Striatal Tyrosine Hydroxylase Research Articles

Oxytocin Protects Nigrostriatal Dopamine Signal via Activating GABAergic Circuit in the MPTP-Induced Parkinson's Disease Model.

The most pronounced neuropathological feature of Parkinson's disease (PD) is the loss of dopamine (DA) neurons in the substantia nigra compacta (SNc), which depletes striatal DA. Hypothalamic oxytocin is found to be reduced in PD patients and closely interacts with the DA system, but the role of oxytocin in PD remains unclear. Here, the disturbances of endogenous oxytocin level and the substantia nigra (SN) oxytocin receptor expression in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model is observed, correlated with the striatal tyrosine hydroxylase (TH) expression reduction. Killing/silencing hypothalamic oxytocin neurons aggravates the vulnerability of nigrostriatal DA signal to MPTP, whereas elevating oxytocin level by intranasal delivery or microinjecting into the SN promotes the resistance. In addition, knocking out SN oxytocin receptors induces the time-dependent reductions of SNc DA neurons, striatal TH expression, and striatal DA level by increasing neuronal excitotoxicity. These results further uncover that oxytocin dampens the excitatory synaptic inputs onto DA neurons via activating oxytocin receptor-expressed SN GABA neurons, which target GABA(B) receptors expressed in SNc DA neuron-projecting glutamatergic axons, to reduce excitotoxicity. Thus, besides the well-known prosocial effect, oxytocin acts as a key endogenous factor in protecting the nigrostriatal DA system.

Repurposing ezetimibe as a neuroprotective agent in a rotenone-induced Parkinson’s disease model in rats: Role of AMPK/SIRT-1/PGC-1α signaling and autophagy

As a severe neurological disorder, Parkinson’s disease (PD) is distinguished by dopaminergic neuronal degeneration in the substantia nigra (SN), culminating in motor impairments. Several studies have shown that activation of the AMPK/SIRT1/PGC1α pathway contributes to an increase in mitochondrial biogenesis and is a promising candidate for the management of PD. Furthermore, turning on the AMPK/SIRT1/PGC1α pathway causes autophagy activation, which is fundamental for maintaining neuronal homeostasis. Interestingly, ezetimibe is an antihyperlipidemic agent that was recently reported to possess pleiotropic properties in neurology by triggering the phosphorylation and activation of AMPK. Thus, our study aimed to investigate the neuroprotective potential of ezetimibe in rats with rotenone-induced PD by activating AMPK. Adult male Wistar rats received rotenone (1.5 mg/kg, s.c.) every other day for 21 days to induce experimental PD. Rats were treated with ezetimibe (5 mg/kg/day, i.p.) 1 h before rotenone. Ezetimibe ameliorated the motor impairments in open field, rotarod and grip strength tests, restored striatal dopamine and tyrosine hydroxylase in the SN, up-regulated p-AMPK, SIRT1, and PGC1α striatal expression, upsurged the expression of ULK1, beclin1, and LC3II/I, reduced Bax/Bcl2 ratio, and alleviated rotenone-induced histopathological changes in striatum and SN. Our findings also verified the contribution of AMPK activation to the neuroprotective effect of ezetimibe by using the AMPK inhibitor dorsomorphin. Together, this work revealed that ezetimibe exerts a neuroprotective impact in rotenone-induced PD by activating AMPK/SIRT-1/PGC-1α signaling, enhancing autophagy, and attenuating apoptosis. Thus, ezetimibe’s activation of AMPK could hold significant therapeutic promise for PD management.

