Tyrosine Hydroxylase Immunoreactivity Research Articles

Co-administration of TiO2-nanowired dl-3-n-butylphthalide (dl-NBP) and mesenchymal stem cells enhanced neuroprotection in Parkinson's disease exacerbated by concussive head injury.

dl-3-n-butylphthalide (dl-NBP) is a powerful antioxidant compound with profound neuroprotective effects in stroke and brain injury. However, its role in Parkinson's disease (PD) is not well known. Traumatic brain injury (TBI) is one of the key factors in precipitating PD like symptoms in civilians and particularly in military personnel. Thus, it would be interesting to explore the possible neuroprotective effects of NBP in PD following concussive head injury (CHI). In this chapter effect of nanowired delivery of NBP together with mesenchymal stem cells (MSCs) in PD with CHI is discussed based on our own investigations. It appears that CHI exacerbates PD pathophysiology in terms of p-tau, α-synuclein (ASNC) levels in the cerebrospinal fluid (CSF) and the loss of TH immunoreactivity in substantia niagra pars compacta (SNpc) and striatum (STr) along with dopamine (DA), dopamine decarboxylase (DOPAC). And homovanillic acid (HVA). Our observations are the first to show that a combination of NBP with MSCs when delivered using nanowired technology induces superior neuroprotective effects in PD brain pathology exacerbated by CHI, not reported earlier.

Neuroprotective Effects of Salidroside on Cerebral Ischemia/Reperfusion-Induced Behavioral Impairment Involves the Dopaminergic System.

Salidroside, a phenylpropanoid glycoside, is the main bioactive component of Rhodiola rosea L. Salidroside has prominent anti-stroke effects in cerebral ischemia/reperfusion models. However, the underlying mechanisms of its actions are poorly understood. This study examined the anti-stroke effects of salidroside in middle cerebral artery occlusion (MCAO)-induced rat model of stroke and its potential mechanisms involving the dopaminergic system. Salidroside administration increased the levels of dopamine (DA), homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) in the ipsilateral striatum after induction of transient ischemia, which were assessed using microdialysis with high-performance liquid chromatography coupled with electrochemical detection (HPLC-ECD). Furthermore, treatment with salidroside ameliorated neurobehavioral impairment, assessed with the modified neurological severity scores (mNSS), the balance beam test, and the foot fault test. Moreover, enzyme-linked immunosorbent assay (ELISA) suggested that MCAO-induced reduction in monoamine oxidase (MAO) was inhibited by salidroside. Immunohistochemical and immunofluorescence analyses revealed high level of tyrosine hydroxylase (TH) in the ipsilateral striatal caudate putamen (CPu) after cerebral ischemia/reperfusion, which could be further elevated by salidroside. In addition, salidroside could reverse the decreased immunoreactivity of TH in the substantia nigra pars compacta (SNpc). These results suggest that the anti-stroke effects of salidroside in MCAO-induced cerebral ischemia/reperfusion may involve the modulation of monoamine metabolism in the striatum and SNpc, which may be related to the function of the dopaminergic system in the rat brain.

Focused ultrasound enhanced intranasal delivery of brain derived neurotrophic factor produces neurorestorative effects in a Parkinson\u2019s disease mouse model

Focused ultrasound-enhanced intranasal (IN + FUS) delivery is a noninvasive approach that utilizes the olfactory pathway to administer pharmacological agents directly to the brain, allowing for a more homogenous distribution in targeted locations compared to IN delivery alone. However, whether such a strategy has therapeutic values, especially in neurodegenerative disorders such as Parkinson’s disease (PD), remains to be established. Herein, we evaluated whether the expression of tyrosine hydroxylase (TH), the rate limiting enzyme in dopamine catalysis, could be enhanced by IN + FUS delivery of brain-derived neurotrophic factor (BDNF) in a toxin-based PD mouse model. Mice were put on the subacute dosing regimen of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), producing bilateral degeneration of the nigrostriatal pathway consistent with early-stage PD. MPTP mice then received BDNF intranasally followed by multiple unilateral FUS-induced blood-brain barrier (BBB) openings in the left basal ganglia for three consecutive weeks. Subsequently, mice were survived for two months and were evaluated morphologically and behaviorally to determine the integrity of their nigrostriatal dopaminergic pathways. Mice receiving IN + FUS had significantly increased TH immunoreactivity in the treated hemisphere compared to the untreated hemisphere while mice receiving only FUS-induced BBB opening or no treatment at all did not show any differences. Additionally, behavioral changes were only observed in the IN + FUS treated mice, indicating improved motor control function in the treated hemisphere. These findings demonstrate the robustness of the method and potential of IN + FUS for the delivery of bioactive factors for treatment of neurodegenerative disorder.

