Cerebral Dopamine Neurotrophic Factor Research Articles

Protective mechanisms by glial cell line-derived neurotrophic factor and cerebral dopamine neurotrophic factor against the α-synuclein accumulation in Parkinson's disease.

Synucleinopathies constitute a disease family named after alpha-synuclein protein, which is a significant component of the intracellular inclusions called Lewy bodies. Accompanying the progressive neurodegeneration, Lewy bodies and neurites are the main histopathologies of synucleinopathies. The complicated role of alpha-synuclein in the disease pathology makes it an attractive therapeutic target for disease-modifying treatments. GDNF is one of the most potent neurotrophic factors for dopamine neurons, whereas CDNF is protective and neurorestorative with entirely different mechanisms of action. Both have been in the clinical trials for the most common synucleinopathy, Parkinson's disease. With the AAV-GDNF clinical trials ongoing and the CDNF trial being finalized, their effects on abnormal alpha-synuclein accumulation are of great interest. Previous animal studies with an alpha-synuclein overexpression model have shown that GDNF was ineffective against alpha-synuclein accumulation. However, a recent study with cell culture and animal models of alpha-synuclein fibril inoculation has demonstrated the opposite by revealing that the GDNF/RET signaling cascade is required for the protective effect of GDNF on alpha-synuclein aggregation. CDNF, an ER resident protein, was shown to bind alpha-synuclein directly. CDNF reduced the uptake of alpha-synuclein fibrils by the neurons and alleviated the behavioral deficits induced by fibrils injected into the mouse brain. Thus, GDNF and CDNF can modulate different symptoms and pathologies of Parkinson's disease, and perhaps, similarly for other synucleinopathies. Their unique mechanisms for preventing alpha-synuclein-related pathology should be studied more carefully to develop disease-modifying therapies.

Augmenting hematoma-scavenging capacity of innate immune cells by CDNF reduces brain injury and promotes functional recovery after intracerebral hemorrhage

During intracerebral hemorrhage (ICH), hematoma formation at the site of blood vessel damage results in local mechanical injury. Subsequently, erythrocytes lyse to release hemoglobin and heme, which act as neurotoxins and induce inflammation and secondary brain injury, resulting in severe neurological deficits. Accelerating hematoma resorption and mitigating hematoma-induced brain edema by modulating immune cells has potential as a novel therapeutic strategy for functional recovery after ICH. Here, we show that intracerebroventricular administration of recombinant human cerebral dopamine neurotrophic factor (rhCDNF) accelerates hemorrhagic lesion resolution, reduces peri-focal edema, and improves neurological outcomes in an animal model of collagenase-induced ICH. We demonstrate that CDNF acts on microglia/macrophages in the hemorrhagic striatum by promoting scavenger receptor expression, enhancing erythrophagocytosis and increasing anti-inflammatory mediators while suppressing the production of pro-inflammatory cytokines. Administration of rhCDNF results in upregulation of the Nrf2-HO-1 pathway, but alleviation of oxidative stress and unfolded protein responses in the perihematomal area. Finally, we demonstrate that intravenous delivery of rhCDNF has beneficial effects in an animal model of ICH and that systemic application promotes scavenging by the brain’s myeloid cells for the treatment of ICH.

DNA Methyltransferase Inhibitors Induce Cerebral Dopamine Neurotrophic Factor Expression in C6 Glioma Cells

DNA Methyltransferase Inhibitors Induce Cerebral Dopamine Neurotrophic Factor Expression in C6 Glioma Cells

Neuroprotective effect of hyperoside in MPP+/MPTP -induced dopaminergic neurodegeneration.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the pathological loss of nigrostriatal dopaminergic neurons, which causes an insufficient release of dopamine (DA) and then induces motor and nonmotor symptoms. Hyperoside (HYP) is a lignan component with anti-inflammatory, antioxidant, and neuroprotective effects. In this study, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active neurotoxic metabolite 1-methyl-4-phenylpyridinium ion (MPP+) were used to induce dopaminergic neurodegeneration. The results showed that HYP (100µg/mL) reduced MPTP-mediated cytotoxicity of SH-SY5Y cells in vitro, and HYP [25mg/(kg d)] alleviated MPTP-induced motor symptoms in vivo. HYP treatment reduced the contents of nitric oxide (NO), H2O2, and malondialdehyde (MDA), as well as the mitochondrial damage of dopaminergic neurons, both in vitro and in vivo. Meanwhile, HYP treatment elevated the levels of neurotrophic factors such as glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor, and recombinant cerebral dopamine neurotrophic factor in vivo, but not in vitro. Finally, Akt signaling was activated after the administration of HYP in MPP+/MPTP-induced dopaminergic neurodegeneration. However, the blockage of the Akt pathway with Akt inhibitor did not abolish the neuroprotective effect of HYP on DA neurons. These results showed that HYP protected the dopaminergic neurons from the MPP+- and MPTP-induced injuries, which did not rely on the Akt pathway.