Moderate intensity aerobic exercise alleviates motor deficits in 6-OHDA lesioned rats and reduces serum levels of biomarkers of Parkinson's disease severity without recovery of striatal dopamine or tyrosine hydroxylase

Moderate intensity aerobic exercise alleviates motor deficits in 6-OHDA lesioned rats and reduces serum levels of biomarkers of Parkinson's disease severity without recovery of striatal dopamine or tyrosine hydroxylase

Effect of dosage duration on oropharyngeal and locomotor in a toxicological rat model of Parkinson’s disease

Parkinson’s Disease (PD) is a prevalent and devastating neurodegenerative disorder that causes progressively worsening motor symptoms affecting locomotor and oropharyngeal function. There is limited research in animal models on swallowing dysfunction in PD. To examine how neurodegeneration in PD produces progressive impairment in the oropharyngeal and locomotor processes, rotenone, a type II mitochondrial inhibitor, was injected into Lewis rat models to reproduce a parkinsonian phenotype. We hypothesized that the animal models injected with the rotenone will exhibit both oropharyngeal dysfunction and locomotor deficiency with an increased deficit that correlates with prolonged treatment. We utilized 18 rats receiving either 2.75 mg/kg of rotenone or vehicle intraperitoneal injections. Animals received daily injections for 17 or 8 days. At the end of the injections in each group brains were perfused and immunostained for striatal tyrosine hydroxylase (TH). High speed (200 fps) videofluoroscopic recording was taken of these rats and average chew cycle length, chewing rate, and total chewing time data were collected from days 0, 1, 4, 7 and 16 of those recordings. The number of rears by a rat in a glass cylinder over 4 minutes was counted on the same days to assess locomotor behavior. We used mixed model ANOVA, controlling for the effect of individual variation, to test the impact of rotenone treatment on feeding and locomotor variables. We used a Kruskall-Wallis non parametric test to test the effect of rotenone treatment on striatal TH levels. Total chewing time, and average chew cycle duration increased in rotenone treated rats from day 0 to day 4, but the difference disappeared from day 7 onwards. However, rearing behavior was consistently reduced in rotenone treated rats for all 16 days. TH staining intensity in the striatum decreased consistently over the course of the injections. These results suggest that rotenone treated rats have temporary/short term deficiency in chewing function, despite sustained reduction in spontaneous locomotor activity. The restoration of function after day 4 may indicate a learned behavior to compensate for this dysfunction in chewing, or point to a different neurological impairment than that seen in locomotor behavior. Further research needs to be undertaken to understand this phenomenon. Internal Rowan funding to F. Gould supported this work. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Motor function is not impaired in all components of the oral phase of feeding in a rat rotenone model of Parkinson’s disease

Parkinson’s disease results in pathological swallowing, or dysphagia, in up to 90% of cases. Severity and extent of functional impairment of feeding is highly variable in this disease. Feeding is a multi step neuromuscular process of tightly coordinated orofacial behaviors -transport, food reduction, pharyngeal swallowing- involving multiple musculoskeletal systems — tongue, jaw muscles, hyolaryngeal muscles — innervated by multiple cranial and cervical spinal nerves. The type of food being ingested further affects this sequence. The pesticide rotenone, a type II mitochondrial inhibitor, has been epidemiologically linked to Parkinson’s disease. The goal of this project is to identify how parkinsonian neurodegeneration affects this sequence in an animal model. We hypothesize that not all elements of the sequence will be equally affected. Twelve young adult male Lewis rats received daily intraperitoneal injections of either 2.75 mg/kg of rotenone or vehicle control for 8 days. The rats were trained to eat breakfast cereal and drink water mixed with barium in front of a high speed (200 fps) videofluoroscope. From the high speed video recording duration of intraoral transport and chewing of solid food as well as lick duration for liquid drinking were measured for multiple swallows per individual on day 0 (before injection), day 1, day 4, and day 7. On day 8 animals were perfused and brains harvested, sliced, stained with immunofluorescent markers for striatal tyrosine hydroxylase to confirm effectiveness of the model. Mixed model ANOVA was used to test the hypothesis that duration of the phases varied over the course of treatment. Duration of intra oral transport changed in neither control nor rotenone treated animals (p=0.1136), but duration of chewing increased in rotenone treated rats only by day 4 (p<0.001). Duration of licks increased in liquid drinking rats from day 0. Different components of the oral feeding process vary in degree and timing of impairment in the rat rotenone model of Parkinson’s disease, with coordinated rhythmic tongue and jaw movements (licking and chewing) being most sensitive. The neurological basis for this differential sensitivity remains unclear. Internal Rowan funds to Dr. Gould supported this work. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Aging accelerates locomotor decline in PINK1 knockout rats in association with decreased nigral, but not striatal, dopamine and tyrosine hydroxylase expression