Olfactory ensheathing cells improve the survival of porcine neural xenografts in a Parkinsonian rat model.

Parkinson's disease (PD) features the motor control deficits resulting from irreversible, progressive degeneration of dopaminergic (DA) neurons of the nigrostriatal pathway. Although intracerebral transplantation of human fetal ventral mesencephalon (hfVM) has been proven effective at reviving DA function in the PD patients, this treatment isclinically limited by availability of hfVMand the relatedethical issues. Homologous tissuesto hfVM, such as porcine fetal ventral mesencephalon (pfVM) thus present a strong clinical potential if immune response following xenotransplantation could be tamed. Olfactory ensheathing cells (OECs) are glial cells showing immunomodulatory properties. It is unclear but intriuging whether these properties can be applied to reducing immune response following neural xenotransplantation of PD. To determine whether OECs may benefit neural xenografts for PD, different compositions of grafting cellswere transplanted into striatum of the PD model rats. We used apomorphine-induced rotational behavior to evaluate effectiveness of the neural grafts on reviving DA function. Immunohistochemistry was applied to investigate the effect of OECs on the survival of neuroxenografts and underlyingmechanisms ofthis effect. Four weeks following the xenotransplantation, we found that the PD rats receiving pfVM+OECs co-graft exhibited a better improvement in apomorphine-induced rotational behavior compared with those receiving only pfVM cells. This result can be explained by higher survival of DA neurons (tyrosine hydroxylase immunoreactivity) in grafted striatum of pfVM+OECs group. Furthermore, pfVM+OECs group has less immune response (CD3+ T cells and OX-6+ microglia) around the grafted area compared with pfVM only group. These results suggest that OECs may enhance the survival of the striatal xenograftsvia dampeningtheimmune responseat the grafted sites. Using allogeneic OECs as a co-graft material for xenogeneic neural grafts could be a feasible therapeutic strategy to enhance results and applicability of the cell replacement therapy for PD.

In rats with estradiol valerate-induced polycystic ovary syndrome, the acute blockade of ovarian \u03b2-adrenoreceptors improve ovulation

BackgroundPolycystic ovary syndrome is characterized by hyperactivity of the ovarian sympathetic nervous system, increases in the content and release of norepinephrine, as well as decreases in the number of β-adrenoreceptors. In the present study, β-adrenoreceptors in the ovaries of rats with polycystic ovary syndrome were blocked and analyzed the resultant effects on ovulation, hormone secretion and the enzymes responsible for the synthesis of catecholamines.MethodsAt 60 days of age, vehicle or estradiol valerate-treated rats were injected with propranolol [10− 4 M] into the ovarian bursas on oestrus day. The animals were sacrificed on the next day of oestrus, and the ovulation response, the steroid hormone levels in the serum and the immunoreactivity of tyrosine hydroxylase and dopamine β-hydroxylase in the ovaries were measured.ResultsIn animals with the induction of polycystic ovary syndrome and β-adrenoreceptor blocking, ovulation was restored in more than half of the animals and resulted in decreased hyperandrogenism with respect to the levels observed in the estradiol valerate-treated group. Tyrosine hydroxylase and dopamine β-hydroxylase were present in the theca cells of the growing follicles and the interstitial gland. Injection of propranolol restored the tyrosine hydroxylase and ovarian dopamine β-hydroxylase levels in rats with polycystic ovary syndrome induction.ConclusionsThe results suggest that a single injection into the ovarian bursas of propranolol, a nonselective antagonist of β-adrenoreceptor receptors, decreases the serum testosterone concentration and the formation of ovarian cysts, improving the ovulation rate that accompanies lower levels of tyrosine hydroxylase and dopamine β-hydroxylase in the ovary.