Erratum to “Cerebral dopamine neurotrophic factor is essential for enteric neuronal development, maintenance, and regulation of gastrointestinal transit”

Erratum to “Cerebral dopamine neurotrophic factor is essential for enteric neuronal development, maintenance, and regulation of gastrointestinal transit”

Cerebral dopamine neurotrophic factor increases proliferation, Migration and differentiation of subventricular zone neuroblasts in photothrombotic stroke model of mouse

BackgroundCerebral ischemic stroke can induce the proliferation of subventricular zone (SVZ) neural stem cells (NSCs) in the adult brain. However, this reparative process is restricted because of NSCs’ death shortly after injury or disability of them to reach the infarct boundary. In the present study, we investigated the ability of cerebral dopamine neurotrophic factor (CDNF) on the attraction of SVZ-resident NSCs toward the lesioned area and neurological recovery in a photothrombotic (PT) stroke model of mice MethodsThe mice were assigned to three groups stroke, stroke+phosphate buffered saline (PBS), and stroke+CDNF. Migration of SVZ NSCs were evaluated by BrdU/doublecortin (DCX) double immunofluorescence method on days 7 and 14 and their differentiation were evaluated by BrdU/ Neuronal Nuclei (NeuN) double immunofluorescence method 28 days after intra-SVZ CDNF injection. Serial coronal sections were stained with cresyl violet to detect the infarct volume and a modified neurological severity score (mNSS) was performed to assess the neurological performance ResultsInjection of CDNF increased the proliferation of SVZ NSCs and the number of DCX-expressing neuroblasts migrated from the SVZ toward the ischemic site. It also enhanced the differentiation of migrated neuroblasts into the mature neurons in the lesioned site. Along with this, the infarct volume was significantly decreased and the neurological performance was improved as compared to other groups ConclusionThese results demonstrate that CDNF is capable of enhancing the proliferation of NSCs residing in the SVZ and their migration toward the ischemia region and finally, differentiation of them in stroke mice, concomitantly decreased infarct volume and improved neurological abilities were revealed.

CDNF Interacts with ER Chaperones and Requires UPR Sensors to Promote Neuronal Survival.

Cerebral dopamine neurotrophic factor (CDNF) is a neurotrophic factor that has beneficial effects on dopamine neurons in both in vitro and in vivo models of Parkinson’s disease (PD). CDNF was recently tested in phase I-II clinical trials for the treatment of PD, but the mechanisms underlying its neuroprotective properties are still poorly understood, although studies have suggested its role in the regulation of endoplasmic reticulum (ER) homeostasis and the unfolded protein response (UPR). The aim of this study was to investigate the mechanism of action of CDNF through analyzing the involvement of UPR signaling in its anti-apoptotic function. We used tunicamycin to induce ER stress in mice in vivo and used cultured primary neurons and found that CDNF expression is regulated by ER stress in vivo and that the involvement of UPR pathways is important for the neuroprotective function of CDNF. Moreover, we used AP-MS and BiFC to perform the first interactome screening for CDNF and report novel binding partners of CDNF. These findings allowed us to hypothesize that CDNF protects neurons from ER-stress-inducing agents by modulating UPR signaling towards cell survival outcomes.

The effectiveness of rehabilitation programs for the mobilization of compensatory-adaptive neuroplasticity processes in patients with Parkinson’s disease according to indicators of neurotrophic factors