Parkinson's disease (PD) rodent models provide insight into the relationship between nigrostriatal dopamine (DA) signaling and locomotor function. Although toxin-based rat models produce frank nigrostriatal neuron loss and eventual motor decline characteristic of PD, the rapid nature of neuronal loss may not adequately translate premotor traits, such as cognitive decline. Unfortunately, rodent genetic PD models, like the Pink1 knockout (KO) rat, often fail to replicate the differential severity of striatal DA and tyrosine hydroxylase (TH) loss, and a bradykinetic phenotype, reminiscent of human PD. To elucidate this inconsistency, we evaluated aging as a progression factor in the timing of motor and non-motor cognitive impairments. Male PINK1 KO and age-matched wild type (WT) rats were evaluated in a longitudinal study from 3 to 16 months old in one cohort, and in a cross-sectional study of young adult (6–7 months) and aged (18–19 months) in another cohort. Young adult PINK1 KO rats exhibited hyperkinetic behavior associated with elevated DA and TH in the substantia nigra (SN), which decreased therein, but not striatum, in the aged KO rats. Additionally, norepinephrine levels decreased in aged KO rats in the prefrontal cortex (PFC), paired with a higher DA levels in young and aged KO. Although a younger age of onset characterizes familial forms of PD, our results underscore the critical need to consider age-related factors. Moreover, the results indicate that compensatory mechanisms may exist to preserve locomotor function, evidenced by increased DA in the SN early in the lifespan, in response to deficient PINK1 function, which declines with aging and the onset of motor decline.

Deficits in basal and evoked striatal dopamine release following alpha-synuclein preformed fibril injection: An in vivo microdialysis study.

Parkinson's disease (PD) is characterized by the accumulation of misfolded alpha-synuclein (α-syn) protein, forming intraneuronal Lewy body (LB) inclusions. The α-syn preformed fibril (PFF) model of PD recapitulates α-syn aggregation, progressive nigrostriatal degeneration and motor dysfunction; however, little is known about the time course of PFF-induced alterations in basal and evoked dopamine (DA). In vivo microdialysis is well suited for identifying small changes in neurotransmitter levels over extended periods. In the present study, adult male Fischer 344 rats received unilateral, intrastriatal injections of either α-syn PFFs or phosphate-buffered saline (PBS). At 4 or 8 months post-injection (p.i.), animals underwent in vivo microdialysis to evaluate basal extracellular striatal DA and metabolite levels, local KCl-evoked striatal DA release and the effects of systemic levodopa (l-DOPA). Post-mortem analysis demonstrated equivalent PFF-induced reductions in tyrosine hydroxylase (TH) immunoreactive nigral neurons (~50%) and striatal TH (~20%) at both time points. Compared with reduction in striatal TH, reduction in striatal dopamine transporter (DAT) was more pronounced and progressed between the 4- and 8-month p.i. intervals (36%➔46%). Significant PFF-induced deficits in basal and evoked striatal DA, as well as deficits in motor performance, were not observed until 8 months p.i. Responses to l-DOPA did not differ regardless of PBS or PFF treatment. These results suggest that basal and evoked striatal DA are maintained for several months following PFF injection, with loss of both associated with motor dysfunction. Our studies provide insight into the time course and magnitude of PFF-induced extracellular dopaminergic deficits in the striatum.

Sex-dependent effects of chronic intermittent ethanol treatment in Wistar rats

Multiple behavioral parameters are associated with vulnerability to alcohol dependence, but the contribution of such factors as cognitive flexibility and sex differences still require further clarification. Our goal was to assess how sex differences mediate relationships between cognitive flexibility, affective state, hierarchy and ethanol preference before and after chronic intermittent ethanol (CIE) exposure in Wistar rats. The results of our study revealed sex-dependent changes in ethanol preference and locomotor activity throughout the time. Anxiety levels were sex-dependently affected by ethanol exposure with a dramatic decrease in ethanol-exposed females. Similarly, striatal tyrosine hydroxylase expression was affected by CIE in a sex-dependent manner, with ethanol-exposed females having higher expression than males. Baseline cognitive flexibility was better in rats with higher locomotor activity and lower anxiety levels but did not correlate with ethanol preference in rats. Taken together, these results are important for understanding sex-dependent alterations in brain and behavior induced by alcohol. This provides important insights into understanding sex differences in the risk for mental disorders.