Neurobehavioral effects of acute and chronic lead exposure in a desert rodent Meriones shawi: Involvement of serotonin and dopamine

Lead (Pb) is a non physiological metal that has been implicated in toxic processes affecting several organs and biological systems, including the central nervous system. Several studies have focused on changes in lead-associated neurobehavioral and neurochemical alterations that occur due to Pb exposure. The present study evaluates the effects of acute and chronic Pb acetate exposure on serotoninergic and dopaminergic systems within the dorsal raphe nucleus, regarding motor activity and anxiety behaviours. Experiments were carried out on adult male Meriones shawi exposed to acute lead acetate intoxication (25 mg/kg b.w., 3 i.p. injections) or to a chronic lead exposure (0,5%) in drinking water from intrauterine age to adult age. Immunohistochemical staining demonstrated that both acute and chronic lead exposure increased anti-serotonin (anti-5HT) and tyrosine hydroxylase (anti-TH) immuno-reactivities in the dorsal raphe nucleus. In parallel, our results demonstrated that a long term Pb-exposure, but not an acute lead intoxication, induced behavioural alterations including, hyperactivity (open field test), and anxiogenic like-effects. Such neurobehavioral impairments induced by Pb-exposure in Meriones shawi may be related to dopaminergic and serotoninergic injuries identified in the dorsal raphe nucleus.

Neuroprotective effects of docosahexaenoic acid against sub-acute manganese intoxication induced dopaminergic and motor disorders in mice

Manganese (Mn) is an essential metallic trace element involved in several vital biological functions. Conversely, exposure to excessive levels of Mn induces manganism, causing neurodegeneration and symptoms similar to those seen in Parkinson's disease (PD). Docosahexaenoic acid (DHA) is a long-chain polyunsaturated fatty acid exhibiting neuroprotective properties against neurodegenerative diseases and brain injuries and is known to easily incorporate into membrane phospholipids of brain cells and meditates its corrective actions. In the present study, mice were used for a sub-acute Mn intoxication model to investigate DHA neuroprotective potential against Mn neurotoxicity. We also seek to understand the mechanism by which Mn intoxication induces these motor impairments at 30 mg/kg, by pretreatment with DHA at 200 mg/kg and assessment of changes in spontaneous locomotor behavior by open field test (OF), motor coordination using the rotarod test (RR) and strength by mean of weights test (WT). To highlight these effects on brain neurotransmission, we evaluated the tyrosine hydroxylase immunoreactivity (TH-IR) within substantia nigra compacta (SNC) and striatum (St). Results showed that Mn intoxication significantly altered motor behavior parameters including, decreased of traveled distance by 46%, decreased mean speed by 36%, reduced the ability to sustain the rotarod test to 42%; Moreover, a drop score was obtained using weights test and reflecting affected strength in Mn-intoxicated animals. Pretreatment by DHA prevents mice from Mn toxicity and maintain normal spontaneous activity, motor coordination and strength. Data also showed the ability of Mn to disrupt dopamine neurotransmission by altering tyrosine hydroxylase activity in the nigrostriatal pathway while in pretreated animals, DHA prevented this disruption. Data approved the potential neurotoxic effect of Mn as a risk factor of the Parkinsonism onset, and then demonstrated for the first time the neuroprotective and nutraceutical outcomes of DHA in the sub-acute Mn-intoxication animal model.

The Impairments of α-Synuclein and Mechanistic Target of Rapamycin in Rotenone-Induced SH-SY5Y Cells and Mice Model of Parkinson's Disease.

