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Brain, Behavior, and Immunity Jul 2024Cognitive impairment in Parkinson's disease is considered an indicator of the prodromal stages of this condition, occurring prior to the onset of classic and...
Cognitive impairment in Parkinson's disease is considered an indicator of the prodromal stages of this condition, occurring prior to the onset of classic and pathognomonic motor symptoms. Among other factors, neuroinflammation is increasingly recognized as a potential mediator of this neurodegenerative process, and glial cells are directly involved. However, the use of neurotrophic factors is associated with neuroprotection and cognitive improvements. Among all those factors, insulin-like growth factor 1 (IGF-1) has attracted considerable attention. In this study, we aimed to investigate the effect of IGF-1 gene therapy in an early animal model of 6-hydroxidopamine (6-OHDA)- induced parkinsonism. For this purpose, we employed male Wistar rats. The animals were first divided into two groups according to the bilateral injection into de Caudate Putamen unit (CPu):(a) VEH group (vehicle solution) and (b) 6-OHDA group (neurotoxic solution). After that, the animals in each group were divided, according to the bilateral injection into the dorsal hippocampus, in a control group (who received a control virus RAd-DSRed) and an experimental group (who received a therapeutic virus (RAd-IGF1). After three weeks of exposure to 6-OHDA, our study showed that IGF-1 gene therapy improved cognitive deficits related to short-term and spatial working memory, it also increased expression levels of tyrosine hydroxylase in the CPu. In addition, the therapy resulted in significant changes in several parameters (area, perimeter, roundness, ramification, and skeleton ́s analyses) related to microglia and astrocyte phenotypes, particularly in the CPu and dorsal hippocampal areas. Our data support the use of IGF-1 as a therapeutic molecule for future gene transfer interventions, that will contribute to a better understanding of the mechanisms correlating cognitive function and inflammatory process.
Topics: Animals; Male; Insulin-Like Growth Factor I; Rats; Rats, Wistar; Genetic Therapy; Disease Models, Animal; Spatial Memory; Memory Disorders; Parkinsonian Disorders; Oxidopamine; Inflammation; Dopaminergic Neurons; Hippocampus; Dopamine
PubMed: 38750702
DOI: 10.1016/j.bbi.2024.05.013 -
Stem Cell Research & Therapy May 2024Clinical trials have provided evidence that transplants of dopaminergic precursors, which may be replaced by new in vitro stem cell sources, can integrate into the host...
BACKGROUND
Clinical trials have provided evidence that transplants of dopaminergic precursors, which may be replaced by new in vitro stem cell sources, can integrate into the host tissue, and alleviate motor symptoms in Parkinson´s disease (PD). In some patients, deterioration of graft function occurred several months after observing a graft-derived functional improvement. Rejection of peripheral organs was initially related to HLA-specific antibodies. However, the role of non-HLA antibodies is now considered also relevant for rejection. Angiotensin-II type-1 receptor autoantibodies (AT1-AA) act as agonists of the AT1 receptors. AT1-AA are the non-HLA antibodies most widely associated with graft dysfunction or rejection after transplantation of different solid organs and hematopoietic stem cells. However, it is not known about the presence and possible functional effects of AT1-AA in dopaminergic grafts, and the effects of treatment with AT1 receptor blockers (ARBs) such as candesartan on graft survival.
METHODS
In a 6-hydroxydopamine PD rat model, we studied the short-term (10 days)- and long-term (3 months) effects of chronic treatment with the ARB candesartan on survival of grafted dopaminergic neurons and microglial graft infiltration, as well as the effects of dopaminergic denervation and grafting on serum and CSF AT1-AA levels. The expression of AT1 receptors in grafted neurons was determined by laser capture microdissection.
RESULTS
At the early period post-grafting, the number of grafted dopaminergic neurons that survived was not significantly different between treated and untreated hosts (i.e., control rats and rats treated with candesartan), probably because, just after grafting, other deleterious factors are predominant for dopaminergic cell death, such as mechanical trauma, lack of growth factors/nutrients and ischemia. However, several months post-grafting, we observed a significantly higher number of surviving dopaminergic neurons and a higher density of striatal dopaminergic terminals in the candesartan-treated group. For several months, grafted rats showed blood and cerebrospinal fluid levels of AT1-AA higher than normal controls, and also higher AT1-AA levels than non-grafted parkinsonian rats.