Formoterol attenuated mitochondrial dysfunction in rotenone-induced Parkinson's disease in a rat model: Role of PINK-1/PARKIN and PI3K/Akt/CREB/BDNF/TrKB axis

β2-adrenoreceptors (β2AR have been identified recently as regulators of the α-synuclein gene (SNCA), one of the key milieus endorsed in injury of dopamine neurons in Parkinson's disease (PD). Accumulation of α-synuclein leads to mitochondrial dysfunction via downregulation of mitophagy proteins (PINK-1 and PARKIN) and inhibition of mitochondria biogenesis (PGC-1α) along with an increase in the master inflammatory regulator NF-κB p65 production that provokes neurodegeneration and diminishes neuroprotective signaling pathway (PI3k/Akt/CREB/BDNF). Recently, formoterol exhibited a promising neuroprotective effect against neurodegenerative conditions associated with brain inflammation. Therefore, the present investigation aims to unveil the possible neuroprotective activity of formoterol, β2AR agonist, against rotenone-induced PD in rats. Rats received rotenone (1.5 mg/kg; s.c.) every other day for 3 weeks and cured with formoterol (25 μg/kg/day; i.p.) 1 hr. after rotenone administration, starting from day 11. Formoterol treatment succeeded in upregulating β2-adrenoreceptor expression in PD rats and preserving the function and integrity of dopaminergic neurons as witnessed by enhancement of muscular performance in tests, open field, grip strength-meter, and Rotarod, besides the increment in substantia nigra and striatal tyrosine hydroxylase immunoexpression. In parallel, formoterol boosted mitophagy by activation of PINK1 and PARKIN and preserved mitochondrial membrane potential. Additionally, formoterol stimulated the neuro-survival signaling axis via stimulation of PI3k/pS473-Akt/pS133-CREB/BDNF cascade to attenuate neuronal loss. Noteworthy formoterol reduces neuro-inflammatory status by decreasing NFκBp65 immunoexpression and TNF-α content. Finally, formoterol's potential as a stimulant therapy of mitophagy via the PINK1/PARKIN axis and regulation of mitochondrial biogenesis by increasing PGC-1α to maintain mitochondrial homeostasis along with stimulation of PI3k/Akt/CREB/BDNF axis.

Fecal Microbiota Transplantation from Aged Mice Render Recipient Mice Resistant to MPTP-Induced Nigrostriatal Degeneration Via a Neurogenesis-Dependent but Inflammation-Independent Manner.

Accumulating data support a crucial role of gut microbiota in Parkinson's disease (PD). However, gut microbiota vary with age and, thus, will affect PD in an age-dependent, but unknown manner. We examined the effects of fecal microbiota transplantation (FMT) pretreatment, using fecal microbiota from young (7weeks) or aged mice (23months), on MPTP-induced PD model. Motor function, pathological changes, striatal neurotransmitters, neuroinflammation, gut inflammation and gut permeability were examined. Gut microbiota composition and metabolites, namely short-chain fatty acids (SCFAs), were analyzed. Neurogenesis was also evaluated by measuring the number of doublecortin-positive (DCX+) neurons and Ki67-positive (Ki67+) cells in the hippocampus. Expression of Cd133 mRNA, a cellular stemness marker, in the hippocampus was also examined. Mice who received FMT from young mice showed MPTP-induced motor dysfunction, and reduction of striatal dopamine (DA), dopaminergic neurons and striatal tyrosine hydroxylase (TH) levels. Interestingly and unexpectedly, mice that received FMT from aged mice showed recovery of motor function and rescue of dopaminergic neurons and striatal 5-hydroxytryptamine (5-HT), as well as decreased DA metabolism after MPTP challenge. Further, they showed improved metabolic profiling and a decreased amount of fecal SCFAs. High-throughput sequencing revealed that FMT remarkably reshaped the gut microbiota of recipient mice. For instance, levels of genus Akkermansia and Candidatus Saccharimonas were elevated in fecal samples of recipient mice receiving aged microbiota (AM + MPTP mice) than YM + MPTP mice. Intriguingly, both young microbiota and aged microbiota had no effect on neuroinflammation, gut inflammation or gut permeability. Notably, AM + MPTP mice showed a marked increase in DCX+ neurons, as well as Ki67+ cells and Cd133 expression in the hippocampal dentate gyrus (DG) compared to YM + MPTP mice. These results suggest that FMT from aged mice augments neurogenesis, improves motor function and restores dopaminergic neurons and neurotransmitters in PD model mice, possibly through increasing neurogenesis.