Parkinson’s disease (PD) is characterized by selective degeneration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc). α-synuclein (α-syn) is known to regulate mitochondrial function and both PINK1 and Parkin have been shown to eliminate damaged mitochondria in PD. Mechanistic target of rapamycin (mTOR) is expressed in several distinct subcellular compartments and mediates the effects of nutrients, growth factors, and stress on cell growth. However, the contributions of these various regulators to DAergic cell death have been demonstrated mainly in culture with serum, which is known to dramatically influence endogenous growth rate and toxin susceptibility through nutrient and growth factor signaling. Therefore, we compared neurotoxicity induced by the mitochondrial inhibitor rotenone (ROT, 5 or 10 μM for 24 h) in SH-SY5Y cells cultured with 10% fetal bovine serum (FBS), 1% FBS, or 1% bovine serum albumin (BSA, serum-free). In addition, C57BL/6J mice were injected with 12 μg ROT into the right striatum, and brains examined by histology and Western blotting 2 weeks later for evidence of DAergic cell death and the underlying signaling mechanisms. ROT dose-dependently reduced SH-SY5Y cell viability in all serum groups without a significant effect of serum concentration. ROT injection also significantly reduced immunoreactivity for the DAergic cell marker tyrosine hydroxylase (TH) in both the mouse striatum and SNpc. Western blotting revealed that ROT inhibited TH and Parkin expression while increasing α-syn and PINK1 expression in both SH-SY5Y cells and injected mice, consistent with disruption of mitochondrial function. Moreover, expression levels of the mTOR signaling pathway components mTORC, AMP-activated protein kinase (AMPK), ULK1, and ATG13 were altered in ROT-induced PD. Further, serum level influenced mTOR signaling in the absence of ROT and the changes in response to ROT. Signs of endoplasmic reticulum (ER) stress and altered expression of tethering proteins mediating mitochondria-associated ER contacts (MAMs) were also altered concomitant with ROT-induced neurodegeneration. Taken together, this study demonstrates that complex mechanism involving mitochondrial dysfunction, altered mTOR nutrient-sensing pathways, ER stress, and disrupted MAM protein dynamics are involved in DAergic neurodegeneration in response to ROT.

In vivo long-lasting alterations of central serotonin transporter activity and associated dopamine synthesis after acute repeated administration of methamphetamine

BackgroundMethamphetamine (METH)-associated alterations in the striatal dopamine (DA) system or dopamine transport (DAT) have been identified in clinical and preclinical studies with positron emission tomography (PET) imaging but have not been well correlated with in vivo serotonin transporter (SERT) availability due to the lack of appropriate imaging agents to assess SERTs. N,N-dimethyl-2-(2-amino-4-[18F]-fluorophenylthio) benzylamine (4-[18F]-ADAM) has been developed by our group and validated for its high affinity and selectivity for SERTs, allowing the in vivo examination of SERT density, location, and binding function. The aims of this study were to investigate the potential of SERT imaging using 4-[18F]-ADAM PET to estimate the long-lasting effects of METH-induced serotonergic neurotoxicity, and further determine whether a correlative relationship exists between SERT availability/activity and tyrosine hydroxylase (TH) activity in various brain regions due to the long-lasting consequences of METH treatment.ResultsMale rats received four administrations of METH (5 or 10 mg/kg, s.c.) or saline (1 ml/kg, s.c.) at 1-h intervals. At 30 days post-administration, in vivo SERT availability and activity were measured by 4-[18F]ADAM PET imaging. In contrast to the controls, the uptake of 4-[18F]ADAM in METH-treated mice was significantly reduced in a dose-dependent manner in the midbrain, followed by the hypothalamus, thalamus, striatum, hippocampus, and frontal cortex. The regional effects of METH on TH activity were assessed by quantitative immunohistochemistry and presented as integrated optical density (IOD). A significant decrease in TH immunostaining and IOD ratios was seen in the caudate, putamen, nucleus accumbens, substantia nigra pars compacta, and substantia nigra pars reticulata in the METH-treated rats compared to controls.ConclusionThe present results suggested that the long-lasting response to METH decreased the uptake of 4-[18F]-ADAM and varied regionally along with TH immunoreactivity. In addition, 4-[18F]ADAM PET could be used to detect serotonergic neuron loss and to evaluate the severity of serotonergic neurotoxicity of METH.

Effect of stromal cell-derived factor-1/CXCR4 axis in neural stem cell transplantation for Parkinson's disease.