The purpose of the study: is to objec- tively evaluate the effectiveness of non- drug rehabilitation programs for patients with Parkinson’s disease (PD) based on in- dicators of specific neurotrophic factors. Sixty-one patients with PD: study group — 33 patients, comparison group — 28 people. There were 33 patients in the ex- perimental group and 28 in the compari- son group. The patients of the experi- mental group did daily physical exercises for two months, unlike the representatives of the comparison group. Patients of both groups were examined for the serum level of the neurotrophic fac- tors: glial cell line-derived neurotrophic factor (GDNF) and cerebral dopamine neurotrophic factor (CDNF) In patients with PD of the comparison group, the synchronous dynamics of CDNF and GDNF indicators occurred and char- acterized the individual course of the dis- ease. On the other hand, in the experimental group, asynchrony of changes of these neuro- trophic factors in blood serum was observed under conditions of physical exertion. Summarizing the data obtained, it is nec- essary to consider many factors that can af- fect the level of neurotrophic factors. There is probably a genetically determined hetero- geneity of the Parkinson’s disease pheno- type, which is also expressed by the features of the synchronous dynamics of CDNF and GDNF parameters. It follows that the initial assessment of these parameters in patients with PD is optimal to identify those for whom motor rehabilitation will cause a long and stable positive effect and ensure the course of the disease according to a favourable type. The multidirectional and asynchrony of changes in neurotrophic factors in blood serum under conditions of physical exer- tion indicates the "sensitivity" of the sys- tem of neurotrophic factors to rehabilitation measures, even if they are used for a short time. Since long-term rehabilitation programs provide positive dynamics in the design of neurotrophic factors, a sufficient dura- tion and regularity of non-drug rehabilitation programs are advisable.

Modulating Microglia/Macrophage Activation by CDNF Promotes Transplantation of Fetal Ventral Mesencephalic Graft Survival and Function in a Hemiparkinsonian Rat Model.

Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in substantia nigra pars compacta, which leads to the motor control deficits. Recently, cell transplantation is a cutting-edge technique for the therapy of PD. Nevertheless, one key bottleneck to realizing such potential is allogenic immune reaction of tissue grafts by recipients. Cerebral dopamine neurotrophic factor (CDNF) was shown to possess immune-modulatory properties that benefit neurodegenerative diseases. We hypothesized that co-administration of CDNF with fetal ventral mesencephalic (VM) tissue can improve the success of VM replacement therapies by attenuating immune responses. Hemiparkinsonian rats were generated by injecting 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle of Sprague Dawley (SD) rats. The rats were then intrastriatally transplanted with VM tissue from rats, with/without CDNF administration. Recovery of dopaminergic function and survival of the grafts were evaluated using the apomorphine-induced rotation test and small-animal positron emission tomography (PET) coupled with [18F] DOPA or [18F] FE-PE2I, respectively. In addition, transplantation-related inflammatory response was determined by uptake of [18F] FEPPA in the grafted side of striatum. Immunohistochemistry (IHC) examination was used to determine the survival of the grated dopaminergic neurons in the striatum and to investigate immune-modulatory effects of CDNF. The modulation of inflammatory responses caused by CDNF might involve enhancing M2 subset polarization and increasing fractal dimensions of 6-OHDA-treated BV2 microglial cell line. Analysis of CDNF-induced changes to gene expressions of 6-OHDA-stimulated BV2 cells implies that these alternations of the biomarkers and microglial morphology are implicated in the upregulation of protein kinase B signaling as well as regulation of catalytic, transferase, and protein serine/threonine kinase activity. The effects of CDNF on 6-OHDA-induced alternation of the canonical pathway in BV2 microglial cells is highly associated with PI3K-mediated phagosome formation. Our results are the first to show that CDNF administration enhances the survival of the grafted dopaminergic neurons and improves functional recovery in PD animal model. Modulation of the polarization, morphological characteristics, and transcriptional profiles of 6-OHDA-stimualted microglia by CDNF may possess these properties in transplantation-based regenerative therapies.

The Unconventional Growth Factors Cerebral Dopamine Neurotrophic Factor and Mesencephalic Astrocyte-Derived Neurotrophic Factor Promote Post-ischemic Neurological Recovery, Perilesional Brain Remodeling, and Lesion-Remote Axonal Plasticity.