CONCLUSIONS
The results suggest the use of ARBs such as candesartan in PD patients, particularly before and after dopaminergic grafts, and the need to monitor AT1-AA levels in PD patients, particularly in those candidates for dopaminergic grafting.
Topics: Animals; Autoantibodies; Receptor, Angiotensin, Type 1; Rats; Dopaminergic Neurons; Parkinson Disease; Disease Models, Animal; Benzimidazoles; Male; Biphenyl Compounds; Tetrazoles; Angiotensin II Type 1 Receptor Blockers; Oxidopamine; Humans; Rats, Sprague-Dawley
PubMed: 38735991
DOI: 10.1186/s13287-024-03751-y -
International Journal of Biological... Jun 2024Parkinson's disease (PD) is a prevalent neurodegenerative disorder, marked by the degeneration of dopamine (DA) neurons in the substantia nigra (SN). Current evidence...
BACKGROUND
Parkinson's disease (PD) is a prevalent neurodegenerative disorder, marked by the degeneration of dopamine (DA) neurons in the substantia nigra (SN). Current evidence strongly suggests that neuroinflammation, primarily mediated by microglia, contributes to PD pathogenesis. Triggering receptor expressed on myeloid cells 2 (TREM2) might serve as a promising therapeutic target for PD due to its ability to suppress neuroinflammation. Dihydroquercetin (DHQ) is an important natural dihydroflavone and confers apparent anti-inflammatory, antioxidant and anti-fibrotic effects. Recently, DHQ-mediated neuroprotection was exhibited. However, the specific mechanisms of its neuroprotective effects remain incompletely elucidated.
METHODS
In this study, rat models were utilized to induce damage to DA neurons using lipopolysaccharide (LPS) and 6-hydroxydopamine (6-OHDA) to assess the impacts of DHQ on the loss of DA neurons. Furthermore, DA neuronal MN9D cells and microglial BV2 cells were employed to investigate the function of TREM2 in DHQ-mediated DA neuroprotection. Finally, TREM2 knockout mice were used to investigate whether the neuroprotective effects mediated by DHQ through a mechanism dependent on TREM2.
RESULTS
The main findings demonstrated that DHQ effectively protected DA neurons against neurotoxicity induced by LPS and 6-OHDA and inhibited microglia-elicited neuroinflammation. Meanwhile, DHQ promoted microglial TREM2 signaling activation. Notably, DHQ failed to reduce inflammatory cytokines release and further present neuroprotection from DA neurotoxicity upon TREM2 silencing. Similarly, DHQ didn't exert DA neuroprotection in TREM2 knockout mice.
CONCLUSIONS
These findings suggest that DHQ exerted DA neuroprotection by regulating microglia TREM2 activation.
Topics: Animals; Male; Mice; Rats; Cell Line; Dopaminergic Neurons; Lipopolysaccharides; Membrane Glycoproteins; Mice, Knockout; Microglia; Neuroprotective Agents; Oxidopamine; Parkinson Disease; Quercetin; Rats, Sprague-Dawley; Receptors, Immunologic; Mice, Inbred C57BL
PubMed: 38723817
DOI: 10.1016/j.ijbiomac.2024.132179 -
Behavioural Brain Research Jun 2024Neurotoxins have been extensively investigated, particularly in the field of neuroscience. They induce toxic damage, oxidative stress, and inflammation on neurons,...
Neurotoxins have been extensively investigated, particularly in the field of neuroscience. They induce toxic damage, oxidative stress, and inflammation on neurons, triggering neuronal dysfunction and neurodegenerative diseases. Here we demonstrate the neuroprotective effect of a silicon (Si)-based hydrogen-producing agent (Si-based agent) in a juvenile neurotoxic mouse model induced by 6-hydroxydopamine (6-OHDA). The Si-based agent produces hydrogen in bowels and functions as an antioxidant and anti-inflammatory agent. However, the effects of the Si-based agent on neural degeneration in areas other than the lesion and behavioral alterations caused by it are largely unknown. Moreover, the neuroprotective effects of Si-based agent in the context of lactation and use during infancy have not been explored in prior studies. In this study, we show the neuroprotective effect of the Si-based agent on 6-OHDA during lactation period and infancy using the mouse model. The Si-based agent safeguards against the degradation and neuronal cell death of dopaminergic neurons and loss of dopaminergic fibers in the striatum (STR) and ventral tegmental area (VTA) caused by 6-OHDA. Furthermore, the Si-based agent exhibits a neuroprotective effect on the length of axon initial segment (AIS) in the layer 2/3 (L2/3) neurons of the medial prefrontal cortex (mPFC). As a result, the Si-based agent mitigates hyperactive behavior in a juvenile neurotoxic mouse model induced by 6-OHDA. These results suggest that the Si-based agent serves as an effective neuroprotectant and antioxidant against neurotoxic effects in the brain, offering the possibility of the Si-based agent as a neuroprotectant for nervous system diseases.