Recovery of motor function is associated with rescue of glutamate biomarkers in the striatum and motor cortex following treatment with Mucuna pruriens in a murine model of Parkinsons disease

There is growing interest in the use of natural products for the treatment of Parkinson's disease (PD). Mucuna pruriens has been used in the treatment of humans with PD. The goal of this study was to determine if daily oral treatment with an extract of Mucuna pruriens, starting after the MPTP-induced loss of nigrostriatal dopamine in male mice, would result in recovery/restoration of motor function, tyrosine hydroxylase (TH) protein expression in the nigrostriatal pathway, or glutamate biomarkers in both the striatum and motor cortex. Following MPTP administration, resulting in an 80 % loss of striatal TH, treatment with Mucuna pruriens failed to rescue either striatal TH or the dopamine transporter back to the control levels, but there was restoration of gait/motor function. There was an MPTP-induced loss of TH-labeled neurons in the substantia nigra pars compacta and in the number of striatal dendritic spines, both of which failed to be recovered following treatment with Mucuna pruriens. This Mucuna pruriens-induced locomotor recovery following MPTP was associated with restoration of two striatal glutamate transporter proteins, GLAST (EAAT1) and EAAC1 (EAAT3), and the vesicular glutamate transporter 2 (Vglut2) within the motor cortex. Post-MPTP treatment with Mucuna pruriens, results in locomotor improvement that is associated with recovery of striatal and motor cortex glutamate transporters but is independent of nigrostriatal TH restoration.

The dopaminergic D1 receptor modulates the hyperactivity of Bapa mutant mice

The mutant bate-palmas (“claps”; symbol - bapa) mice induced by the mutagenic chemical ENU present motor incoordination and postural alterations. A previous study showed that bapa mice present increased motor/exploratory behaviors during the prepubertal period due to increased striatal tyrosine hydroxylase expression, suggesting striatal dopaminergic system hyperactivity. This study aimed to evaluate the involvement of striatal dopaminergic receptors in the hyperactivity of bapa mice. Male bapa mice and their wild strain (WT) were used. Spontaneous motor behavior was observed in the open-field test, and stereotypy was evaluated after apomorphine administration. The effects of DR1 and DR2 dopaminergic antagonists (SCH-23,390; sulpiride) and the striatal DR1 and D2 receptor gene expression were evaluated. Relative to WT, bapa mice showed: 1) increased general activity for four days; 2) increased rearing and sniffing behavior and decreased immobility after apomorphine; 3) blockage of rearing behavior after the DR2 antagonist but no effect after DR1 antagonist; 4) blockage of sniffing behavior after the DR1 antagonist in bapa and WT mice but no effect after the DR2 antagonist; 5) increased immobility after the DR1 antagonist but no effect after the DR2 antagonist; 6) increased expression of striatal DR1 receptor gene and reduced the DR2 expression gene after apomorphine administration. Bapa mice showed increased activity in open field behavior. The increased rearing behavior induced by apomorphine of bapa mice resulted from the increased gene expression of the DR1 receptor.