Considerable efforts are currently made to develop strategies that boost endogenous recovery once a stroke has occurred. Owing to their restorative properties, neurotrophic factors are attractive candidates that capitalize on endogenous response mechanisms. Non-conventional growth factors cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) promote neuronal survival and reduce neurological deficits in the acute phase of ischemic stroke in mice. Their effects on endogenous repair and recovery mechanisms in the stroke recovery phase were so far unknown. By intracerebroventricular delivery of CDNF or MANF starting 3days post-stroke (1µg/day for 28days via miniosmotic pumps), we show that delayed CDNF and MANF administration promoted functional neurological recovery assessed by a battery of behavioral tests, increased long-term neuronal survival, reduced delayed brain atrophy, glial scar formation, and, in case of CDNF but not MANF, increased endogenous neurogenesis in the perilesional brain tissue. Besides, CDNF and MANF administration increased long-distance outgrowth of terminal axons emanating from the contralesional pyramidal tract, which crossed the midline to innervate ipsilesional facial nucleus. This plasticity promoting effect was accompanied by downregulation of the axonal growth inhibitor versican and the guidance molecules ephrin B1 and B2 in the previously ischemic hemisphere at 14 dpi, which represents a sensitive time-point for axonal growth. CDNF and MANF reduced the expression of the proinflammatory cytokines IL1β and TNFα in both hemispheres. The effects of non-conventional growth factors in the ischemic brain should further be examined since they might help to identify targets for restorative stroke therapy.

Wuzi Yanzong pill attenuates MPTP-induced Parkinson’s Disease via PI3K/Akt signaling pathway

Wuzi Yanzong Pill (WYP) was found to play a protective role on nerve cells and neurological diseases, however the molecular mechanism is unclear. To understand the molecular mechanisms that underly the neuroprotective effect of WYP on dopaminergic neurons in Parkinson's disease (PD). PD mouse model was induced by the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Gait and hanging tests were used to assess motor behavioral function. Immunofluorescence assay was used to determine TH-positive neurons in substantia nigra (SN). Apoptosis, dopamine and neurotrophic factors as well as expression of PI3K/Akt pathway were detected by TUNEL staining, ELISA and western blotting, respectively. First, it was observed that WYP intervention improved abnormal motor function in MPTP-induced PD model, alleviated the loss of TH+ neurons in SN, and increased dopamine content in brain, revealing a potential protective effect. Second, network pharmacology was used to analyze the possible targets and pathways of WYP action in the treatment of PD. A total of 126 active components related to PD were screened in WYP, and the related core targets included ALB, GAPDH, Akt1, TP53, IL6 and TNF. Particularly, the effect of WYP on PD may be medicate through PI3K/Akt signaling pathway and apoptotic regulation. The WYP treated PD mice had higher expression of p-PI3K, p-Akt and Bcl-2 but lower expression of Bax and cleaved caspase-3 than the non-WYP treated PD mice. Secretion of brain-derived neurotrophic factor (BDNF) and cerebral dopamine neurotrophic factor (CDNF) were also increased in the treated mice. WYP may inhibit apoptosis and increase the secretion of neurotrophic factor via activating PI3K/ Akt signaling pathway, thus protecting the loss of dopamine neurons in MPTP-induced PD mice.

CDNF and MANF regulate ER stress in a tissue-specific manner

Cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) display cytoprotective effects in animal models of neurodegenerative diseases. These endoplasmic reticulum (ER)-resident proteins belong to the same protein family and function as ER stress regulators. The relationship between CDNF and MANF function, as well as their capability for functional compensation, is unknown. We aimed to investigate these questions by generating mice lacking both CDNF and MANF. Results showed that CDNF-deficient Manf−/− mice presented the same phenotypes of growth defect and diabetes as Manf−/− mice. In the muscle, CDNF deficiency resulted in increased activation of unfolded protein response (UPR), which was aggravated when MANF was ablated. In the brain, the combined loss of CDNF and MANF did not exacerbate UPR activation caused by the loss of MANF alone. Consequently, CDNF and MANF deficiency in the brain did not cause degeneration of dopamine neurons. In conclusion, CDNF and MANF present functional redundancy in the muscle, but not in the other tissues examined here. Thus, they regulate the UPR in a tissue-specific manner.

The Effect of RADA16-I and CDNF on Neurogenesis and Neuroprotection in Brain Ischemia-Reperfusion Injury.

Scaffold materials, neurotrophic factors, and seed cells are three elements of neural tissue engineering. As well-known self-assembling peptide-based hydrogels, RADA16-I and modified peptides are attractive matrices for neural tissue engineering. In addition to its neuroprotective effects, cerebral dopamine neurotrophic factor (CDNF) has been reported to promote the proliferation, migration, and differentiation of neural stem cells (NSCs). However, the role of RADA16-I combined with CDNF on NSCs remains unknown. First, the effect of RADA16-I hydrogel and CDNF on the proliferation and differentiation of cultured NSCs was investigated. Next, RADA16-I hydrogel and CDNF were microinjected into the lateral ventricle (LV) of middle cerebral artery occlusion (MCAO) rats to activate endogenous NSCs. CDNF promoted the proliferation of NSCs, while RADA16-I induced the neural differentiation of NSCs in vitro. Importantly, both RADA16-I and CDNF promoted the proliferation, migration, and differentiation of endogenous NSCs by activating the ERK1/2 and STAT3 pathways, and CDNF exerted an obvious neuroprotective effect on brain ischemia-reperfusion injury. These findings provide new information regarding the application of the scaffold material RADA16-I hydrogel and the neurotrophic factor CDNF in neural tissue engineering and suggest that RADA16-I hydrogel and CDNF microinjection may represent a novel therapeutic strategy for the treatment of stroke.

