSC) proliferation and therapeutic efficiency for alleviating rotenone-induced PD was investigated. Therefore, we compared the influence of stem cell preconditioning with erythropoietin versus LLLT on MSCs’ homing ability and the chances of survival. Forty-eight male Swiss mice were included in the in vivo protocol and ten in the in vitro work. The mice in the in vivo study were divided randomly into six groups (8 in each); group I; control group and group II; induced PD (untreated) group, group III; L-dopa, group IV; MSCs, group V; EPO-activated MSCs and group VI; laser-activated MSCs. Treatment with MSCs (either preconditioned or not) improved these neurological features by restoring the normal balance between glutamate and GABA neurotransmitters, and dopamine as well as increased tyrosine hydroxylase levels. Stem cell therapy decreased oxidative stress, miRNA-155 levels, enhanced neuronal architecture in SN, and decreased the number of apoptotic cells. LLLT enhanced MSC expression of integrin β1 which was reflected in the homing of PKH26-labelled MSCs into corpus striatum and SN. Thus, the optimum results were achieved with laser-activated MSCs.

6-Hydroxy-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline Alleviates Oxidative Stress and NF-κB-Mediated Inflammation in Rats with Experimental Parkinson's Disease.

A study was conducted to investigate the effects of different doses of 6-hydroxy-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline (HTHQ) on motor coordination scores, brain tissue morphology, the expression of tyrosine hydroxylase, the severity of oxidative stress parameters, the levels of the p65 subunit of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) factor, and the inflammatory response in rats during the development of rotenone-induced Parkinsonism. The findings indicate that HTHQ, with its antioxidant attributes, reduced the levels of 8-isoprostane, lipid oxidation products, and protein oxidation products. The decrease in oxidative stress due to HTHQ led to a reduction in the mRNA content of proinflammatory cytokines and myeloperoxidase activity, accompanying the drop in the expression of the factor NF-κB. These alterations promoted an improvement in motor coordination scores and increased tyrosine hydroxylase levels, whereas histopathological changes in the brain tissue of the experimental animals were attenuated. HTHQ exhibited greater effectiveness than the comparative drug rasagiline based on the majority of variables.

Identification of Clec7a as the therapeutic target of rTMS in alleviating Parkinson's disease: targeting neuroinflammation

Parkinson's disease (PD) is a neurodegenerative disease. Repetitive transcranial magnetic stimulation (rTMS) is a therapeutic tool in PD. High-throughput sequencing was performed to screen potential therapeutic targets in unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. The candidate gene, Clec7a, was screened out and validated. Clec7a is a pattern recognition receptor involved in neuroinflammation. The higher expression of Clec7a was observed in the substantia nigra (SN) and striatum of PD rats with dopaminergic neurons damage and was mainly localized in the microglial. Adeno-associated virus (AAV)-mediated specific knockdown of Clec7a in microglial alleviated 6-OHDA induced motor deficits and nigrostriatal dopaminergic neuron damage of rats, as evidenced by the increase of tyrosine hydroxylase (TH) -positive neurons in SN, as well as dopaminergic nerve fibers in the striatum. Clec7a knockdown restrained the neuroinflammation by suppressing inflammatory factors (IFN-γ, TNF-α, IL-1β, IL-18, and IL-6) release in SN, which might result from enhanced Arg-1 expression (M2 polarization) and defective inducible nitric oxide synthase (iNOS) expression (M1 polarization). The same phenomena were also observed in the LPS inflammatory rat model of PD. In vitro, α-synuclein fibrils induced upregulation of Clec7a expression and microglia polarization to a pro-inflammatory state of BV2 cells, leading to increased release of cytokines. However, Clec7a knockdown reversed those changes and induced a shift to an anti-inflammatory phenotype in BV2 cells. In conclusion, our study suggested that Clec7a was involved in PD pathogenesis, and its inhibition might protect rats from PD by depressing neuroinflammation through microglial polarization.

Lacosamide exhibits neuroprotective effects in a rat model of Parkinson's disease