Neuroprotective effect of Eugenia uniflora against intranasal MPTP-induced memory impairments in rats: The involvement of pro-BDNF/p75NTR pathway

Parkinson's disease is a multisystemic neurodegenerative disorder that includes motor and non-motor symptoms, and common symptoms include memory loss and learning difficulties. Thus, we investigated the neuroprotective potential of a hydroalcoholic extract of Brazilian purple cherry (Eugenia uniflora) (HAE-BC) on memory impairments induced by intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in rats and the involvement of hippocampal BDNF/TrkB/p75NTR pathway in its effects. Adult male Wistar rats were exposed to MPTP (1 mg/nostril) or vehicle. Twenty-four hours later, the HAE-BC treatments began at doses of 300 or 2000 mg/kg/day or vehicle for 14 days. From 7 days after the MPTP induction, the animals were subjected to behavioral tests to evaluate several cognitive paradigms. HAE-BC treatments, at both doses, blocked the MPTP-caused disruption in the social recognition memory, short- and long-term object recognition memories, and working memory. Furthermore, MPTP-induced motor deficit linked to striatal tyrosine hydroxylase levels decreased, which was blocked by HAE-BC. Our findings demonstrated that HAE-BC blocked the MPTP-induced increase in the hippocampal pro-BDNF, TrkB.t1, and p75NTR levels. The pro-BDNF/p75NTR interaction negatively regulates synaptic transmission and plasticity, and the neuroprotective effect of HAE-BC was related, at least partly, to the modulation of this hippocampal signaling pathway. Thus, our study reports the first evidence of the potential therapeutic of E. uniflora in a Parkinson's disease model in rodents.

Genetic effects in a progressive model of parkinsonism induced by reserpine

We investigated the locomotor, emotional, physiological, and neurobiological effects induced by low-dose reserpine repeated treatment (0.1mg/kg; 14 injections) in males from the Lewis (LEW), Spontaneously Hypertensive Rats (SHR), and SHR.LEW-(D4Rat76-D4Mgh11) (SLA16) isogenic rat strains, which have different genetic backgrounds on chromosome 4. Behavioral responses in the catalepsy, open-field, and oral movements' tests were coupled with blood pressure, body weight, and striatal tyrosine hydroxylase (TH) level assessments to establish neurobiological comparisons between reserpine-induced impairments and genetic backgrounds RESULTS: Results revealed the SHR strain was more sensitive in the catalepsy test and exhibited higher TH immunoreactivity in the dorsal striatum. The SLA16 strain presented more oral movements, suggesting increased susceptibility to develop oral dyskinesia. Our results showed the efficacy of repeated treatment with a low dose of reserpine and demonstrated, for the first time, the genetic influence of a specific region of chromosome 4 on the expression of these effects.

Curcumin modulation of L-dopa and rasagiline-induced neuroprotection in rotenone model of Parkinson's disease.

Parkinson's disease (PD) is one of the most incurable, chronic, and progressive neurodegenerative disorders Worldwide. Curcumin, a natural polyphenolic anti-oxidant compound, has a long history in traditional medicine. We investigate the effect of curcumin on brain oxidative stress, DNA fragmentation, and motor changes in rotenone-induced PD in mice. The possible modulation of the anti-parkinsonian action of drugs L-dopa and rasagiline by curcumin was also studied. Mice received rotenone 1.5 mg/kg and were treated with curcumin (150 mg/kg), L-dopa (25 mg/kg), rasagiline (1 mg/kg), L-dopa+curcumin, or rasagiline+curcumin. Striatal malondialdehyde, reduced glutathione, nitric oxide, tyrosine hydroxylase, and brain DNA fragmentations were measured. Histopathological examination of brain tissues was done. Motor coordination and behavioral tests such as wire-hanging, stair, and wood-waking tests were included. Rotenone caused elevation in brain malondialdehyde and nitric oxide contents, depletion of reduced glutathione accompanied by a reduction in rearing behavior, and impairment of motor activity in wire-hanging, stair, and wood-waking tests. Also, severe DNA fragmentation in the striatum, marked decrease of substantia nigra pigmented neurons, neuronal degeneration in the cerebral cortex and hippocampus, decreased glial fibrillary acidic protein reaction (GFAP) and glial cell size in the cerebral cortex were caused by rotenone. In rotenone-treated mice, brain oxidative stress was decreased by curcumin, L-dopa, rasagiline, curcumin+L-dopa, and curcumin+rasagiline. These treatments also prevented DNA fragmentation and markedly improved the motor and behavioral impairment caused by rotenone. Rotenone-induced histopathological changes were ameliorated by curcumin which had an additive effect to that of l-dopa or rasagiline. These data indicate that curcumin showed additive neuroprotective effects to L-dopa or rasagiline and ameliorated neurodegeneration, DNA fragmentation, and motor defects caused by rotenone in mice.