Glial cell line derived neurotrophic factor in brain repair after focal ischemic stroke.

Glial cell line derived neurotrophic factor in brain repair after focal ischemic stroke.

Decreased Expression of Cerebral Dopamine Neurotrophic Factor in Platelets of Probable Alzheimer Patients.

Alzheimer disease (AD) patients experience progressive neurological and cognitive decline attributed to neurodegeneration. Cerebral dopamine neurotrophic factor (CDNF) has been identified to protect and rescue neurons in various preclinical neurodegeneration models. The expression of this protein occurs in both the central nervous system and peripheral blood. Blood platelets exhibit several biochemical impairments similar to the brain tissues of patients with neurological disorders. This study examines CDNF mRNA expression in human blood platelets in healthy subjects and Alzheimer-probable patients. Platelets were extracted from whole blood from patients. mRNA was extracted to synthesize cDNA and quantify CDNF gene expression from 21 Alzheimer-probable patients and 73 healthy age-matched control subjects using real-time qPCR. Grouping analysis of the data with regard to sex was conducted. CDNF mRNA expression was significantly decreased in Alzheimer-probable patients relative to the control subjects (P<0.05). Further analysis demonstrated reduced CDNF expression in male Alzheimer-probable patients compared with their age and sex-matched controls (P<0.05). However, no change in female subjects was observed. Interestingly, there is a lower level of CDNF expression in the female control group relative to the control male group (P<0.05). Alzheimer-probable male patients demonstrated significant reductions in CDNF expression, suggesting that CDNF plays a significant role in the pathogenesis of AD. In addition, it may assist in diagnosing male Alzheimer patients.

Human-Specific Regulation of Neurotrophic Factors MANF and CDNF by microRNAs.

Mesencephalic astrocyte derived neurotrophic factor (MANF) and cerebral dopamine neurotrophic factor (CDNF) are novel evolutionary conserved trophic factors, which exhibit cytoprotective activity via negative regulation of unfolded protein response (UPR) and inflammation. Despite multiple reports demonstrating detrimental effect of MANF/CDNF downregulation, little is known about the control of their expression. miRNAs—small non-coding RNAs—are important regulators of gene expression. Their dysregulation was demonstrated in multiple pathological processes and their ability to modulate levels of other neurotrophic factors, glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), was previously reported. Here, for the first time we demonstrated direct regulation of MANF and CDNF by miRNAs. Using bioinformatic tools, reporter assay and analysis of endogenous MANF and CDNF, we identified that miR-144 controls MANF expression, and miR-134 and miR-141 downregulate CDNF levels. We also demonstrated that this effect is human-specific and is executed via predicted binding sites of corresponding miRNAs. Finally, we found that miR-382 suppressed hCDNF expression indirectly. In conclusion, we demonstrate for the first time direct regulation of MANF and CDNF expression by specific miRNAs, despite the fact their binding sites are not strongly evolutionary conserved. Furthermore, we demonstrate a functional effect of miR-144 mediated regulation of MANF on ER stress response markers. These findings emphasize that (1) prediction of miRNA targets based on evolutionary conservation may miss biologically meaningful regulatory pairs; and (2) interpretation of miRNA regulatory effects in animal models should be cautiously validated.