BackgroundParkinson's disease (PD) is a chronic and progressive neurodegenerative disorder that primarily affects the motor system. Although there are several treatments available to alleviate PD symptoms, there is currently no cure for the disease. Lacosamide, an anti-epileptic drug, has shown promising results in preclinical studies as a potential neuroprotective agent for PD. In this study, we aimed to investigate the neuroprotective effect of lacosamide in a murine model of PD. MethodsTwenty-one adult male rats were randomly divided into the following three groups (n = 7): 1 group received stereotaxical infusion of dimethyl sulfoxide (vehicle, group 1), and the others received stereotaxical infusion of rotenone (groups 2 and 3). The apomorphine-induced rotation test was applied to the rats after 10 days. Thereafter, group 2 was administered isotonic saline, whereas group 3 was administered lacosamide (20 mg/kg,i.p.) for 28 days. Apomorphine-induced rotation tests were performed to assess the effect of lacosamide on motor function. In addition, immunohistochemistry and biochemistry were used to assess the dopaminergic neuron loss in the substantia nigra and MDA, TNF-α and HVA levels, respectively. ResultsIn rats with Parkinson's disease induced by rotenone, levels of malondialdehyde and TNF-α significantly increased and HVA levels decreased, whereas in mice treated with lacosamide, levels of malondialdehyde and TNF-α significantly decreased and HVA levels increased. The apomorphine-induced rotation test scores of lacosamide-treated mice were lower compared with the untreated group. Furthermore, treatment with lacosamide significantly mitigated the degeneration of dopaminergic projections within the striatum originating from the substantia nigra and increased tyrosine hydroxylase (TH) immunofluorescence, indicative of preserved dopaminergic neuronal function. ConclusionIn conclusion, our study provides evidence that lacosamide has a neuroprotective effect on the rat model of PD. Further studies are required to investigate the underlying mechanisms and evaluate the potential clinical use of lacosamide as a neuroprotective agent for PD.

Lapatinib ditosylate rescues motor deficits in rotenone-intoxicated rats: Potential repurposing of anti-cancer drug as a disease-modifying agent in Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor deficits induced by dopaminergic neuronal death in the substantia nigra (SN). Finding a successful neuroprotective therapy is still challenging despite improved knowledge of the etiology of PD and a variety of medications intended to reduce symptoms. Lapatinib (LAP), an FDA-approved anti-cancer medication, has been stated to exert its effect through the modulation of oxidative stress. Furthermore, recent studies display the neuroprotective effects of LAP in epilepsy, encephalomyelitis, and Alzheimer's disease in rodent models through the modulation of oxidative stress and ferroptosis. Nevertheless, it is questionable whether LAP exerts neuroprotective effects in PD. In the current study, administration of 100 mg/kg LAP in rotenone-treated rats for 21 days ameliorates motor impairment, debilitated histopathological alterations, and revived dopaminergic neurons by increasing tyrosine hydroxylase (TH) expression in SN, along with increased dopamine level. LAP remarkably restored the antioxidant defense mechanism system, GPX4/GSH/NRF2 axis, inhibiting oxidative markers, including iron, TfR1, PTGS2, and 4-HNE, along with suppression of p-EGFR/c-SRC/PKCβII/PLC-γ/ACSL-4 pathway. Moreover, LAP modulates HSP90/CDC37 chaperone complex, regulating many key pathological markers of PD, including LRRK2, c-ABL, and α-syn. It is concluded that LAP has neuroprotective effects in PD via modulation of many key parameters implicated in PD pathogenesis. Taken together, the current study offers insights into the potential repositioning of LAP as a disease-modifying drug in PD.

The Transcription Factor Nrf2 Mediates the Effects of Antrodia camphorata Extract on Neuropathological Changes in a Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is a disorder that is characterized by progressive and selective neuronal injury and cell death. Recent studies have provided accumulating evidence for a significant role of the immune system and neuroinflammation in PD pathogenesis. On this basis, many scientific articles have highlighted the anti-inflammatory and neuroprotective properties of Antrodia camphorata (AC), an edible fungus containing various bioactive compounds. This study aimed to evaluate the inhibitory effect of AC administration on neuroinflammation and oxidative stress in a murine model of MPTP-induced dopaminergic degeneration. AC (10, 30, 100 mg/kg) was administered daily by oral gavage starting 24 h after the first administration of MPTP, and mice were sacrificed 7 days after MPTP induction. In this study, treatment with AC significantly reduced the alteration of PD hallmarks, increasing tyrosine hydroxylase expression and reducing the number of alpha-synuclein-positive neurons. In addition, AC treatment restored the myelination process of neurons associated with PD and attenuated the neuroinflammatory state. Furthermore, our study demonstrated that AC was able to reduce the oxidative stress induced by MPTP injection. In conclusion, this study highlighted that AC could be a potential therapeutic agent for the treatment of neurodegenerative disorders such as PD.

Pharmacological evaluation of lateral habenula and rostromedial tegmental nucleus in the expression of ethanol-induced place preference.