Previous studies have shown that neural stem cell transplantation has the potential to treat Parkinson's disease, but its specific mechanism of action is still unclear. Stromal cell-derived factor-1 and its receptor, chemokine receptor 4 (CXCR4), are important regulators of cell migration. We speculated that the CXCR4/stromal cell-derived factor 1 axis may be involved in the therapeutic effect of neural stem cell transplantation in the treatment of Parkinson's disease. A Parkinson's disease rat model was injected with 6-hydroxydopamine via the right ascending nigrostriatal dopaminergic pathway, and then treated with 5 μL of neural stem cell suspension (1.5 × 104/L) in the right substantia nigra. Rats were intraperitoneally injected once daily for 3 days with 1.25 mL/kg of the CXCR4 antagonist AMD3100 to observe changes after neural stem cell transplantation. Parkinson-like behavior in rats was detected using apomorphine-induced rotation. Immunofluorescence staining was used to determine the immunoreactivity of tyrosine hydroxylase, CXCR4, and stromal cell-derived factor-1 in the brain. Using quantitative real-time polymerase chain reaction, the mRNA expression of stromal cell-derived factor-1 and CXCR4 in the right substantia nigra were measured. In addition, western blot assays were performed to analyze the protein expression of stromal cell-derived factor-1 and CXCR4. Our results demonstrated that neural stem cell transplantation noticeably reduced apomorphine-induced rotation, increased the mRNA and protein expression of stromal cell-derived factor-1 and CXCR4 in the right substantia nigra, and enhanced the immunoreactivity of tyrosine hydroxylase, CXCR4, and stromal cell-derived factor-1 in the brain. Injection of AMD3100 inhibited the aforementioned effects. These findings suggest that the stromal cell-derived factor-1/CXCR4 axis may play a significant role in the therapeutic effect of neural stem cell transplantation in a rat model of Parkinson's disease. This study was approved by the Animal Care and Use Committee of Kunming Medical University, China (approval No. SYXKK2015-0002) on April 1, 2014.

Antibiotic-induced microbiome depletion protects against MPTP-induced dopaminergic neurotoxicity in the brain.

Although the brain–gut axis appears to play a role in the pathogenesis of Parkinson’s disease, the precise mechanisms underlying the actions of gut microbiota in this disease are unknown. This study was undertaken to investigate whether antibiotic-induced microbiome depletion affects dopaminergic neurotoxicity in the mouse brain after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP significantly decreased dopamine transporter (DAT) immunoreactivity in the striatum and tyrosine hydroxylase (TH) immunoreactivity in the substantia nigra of water-treated mice. However, MPTP did not decrease DAT or TH immunoreactivity in the brains of mice treated with an antibiotic cocktail. Furthermore, antibiotic treatment significantly decreased the diversity and altered the composition of the host gut microbiota at the genus and species levels. Interestingly, MPTP also altered microbiome composition in antibiotic-treated mice. These findings suggest that antibiotic-induced microbiome depletion might protect against MPTP-induced dopaminergic neurotoxicity in the brain via the brain–gut axis.

Involvement of CB2 Receptors in the Neurobehavioral Effects of Catha Edulis (Vahl) Endl. (Khat) in Mice.

There is behavioral evidence for the interaction between crude khat extract and the endocannabinoid system, whereby the endocannabinoid system alters khat extract-mediated behavioral effects through modulation of the monoaminergic system. The objective of this study was to investigate the role of the endocannabinoid system on the neurobehavioral effect of khat extract in mice following concomitant administration of khat extract and the CB2R agonist, JWH133. Locomotor activity test, immunohistochemistry, and reverse transcriptase polymerase chain reaction technique were utilized to assess locomotor activity, tyrosine hydroxylase immunoreactivity, and expression of dopamine transporter mRNA gene. The results show sub-acute administration of khat extract alone increased locomotor activity in mice and co-administration of the CB2R agonist, JWH133, reduced khat extract induced hyperlocomotor activity. The data revealed that cell type specific deletion of CB2Rs on dopaminergic neurons increased the hyperlocomotor behavior of khat extract. Furthermore, the results revealed that khat extract attenuated MPTP induced motor deficits, which is enhanced by JWH133. Khat extract also increased expression of tyrosine hydroxylase positive cells and expression of dopamine transporter mRNA gene in wild type mice. Nevertheless, JWH133 did not alter the effect of khat extract on tyrosine hydroxylase immunoreactivity and dopamine transporter mRNA expression when given together with khat extract. Taken together, the results suggest that the CB2Rs selectively interact with khat extract-mediated locomotor effects and could be utilized as therapeutic target in central nervous system movement disorders associated with dopamine dysregulation.