Topics: Animals; Neuroprotective Agents; Oxidopamine; Mice; Silicon; Disease Models, Animal; Dopaminergic Neurons; Female; Hydrogen; Male; Neurotoxicity Syndromes; Corpus Striatum; Ventral Tegmental Area; Mice, Inbred C57BL
PubMed: 38723675
DOI: 10.1016/j.bbr.2024.115040 -
The effects of L-DOPA on gait abnormalities in a unilateral 6-OHDA rat model of Parkinson's disease.Physiology & Behavior Jul 2024Parkinson's Disease (PD) is a neurodegenerative movement disorder characterized by dopamine (DA) cell loss in the substantia nigra pars compacta (SNc). As PD progresses,...
Parkinson's Disease (PD) is a neurodegenerative movement disorder characterized by dopamine (DA) cell loss in the substantia nigra pars compacta (SNc). As PD progresses, patients display disruptions in gait such as changes in posture, bradykinesia, and shortened stride. DA replacement via L-DOPA alleviates many PD symptoms, though its effects on gait are not well demonstrated. This study aimed to assess the relationship between DA lesion, gait, and deficit-induced reversal with L-DOPA. To do so, Sprague-Dawley rats (N = 25, 14 males, 11 females) received unilateral medial forebrain bundle (MFB) DA lesions with 6-hydroxydopamine (6-OHDA). An automated gait analysis system assessed spatiotemporal gait parameters pre- and post-lesion, and after various doses of L-DOPA (0, 3, or 6 mg/kg; s.c.). The forepaw adjusting steps (FAS) test was implemented to evaluate lesion efficacy while the abnormal involuntary movements (AIMs) scale monitored the emergence of L-DOPA-induced dyskinesia (LID). High performance liquid chromatography (HPLC) assessed changes in brain monoamines on account of lesion and treatment. Results revealed lesion-induced impairments in gait, inclusive of max-contact area and step-sequence alterations that were not reversible with L-DOPA. However, the emergence of AIMs were observed at higher doses. Post-mortem, 6-OHDA lesions induced a loss of striatal DA and norepinephrine (NE), while prefrontal cortex (PFC) displayed noticeable reduction in NE but not DA. Our findings indicate that hemiparkinsonian rats display measurable gait disturbances similar to PD patients that are not rescued by DA replacement. Furthermore, non-DA mechanisms such as attention-related NE in PFC may contribute to altered gait and may constitute a novel target for its treatment.
Topics: Animals; Levodopa; Oxidopamine; Male; Rats, Sprague-Dawley; Female; Rats; Gait Disorders, Neurologic; Antiparkinson Agents; Disease Models, Animal; Medial Forebrain Bundle; Parkinsonian Disorders; Dopamine; Dose-Response Relationship, Drug; Functional Laterality; Parkinson Disease; Gait; Dyskinesia, Drug-Induced
PubMed: 38723388
DOI: 10.1016/j.physbeh.2024.114563 -
Behavioural Brain Research Jun 2024Parkinson's Disease is a progressive neurodegenerative disorder characterized by motor symptoms resulting from the loss of nigrostriatal dopaminergic neurons....