Neuroprotective effect of secukinumab against rotenone induced Parkinson's disease in rat model: Involvement of IL-17, HMGB-1/TLR4 axis and BDNF/TrKB cascade.

Neuroinflammatory status produced via activation of toll like receptor-4 (TLR-4) and interleukin-17 receptor (IL-17R) is one of the principal mechanisms involved in dopaminergic neuronal loss in Parkinson's disease (PD). Activation of TLR-4 and IL-17R stimulates reactive oxygen species (ROS) and proinflammatory cytokines (IL-17, IL-1β, TNFα, IL-6) production that augments neurodegeneration and reduces neuro-survival axis (TrKB/Akt/CREB/BDNF). So, reducing IL-17-driven neuroinflammation via secukinumab, monoclonal antibody against IL-17A, may be one of therapeutic approach for PD. Moreover, the aim was extended to delineate the possible neuroprotective mechanism involved against neuronal loss in rotenone induced PD in rats. Rats received 11 subcutaneous injection of rotenone (1.5mg/kg) every other day for 21 consecutive days and treated with 2 subcutaneous injections of secukinumab (15mg/kg) on day 9 and 15, one hour after rotenone administration. Treatment with secukinumab improved motor impairment and muscle incoordination induced by rotenone, as verified by open field and rotarod tests. Moreover, secukinumab attenuated neuronal loss and improve histopathological profile. Noteworthy, secukinumab reduces neuro-inflammatory status by hindering the interaction between IL and 17A and IL-17RA together with inhibiting the activation of TLR-4 and its downstream cascade including pS536-NFκB p65, IL-1β and HMGB-1. Additionally, secukinumab stimulated neuro-survival signalling cascade via activation pY515-TrKB receptor and triggered upsurge in its downstream targets (pS473-Akt/pS133-CREB/BDNF). Furthermore, secukinumab increased striatal tyrosine hydroxylase immunoexpression, the rate limiting step in dopamine biosynthesis, to guard against dopaminergic neuronal loss. In conclusion, secukinumab exerts a neuroprotective effect against rotenone induced neuronal loss via inhibition IL17A/IL17RA interaction and HMGB-1/TLR-4/NF-κBp65/IL1β signalling cascade, together with activation of TrKB/ Akt/CREB/BDNF axis.

The proSAAS Chaperone Provides Neuroprotection and Attenuates Transsynaptic α-Synuclein Spread in Rodent Models of Parkinson's Disease.

Parkinson's disease involves aberrant aggregation of the synaptic protein alpha-synuclein (aSyn) in the nigrostriatal tract. We have previously shown that proSAAS, a small neuronal chaperone, blocks aSyn-induced dopaminergic cytotoxicity in primary nigral cultures. To determine if proSAAS overexpression is neuroprotective in animal models of Parkinson's disease. proSAAS- or GFP-encoding lentivirus was injected together with human aSyn-expressing AAV unilaterally into the substantia nigra of rats and motor asymmetry assessed using a battery of motor performance tests. Dopamine neuron survival was assessed by nigral stereology and striatal tyrosine hydroxylase (TH) densitometry. To examine transsynaptic spread of aSyn, aSyn AAV was injected into the vagus of mice in the presence of AAVs encoding either GFP or proSAAS; the spread of aSyn-positive neurites into rostral nuclei was quantified following immunohistochemistry. Coinjection of proSAAS-encoding lentivirus profoundly reduced the motor asymmetry caused by unilateral nigral AAV-mediated human aSyn overexpression. This was accompanied by significant amelioration of the human aSyn-induced loss of both nigral TH-positive cells and striatal TH-positive terminals, demonstrating clear proSAAS-mediated protection of the nigrostriatal tract. ProSAAS overexpression reduced human aSyn protein levels in nigra and striatum and reduced the loss of TH protein in both regions. Following vagal administration of human aSyn-encoding AAV, the number of human aSyn-positive neurites in the pons and caudal midbrain was considerably reduced in mice coinjected with proSAAS-, but not GFP-encoding AAV, supporting proSAAS-mediated blockade of transsynaptic aSyn transmission. The proSAAS chaperone may represent a promising target for therapeutic development in Parkinson's disease.