Early Postnatal Exposure to Paraquat and Maneb in Mice Increases Nigrostriatal Dopaminergic Susceptibility to a Re-challenge with the Same Pesticides at Adulthood: Implications for Parkinson’s Disease

Exposure to environmental contaminants represents an important etiological factor in sporadic Parkinson's disease (PD). It has been reported that PD could arise from events that occur early in development and that lead to delayed adverse consequences in the nigrostriatal dopaminergic system at adult life. We investigated the occurrence of late nigrostriatal dopaminergic neurotoxicity induced by exposures to the pesticides paraquat (PQ) and maneb (MB) during the early postnatal period in mice, as well as whether the exposure to pesticides during development could enhance mice vulnerability to subsequent challenges. Male Swiss mice were exposed to a combination of 0.3mg/kg PQ and 1.0mg/kgMB (PQ + MB) from postnatal (PN) day 5 to 19. PN exposure to pesticides neither induced mortally nor modified motor-related parameters. However, PN pesticides exposure decreased the number of tyrosine hydroxylase (TH)- and dopamine transporter (DAT)-positive neurons in the substantia nigra pars compacta (SNpc), as well as reduced TH and DAT immunoreactivity in the striatum. A parallel group of animals developmentally exposed to the pesticides was re-challenged at 3months of age with 10mg/kg PQ plus 30mg/kgMB (twice a week, 6weeks). Mice exposed to pesticides at both periods (PN + adulthood) presented motor deficits and reductions in the number of TH- and DAT-positive neurons in the SNpc. These findings indicate that the exposure to PQ + MB during the early PN period can cause neurotoxicity in the mouse nigrostriatal dopaminergic system, rendering it more susceptible to a subsequent adult re-challenge with the same pesticides.

Moxibustion Exerts a Neuroprotective Effect through Antiferroptosis in Parkinson's Disease.

The objective of this study was to explore the neuroprotective effect of moxibustion on rats with Parkinson's disease (PD) and its mechanism. A Parkinson's disease model was established in rats using a two-point stereotactic 6-hydroxydopamine injection in the right substantia nigra (SN) and ventral tegmental area. The rats received moxibustion at the Baihui (GV20) and Sishencong (EX-HN1) acupoints for 20 minutes, six times a week, for 6 weeks. The right SN tissue was histologically and immunohistochemically examined. Differentially expressed genes (DEGs) were identified through RNA sequencing. In addition, the levels of tyrosine hydroxylase (TH), glutathione peroxidase 4 (GPX4), and ferritin heavy chain 1 (FTH1) in SN were measured. In comparison to the model group, the moxibustion group showed a significantly greater TH immunoreactivity and a higher behavioural score. In particular, moxibustion led to an increase in the number and morphological stability of SN neural cells. The functional pathway analysis showed that DEGs are closely related to the ferroptosis pathway. GPX4 and FTH1 in the SN were significantly overexpressed in the moxibustion-treated rats with PD. Moxibustion can effectively reduce the death of SN neurons, decrease the occurrence of ferroptosis, and increase the TH activity to protect the neurons in rats with PD. The protective mechanism may be associated with suppression of the ferroptosis.

Electroacupuncture relieved visceral and referred hindpaw hypersensitivity in colitis rats by inhibiting tyrosine hydroxylase expression in the sixth lumbar dorsal root ganglia

Irritable bowel syndrome patients frequently complain of pain in body regions somatotopically distinct from the gut, suggesting the involvement of an exaggerated signaling process in both visceral and somatic sensory pathways. Increasing evidence has shown that sprouting of tyrosine hydroxylase immunoreactive (TH-IR) fibers toward sensory neurons in dorsal root ganglia maintains and exacerbates the neuropathic and inflammatory pain, as well as colonic inflammation. The aim of the present study was to determine whether electroacupuncture could alleviate the visceral and secondary somatic hyperalgesia in colitis rats by suppressing the TH-IR expression in related dorsal root ganglia. After trinitrobenzene sulfonic acid irritation, rats developed inflammatory tissue damage in the distal colon, which was accompanied by visceral hypersensitivity and secondary hind paw hyperalgesia, as indicated by enhanced visceromotor response to colorectal distension and decreased mechanical and thermal withdrawal latency of the hind paw. Additionally, excessive TH-IR fibers sprouted toward calcitonin gene-related peptide immunoreactive sensory neurons, and TH-IR neurons also increased in the sixth lumbar dorsal root ganglia of colitis rats. Both electroacupuncture and guanethidine attenuated visceral and referred hind paw hyperalgesia by inhibiting the over-expression of TH-IR neurons and fibers in the sixth lumbar dorsal root ganglia. Moreover local inflammatory damage in the distal colon was restored after 7 days of electroacupuncture intervention. These results suggest that electroacupuncture relieved visceral and referred hind paw hypersensitivity in colitis rats by inhibiting TH expression in the sixth lumbar dorsal root ganglia.