Parkinson's Disease is a progressive neurodegenerative disorder characterized by motor symptoms resulting from the loss of nigrostriatal dopaminergic neurons. Kisspeptins (KPs) are a family of neuropeptides that are encoded by the Kiss-1 gene, which exert their physiological effects through interaction with the GPR54 receptor. In the current investigation, we investigated the prospective protective effects of central KP-54 treatments on nigrostriatal dopaminergic neurons and consequent motor performance correlates in 6-hydroxydopamine (6-OHDA)-lesioned rats. Male adult Sprague Dawley rats underwent stereotaxic injection of 6-OHDA into the right medial forebrain bundle to induce hemiparkinsonism. Following surgery, rats received chronic central treatments of nasal or intracerebroventricular KP-54 (logarithmically increasing doses) for seven consecutive days. Motor performance was evaluated seven days post-surgery utilizing the open field test and catalepsy test. The levels of dopamine in the striatum were determined with mass spectrometry. Immunohistochemical analysis was conducted to assess the immunoreactivities of tyrosine hydroxylase (TH) and the GPR54 in the substantia nigra. The dose-response curve revealed a median effective dose value of ≈3 nmol/kg for both central injections. Due to its non-invasive and effective nature, nasal administration was utilized in the second phase of our study. Chronic administration of KP-54 (3nmol/kg, nasally) significantly protected 6-OHDA-induced motor deficits. Nasal KP-54 attenuated the loss of nigrostriatal dopaminergic neurons induced by 6-OHDA. Additionally, significant correlations were observed between motor performance and nigrostriatal dopamine levels. Immunohistochemical analysis demonstrated the localization of the GPR54 within TH-positive nigral cells. These findings suggest the potential efficacy of central KP-54 on motor impairments in hemiparkinsonism.
Topics: Animals; Male; Rats, Sprague-Dawley; Substantia Nigra; Dopamine; Oxidopamine; Rats; Corpus Striatum; Administration, Intranasal; Kisspeptins; Parkinsonian Disorders; Dopaminergic Neurons; Disease Models, Animal; Motor Activity; Tyrosine 3-Monooxygenase
PubMed: 38703793
DOI: 10.1016/j.bbr.2024.115035 -
Basic & Clinical Pharmacology &... Jul 2024Parkinson's disease (PD) is a neurodegenerative disease that affects dopaminergic neurons, thus impairing dopaminergic signalling. Quercetin (QUE) has antioxidant and...
Parkinson's disease (PD) is a neurodegenerative disease that affects dopaminergic neurons, thus impairing dopaminergic signalling. Quercetin (QUE) has antioxidant and neuroprotective properties that are promising for the treatment of PD. This systematic review aimed to investigate the therapeutic effects of QUE against PD in preclinical models. The systematic search was performed in PubMed, Scopus and Web of Science. At the final screening stage, 26 articles were selected according to pre-established criteria. Selected studies used different methods for PD induction, as well as animal models. Most studies used rats (73.08%) and mice (23.08%), with 6-OHDA as the main strategy for PD induction (38.6%), followed by rotenone (30.8%). QUE was tested immersed in oil, nanosystems or in free formulations, in varied routes of administration and doses, ranging from 10 to 400 mg/kg and from 5 to 200 mg/kg in oral and intraperitoneal administrations, respectively. Overall, evidence from published data suggests a potential use of QUE as a treatment for PD, mainly through the inhibition of oxidative stress, neuroinflammatory response and apoptotic pathways.
Topics: Animals; Humans; Mice; Rats; Antioxidants; Apoptosis; Disease Models, Animal; Neuroprotective Agents; Oxidative Stress; Oxidopamine; Parkinson Disease; Parkinsonian Disorders; Quercetin; Rotenone
PubMed: 38682342
DOI: 10.1111/bcpt.14011 -
Journal of Integrative Neuroscience Apr 2024Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established treatment for the motor symptoms of Parkinson's disease (PD). While PD is primarily...
BACKGROUND
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established treatment for the motor symptoms of Parkinson's disease (PD). While PD is primarily characterized by motor symptoms such as tremor, rigidity, and bradykinesia, it also involves a range of non-motor symptoms, and anxiety is one of the most common. The relationship between PD and anxiety is complex and can be a result of both pathological neural changes and the psychological and emotional impacts of living with a chronic progressive condition. Managing anxiety in PD is critical for improving the patients' quality of life. However, patients undergoing STN DBS can occasionally experience increased anxiety.
METHODS
This study investigates changes in risk-avoidant behavior following STN DBS in a pre-motor animal model of PD under chronic and acute unilateral high frequency stimulation.
RESULTS
No significant changes in risk-avoidant behaviors were observed in rats who underwent STN DBS compared with sham stimulation controls. Chronic stimulation prevented sensitization in the elevated zero maze.
CONCLUSIONS
These results suggest that unilateral stimulation of the STN may have minimal effects on risk-avoidant behaviors in PD. However, additional research is required to fully understand the mechanisms responsible for changes in anxiety during STN DBS for PD.