Although ethanol administration produces a range of physiological effects, the rewarding aspect associated with its consumption is a major contributory factor to its abuse liability. Recently, lateral habenula (LHb) has been shown to be engaged by both rewarding and aversive stimuli. Its major glutamatergic output, the fasciculus retroflexus, projects to the rostromedial tegmental nucleus (RMTg) and controls the activity of the ventral tegmental area (VTA) dopaminergic system to promote reward circuitry. While several attempts have been made to understand the relationship between LHb and addiction, there is still a lack of knowledge in relation to ethanol addiction. In the present study, by pharmacologically exacerbating or inhibiting the LHb or RMTg neuronal activity during a post-conditioning test, we investigated the role of LHb-RMTg fasciculus retroflexus in ethanol-induced reward behavior using the conditioned place preference (CPP) test. We found that activation of LHb glutamatergic system by intra-LHb administration of l-trans-2,4-pyrrolidine dicarboxylate (PDC) (glutamate transporter inhibitor) significantly decreased CPP score; on the contrary, lamotrigine (inhibits glutamate release) significantly increased CPP score and showed a rewarding effect in CPP. Instead, intra-RMTg administration of muscimol (GABAA receptor agonist) significantly increased CPP score, whereas bicuculline (GABAA antagonist) treatment decreased CPP score. In immunohistochemistry, we found that PDC administration significantly decreased, whereas lamotrigine treatment significantly increased tyrosine hydroxylase immunoreactivity (TH-ir) in VTA and nucleus accumbens (NAc). Furthermore, while intra-RMTg administration of muscimol increased, the bicuculline treatment significantly decreased the TH-ir in VTA and NAc. Together, our behavioral and immunohistochemical results signify the role of LHb and RMTg in the expression of ethanol-conditioned reward behavior.

Downregulation of microRNA-330-5p induces manic-like behaviors in REM sleep-deprived rats by enhancing tyrosine hydroxylase expression.

In our pilot study, we found an increase in tyrosine hydroxylase (Th) mRNA expression in the prefrontal cortex of 72-h REM sleep-deprived (SD) rats, a mania model. Additionally, the expression levels of miR-325-3p, miR-326-3p, and miR-330-5p, the predicted target miRNAs on TH, were significantly decreased. Based on these results, in this study, we investigated whether miRNA-325-3p, miR-326-3p, and miR-330-5p modulate TH and manic-like behaviors in SD rats. Manic-like behaviors were assessed using the open field test (OFT) and elevated plus-maze (EPM) test. The direct binding activity of miRNAs to the 3'-untranslated region (3'-UTR) of the Th gene was measured in HEK-293 cells using a luciferase reporter system. We also examined mRNA and protein expression of TH after intracerebroventricular (ICV) injection of miR-330-5p agomir to SD rats, along with manic-like behaviors. We observed an upregulation in mRNA and protein expression of TH and downregulation in miRNA-325-3p, miR-326-3p, and miR-330-5p expressions in the prefrontal cortex of SD rats, together with increased manic-like behaviors. The luciferase reporter assay showed that miR-330-5p could repress TH expression through direct binding to its target site in the 3'-UTR of Th, whereas miR-326-3p and miR-330-5p could not. In addition, ICV injection of miR-330-5p agomir alleviated the increase in TH expression in the prefrontal cortex of SD rats and manic-like behaviors. TH expression regulation through miR-330-5p may be implicated in the pathophysiology of mania in SD rats.

Antidepressant and Neuroprotective Effects of 3-Hydroxy Paroxetine, an Analog of Paroxetine in Rats.

Paroxetine (PX) is a widely used antidepressant with side effects such as weakness, dizziness, and trouble sleeping. In search of novel compounds with better efficacy and fewer side effects, we synthesized 3HPX, a hydroxylated analog of PX, and compared the 2 in silico for their pharmacokinetic and binding properties and in vivo for their antidepressant and potential neuroprotective effects. In silico studies compared pharmacological properties as well as interactions of PX and 3HPX with the serotonin transporter. In vivo studies utilized an animal model of comorbid depression-Parkinson disease. Adult male Wistar rats were injected (sterotaxically) with lipopolysaccharide in the striatum (unilaterally), followed by 14 days of once-daily injections (i.p.) of 10 mg/kg PX or 3HPX. Animals were tested for motor asymmetry and locomotor activity as well as indices of anhedonia and helplessness using sucrose preference and forced swim tests, respectively. Brains of these animals were collected after the last test, and tyrosine hydroxylase-positive neurons in substantia nigra pars compacta and Iba-1-positive stained microglia in ipsilateral striatum were measured. In silico findings indicated that 3HPX could bind stronger to serotonin transporter and also have a better clearance and hence less toxicity compared with PX. In vivo results revealed a more effective reversal of immobility in the swim test, substantial increase in tyrosine hydroxylase-positive cells in the substantia nigra pars compacta, and more ramified Iba-1+ cells by 3HPX compared with PX. The findings suggest superior effectiveness of 3HPX as an antidepressant and neuroprotectant compared with PX and hence potential utility in Parkinson disease depression co-morbidity.