Age-Related Decrease in Tyrosine Hydroxylase Immunoreactivity in the Substantia Nigra and Region-Specific Changes in Microglia Morphology in HIV-1 Tg Rats.

Animal models have been used to study cellular processes related to human immunodeficiency virus-1 (HIV-1)-associated neurocognitive disorders (HAND). The HIV-1 transgenic (Tg) rat expresses HIV viral genes except the gag-pol replication genes and exhibits neuropathological features similar to HIV patients receiving combined antiretroviral therapy (cART). Using this rat, alterations in dopaminergic function have been demonstrated; however, the data for neuroinflammation and glial reactivity is conflicting. Differences in behavior, tyrosine hydroxylase (TH) immunoreactivity, neuroinflammation, and glia reactivity were assessed in HIV-1 Tg male rats. At 6 and 12weeks of age, rotarod performance was diminished, motor activity was not altered, and active avoidance latency performance and memory were diminished in HIV-1 Tg rats. TH+ immunoreactivity in the substantia nigra (SN) was decreased at 8months but not at 2-5months. At 5months, astrocyte and microglia morphology was not altered in the cortex, hippocampus, or SN. In the striatum, astrocytes were unaltered, microglia displayed slightly thickened proximal processes, mRNA levels for Iba1 and Cd11b were elevated, and interleukin (Il)1α,Cxcr3, and cell adhesion molecule, Icam, decreased. In the hippocampus, mRNA levels for Tnfa and Cd11b were slightly elevated. No changes were observed in the cortex or SN. The data support an age-related effect of HIV proteins upon the nigrostriatal dopaminergic system and suggest an early response of microglia in the terminal synaptic region with little evidence of an associated neuroinflammatory response across brain regions.

Association of MAPT H1 subhaplotypes with neuropathology of lewy body disease.

Genetic variation at the microtubule-associated protein tau locus is associated with clinical parkinsonism. However, it is unclear as to whether microtubule-associated protein tau H1 subhaplotypes are associated with the burden of neuropathological features of Lewy body disease. To evaluate associations of microtubule-associated protein tau haplotypes with severity of Lewy body pathology and markers of SN neuronal loss in Lewy body disease cases. Five hundred eighty-five autopsy-confirmed Lewy body disease cases were included. Six microtubule-associated protein tau variants (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, and rs7521) were genotyped to define common microtubule-associated protein tau haplotypes. Lewy body counts were measured in five cortical regions. Ventrolateral and medial SN neuronal loss were assessed semiquantitatively. Nigrostriatal dopaminergic degeneration was quantified by image analysis of tyrosine hydroxylase immunoreactivity in the dorsolateral and ventromedial putamen. The common microtubule-associated protein tau H2 haplotype did not show a strong effect on pathological burden in Lewy body disease. The rare H1j haplotype (1.3%) was significantly associated with a lower dorsolateral putaminal tyrosine hydroxylase immunoreactivity (and therefore greater dopaminergic degeneration) compared to other microtubule-associated protein tau haplotypes (P = 0.0016). Microtubule-associated protein tau H1j was also nominally (P ≤ 0.05) associated with a lower ventromedial putaminal tyrosine hydroxylase immunoreactivity (P = 0.010), but this did not survive multiple testing correction. Other nominally significant associations between microtubule-associated protein tau H1 subhaplotypes and neuropathological outcomes were observed. A rare microtubule-associated protein tau H1 subhaplotype (H1j) may be associated with more severe putaminal dopaminergic degeneration in Lewy body disease cases. Microtubule-associated protein tau H1j has been associated previously with an increased risk of PD, and therefore our exploratory findings provide insight into the mechanism by which H1j modulates PD risk. © 2019 International Parkinson and Movement Disorder Society.