Topics: Subthalamic Nucleus; Deep Brain Stimulation; Animals; Oxidopamine; Male; Disease Models, Animal; Behavior, Animal; Parkinsonian Disorders; Anxiety; Rats; Rats, Sprague-Dawley; Avoidance Learning; Parkinson Disease
PubMed: 38682230
DOI: 10.31083/j.jin2304084 -
Bioorganic Chemistry Jun 2024Two pairs of enantiomers (1a-2b), namely (±)-alterpyrone F and (±)-alterpyrone G, along with a rare benzothiazole meroterpenoid granulathiazole A (3, GA), and two...
Two pairs of enantiomers (1a-2b), namely (±)-alterpyrone F and (±)-alterpyrone G, along with a rare benzothiazole meroterpenoid granulathiazole A (3, GA), and two undescribed compounds called respectively granulahydeoate (4) and granulaone (5), were obtained from the co-cultivation of Alternaria brassicicola and Penicillium sp. HUBU0120. Exhaustive analyses of NMR, single crystal XRD, Mo(OAc)-induced circular dichroism data, and a modified Mosher's method distinguished the absolute configurations of isolates. Bioactive evaluations exhibited that GA possessed promising anti-PD activity in both in vitro and in vivo PD models viz. 6-OHDA-induced SH-SY5Y cells and 6-OHDA-induced zebrafish, respectively. Moreover, our research demonstrated that ferroptosis activated by 6-OHDA was mitigated in PD models after treated with GA. Extensive molecular mechanism studies in PD-modelled cells manifested that GA attenuated the decreased expressions of SLC7A11, GPX4, and FSP-1, and the increased level of ACSL4 via activating Nrf2/HO-1 pathway as well as ameliorated the accumulation of α-synuclein.
Topics: Ferroptosis; Oxidopamine; NF-E2-Related Factor 2; Humans; Animals; Molecular Structure; Heme Oxygenase-1; Parkinson Disease; Zebrafish; Structure-Activity Relationship; Dose-Response Relationship, Drug; Neuroprotective Agents
PubMed: 38678778
DOI: 10.1016/j.bioorg.2024.107399 -
International Journal of Molecular... Apr 2024In Parkinson's disease (PD), along with typical motor dysfunction, abnormal breathing is present; the cause of which is not well understood. The study aimed to analyze...
In Parkinson's disease (PD), along with typical motor dysfunction, abnormal breathing is present; the cause of which is not well understood. The study aimed to analyze the effects of stimulation of the serotonergic system with 5-HT and 5-HT agonists in a model of PD induced by injection of 6-hydroxydopamine (6-OHDA). To model PD, bilateral injection of 6-OHDA into both striata was performed in male Wistar rats. Respiratory disturbances in response to 7% hypercapnia (CO in O) in the plethysmographic chamber before and after stimulation of the serotonergic system and the incidence of apnea were studied in awake rats 5 weeks after 6-OHDA or vehicle injection. Administration of 6-OHDA reduced the concentration of serotonin (5-HT), dopamine (DA) and norepinephrine (NA) in the striatum and the level of 5-HT in the brainstem of treated rats, which have been associated with decreased basal ventilation, impaired respiratory response to 7% CO and increased incidence of apnea compared to Sham-operated rats. Intraperitoneal (i.p.) injection of the 5-HTR agonist 8-OH-DPAT and 5-HTR agonist NBOH-2C-CN increased breathing during normocapnia and hypercapnia in both groups of rats. However, it restored reactivity to hypercapnia in 6-OHDA group to the level present in Sham rats. Another 5-HTR agonist TCB-2 was only effective in increasing normocapnic ventilation in 6-OHDA rats. Both the serotonergic agonists 8-OH-DPAT and NBOH-2C-CN had stronger stimulatory effects on respiration in PD rats, compensating for deficits in basal ventilation and hypercapnic respiration. We conclude that serotonergic stimulation may have a positive effect on respiratory impairments that occur in PD.
Topics: Animals; Male; Rats; Disease Models, Animal; Dopamine; Hypercapnia; Norepinephrine; Oxidopamine; Parkinson Disease; Rats, Wistar; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Respiration; Serotonin; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Agonists
PubMed: 38673988
DOI: 10.3390/ijms25084403