Metabolomics and biochemical alterations caused by pleiotrophin in the 6-hydroxydopamine mouse model of Parkinson\u2019s disease

Pleiotrophin (PTN) is a cytokine involved in nerve tissue repair processes, neuroinflammation and neuronal survival. PTN expression levels are upregulated in the nigrostriatal pathway of Parkinson’s Disease (PD) patients. We aimed to characterize the dopaminergic injury and glial responses in the nigrostriatal pathway of mice with transgenic Ptn overexpression in the brain (Ptn-Tg) after intrastriatal injection of the catecholaminergic toxic 6-hydroxydopamine (6-OHDA) at a low dose (5 µg). Ten days after surgery, the injection of 6-OHDA induced a significant decrease of the number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra and of the striatal TH contents in Wild type (Wt) mice. In contrast, these effects of 6-OHDA were absent in Ptn-Tg mice. When the striatal Iba1 and GFAP immunoreactivity was studied, no statistical differences were found between vehicle-injected Wt and Ptn-Tg mice. Furthermore, 6-OHDA did not cause robust glial responses neither on Wt or Ptn-Tg mice 10 days after injections. In metabolomics studies, we detected interesting metabolites that significantly discriminate the more injured 6-OHDA-injected Wt striatum and the more protected 6-OHDA-injected Ptn-Tg striatum. Particularly, we detected groups of metabolites, mostly corresponding to phospholipids, whose trends were opposite in both groups. In summary, the data confirm lower 6-OHDA-induced decreases of TH contents in the nigrostriatal pathway of Ptn-Tg mice, suggesting a neuroprotective effect of brain PTN overexpression in this mouse model of PD. New lipid-related PD drug candidates emerge from this study and the data presented here support the increasingly recognized “lipid cascade” in PD.

Bate palmas (bapa) mutant mouse, a model of Kabuki syndrome presents behavioral hyperactivity via increased striatal tyrosine hydroxylase expression

Bate palmas (bapa) mutant mouse, a model of Kabuki syndrome presents behavioral hyperactivity via increased striatal tyrosine hydroxylase expression

Impact of adolescent methamphetamine use on social cognition: A human-mice reverse translation study

BackgroundMethamphetamine dependence is associated with social cognition deficits that may underpin negative social outcomes. However, there are considerable inter-individual differences in social cognition within people with methamphetamine dependence, with age of onset of methamphetamine use being a potential contributing factor. Materials and methodsWe conducted two sequential studies examining the link between age of onset of methamphetamine use (adolescence versus young adulthood) and performance in social cognition tests: (1) a human cross-sectional study in 95 participants with methamphetamine dependence varying in age of onset (38 with adolescent onset and 57 with adult onset) and 49 drug-naïve controls; (2) a mice study in which we tested the effects of methamphetamine exposure during adolescence versus young adulthood on social interaction and aggression, and their potential neurochemical substrates in the striatal dopaminergic system. ResultsWe initially showed that people with methamphetamine dependence who started use in adolescence had higher antisocial beliefs (p = 0.046, Cohen’s d=0.42) and worse emotion recognition (p = 0.031, Cohen’s d=0.44) than those who started use during adulthood. We reasoned that this could be due to either social cognition deficits leading to earlier onset of methamphetamine use, or methamphetamine-induced neuroadaptive effects specific to adolescence. Mice experiments showed that methamphetamine exposure during adolescence specifically decreased social investigation during social interaction and upregulated striatal tyrosine hydroxylase (p < 0.05, Bonferroni corrected). There was no evidence of adolescent-specific methamphetamine effects on aggression or other measures of dopaminergic function. ConclusionTogether, translational findings demonstrate heightened sensitivity to methamphetamine effects on social cognition during adolescence.