Neurotoxicity to dopamine neurons after the serial exposure to alcohol and methamphetamine: Protection by COX-2 antagonism

A significant co-morbidity exists between alcohol and methamphetamine (Meth) in humans but the consequences and mechanisms underlying their co-morbid effects remain to be identified. A consequence associated with the abuse of either alcohol or Meth involves inflammation but little is known about the role of inflammation in a possible neurotoxicity arising from their co-exposure. Sprague Dawley rats were allowed 28 days of intermittent, voluntary access to 10% ethanol (EtOH) followed by a neurotoxic binge administration of Meth. EtOH drinking followed by Meth increased microglial cell counts and produced morphological changes in microglia of the substantia nigra pars compacta 2 h after Meth administration that were distinct from those produced by either EtOH or Meth alone. These effects preceded the activation of cleaved caspase-3 in dopamine cell bodies, as well as decreases in tyrosine hydroxylase (TH) immunoreactivity in the substantia nigra and dopamine transporter (DAT) immunoreactivity in the striatum measured at 7 days after Meth. Intervention with a selective COX-2 inhibitor during EtOH drinking prevented the changes in microglia, and attenuated the increase in cleaved caspase-3, and decreases in TH and DAT after Meth administration. Furthermore, motor dysfunction measured by a rotarod test was evident but only in rats that were exposed to both EtOH and Meth. The motor dysfunction was ameliorated by prior inhibition of COX-2 during EtOH drinking. The exaggerated neurochemical and behavioral deficits indicate that the comorbidity of EtOH and Meth induces a degeneration of the nigrostriatal pathway and support the role of inflammation produced by EtOH drinking that primes and mediates the neurotoxic consequences associated with the common co-morbidity of these drugs.

On the G Protein-Coupled Receptor Neuromodulation of the Claustrum

G protein-coupled receptors modulate the synaptic glutamate and GABA transmission of the claustrum. The work focused on the transmitter–receptor relationships in the claustral catecholamine system and receptor–receptor interactions between kappa opioid receptors (KOR) and SomatostatinR2 (SSTR2) in claustrum. Methods used involved immunohistochemistry and in situ proximity ligation assay (PLA) using confocal microscopy. Double immunolabeling studies on dopamine (DA) D1 receptor (D1R) and tyrosine hydroxylase (TH) immunoreactivities (IR) demonstrated that D1R IR existed in almost all claustral and dorsal endopiriform nucleus (DEn) nerve cell bodies, known as glutamate projection neurons, and D4R IR in large numbers of nerve cell bodies of the claustrum and DEn. However, only a low to moderate density of TH IR nerve terminals was observed in the DEn versus de few scattered TH IR terminals found in the claustrum. These results indicated that DA D1R and D4R transmission in the rat operated via long distance DA volume transmission in the rat claustrum and DEn to modulate claustral-sensory cortical glutamate transmission. Large numbers of these glutamate projection neurons also expressed KOR and SSTR2 which formed KOR-SSTR2 heteroreceptor complexes using PLA. Such receptor–receptor interactions can finetune the activity of the glutamate claustral-sensory cortex projections from inhibition to enhancement of their sensory cortex signaling. This can give the sensory cortical regions significant help in deciding on the salience to be given to various incoming sensory stimuli.

Curcumin prevents the midbrain dopaminergic innervations and locomotor performance deficiencies resulting from chronic aluminum exposure in rat

Aluminum (Al) among the abundant metals on the earth crust, is able to cross the biological barriers via the gastrointestinal and lung tissues. Once in the body, this heavy metal accumulates in different organs, especially the central nervous system. Though its influence is evidently shown in the substantia nigra of Parkinson’s disease patients and other brain areas in other neurodegenerative diseases, few studies have demonstrated that Al could trigger profound changes in neurotransmission systems including the dopaminergic (DAergic) system. A variety of medicinal plants may be prescribed in such contamination, including some culinary spices such as Curcumin (Cur). Several studies have proven Cur to exhibit a wide variety of biological and pharmacological activities, especially its antioxidant potential. Using the immunohistochemistry, of tyrosine hydroxylase (TH), in the midbrain substantia nigra pars compact (SNc) and the ventral tegmental area (VTA) and the open field test, we examined the DAergic system together with the locomotor behavior respectively in rats exposed chronically to Al (0,3%) in drinking water during 4 months since the intra-uterine age, as well as the neuroprotective effect of the concomitant administration of Cur I (30 mg/kg B.W) of chronic Al exposed rats. Our results have shown a significant decrease of TH immureactivity in both SNc and VTA associated to a loss of the number of crossed boxes, leading to a difficient locomotor performance in the Al group while Cur I prevents such TH immunoreactivity impairment and maintains a higher locomotor activity in the Al-CurI group. Our findings lead to suppose a powerful and obvious neuroprotective potential of CurI against Al-induced neurotoxicity of the DAergic system involved in the control of the locomotor behavior.