CDNF: An innovative actor in disease-modifying approaches for Parkinson’s disease

Although cerebral dopamine neurotrophic factor (CDNF) is considered a “neurotrophic factor (NF),” its mechanism of action differs from classic NFs that increase cell survival through intracellular signaling. CDNF is located in the endoplasmic reticulum (ER), is secreted in response to ER stress, and reduces ER stress after internalization. 1 Voutilainen M.H. Arumäe U. Airavaara M. Saarma M. Therapeutic potential of the endoplasmic reticulum located and secreted CDNF/MANF family of neurotrophic factors in Parkinson’s disease. FEBS Lett. 2015; 589: 3739-3748 Crossref PubMed Scopus (54) Google Scholar In this issue of Molecular Therapy, Albert et al. 2 Albert K. Raymundo D.P. Panhelainen A. Eesmaa A. Shvachiy L. Araújo G.R. Chmielarz P. Yan X. Singh A. Cordeiro Y. et al. Cerebral dopamine neurotrophic factor reduces α-synuclein aggregation and propagation and alleviates behavioral alterations in vivo. Mol. Ther. 2021; 29: 2821-2840 Abstract Full Text Full Text PDF Scopus (8) Google Scholar demonstrate that CDNF directly binds to α-synuclein in vitro and in vivo. They further show that CDNF reduced α-synuclein aggregation as well as internalization of α-synuclein preformed fibrils (PFFs) in neuronal cultures. Delivery of CDNF alleviated behavioral deficits induced by α-synuclein PFFs. Interestingly, in this model, the behavioral abnormalities appeared in the absence of DA neuronal cell death. The data suggest that CDNF can reverse neuronal dysfunction at a very early stage, before the appearance of evident neurodegeneration. Cerebral dopamine neurotrophic factor reduces α-synuclein aggregation and propagation and alleviates behavioral alterations in vivoAlbert et al.Molecular TherapyApril 30, 2021In BriefAiravaara, Almeida, and colleagues show that CDNF, a therapeutic protein that is in clinical trials for Parkinson’s disease, interacts with α-synuclein. α-synuclein aggregates to form Lewy bodies, often observed in postmortem brains of Parkinson’s patients. They show that this CDNF-α-synuclein interaction modifies its aggregation and may lead to functional recovery in their animal model. Full-Text PDF Open Access

Cerebral dopamine neurotrophic factor transfection in dopamine neurons using neurotensin-polyplex nanoparticles reverses 6-hydroxydopamine-induced nigrostriatal neurodegeneration.

Overexpression of neurotrophic factors in nigral dopamine neurons is a promising approach to reverse neurodegeneration of the nigrostriatal dopamine system, a hallmark in Parkinson's disease. The human cerebral dopamine neurotrophic factor (hCDNF) has recently emerged as a strong candidate for Parkinson's disease therapy. This study shows that hCDNF expression in dopamine neurons using the neurotensin-polyplex nanoparticle system reverses 6-hydroxydopamine-induced morphological, biochemical, and behavioral alterations. Three independent electron microscopy techniques showed that the neurotensin-polyplex nanoparticles containing the hCDNF gene, ranging in size from 20 to 150 nm, enabled the expression of a secretable hCDNF in vitro. Their injection in the substantia nigra compacta on day 21 after the 6-hydroxydopamine lesion resulted in detectable hCDNF in dopamine neurons, whose levels remained constant throughout the study in the substantia nigra compacta and striatum. Compared with the lesioned group, tyrosine hydroxylase-positive (TH+) nigral cell population and TH+ fiber density rose in the substantia nigra compacta and striatum after hCDNF transfection. An increase in βIII-tubulin and growth-associated protein 43 phospho-S41 (GAP43p) followed TH+ cell recovery, as well as dopamine and its catabolite levels. Partial reversal (80%) of drug-activated circling behavior and full recovery of spontaneous motor and non-motor behavior were achieved. Brain-derived neurotrophic factor recovery in dopamine neurons that also occurred suggests its participation in the neurotrophic effects. These findings support the potential of nanoparticle-mediated hCDNF gene delivery to develop a disease-modifying treatment against Parkinson's disease. The Institutional Animal Care and Use Committee of Centro de Investigación y de Estudios Avanzados approved our experimental procedures for animal use (authorization No. 162-15) on June 9, 2019.

Effect of Chronic Treatment with D2 Allosteric Modulator PAOPA on the Expression of Cerebral Dopamine Neurotrophic Factor (CDNF) in Select Brain Regions

Effect of Chronic Treatment with D2 Allosteric Modulator PAOPA on the Expression of Cerebral Dopamine Neurotrophic Factor (CDNF) in Select Brain Regions

Physical exercise increases the production of tyrosine hydroxylase and CDNF in the spinal cord of a Parkinson’s disease mouse model

Previous research advocates that exercise is a non-pharmacological therapy for Parkinson’s disease (PD). However, few studies have investigated the effects of exercise on central nervous system structures other than the nigrostriatal pathway by using PD animal models. This study investigated the effects of exercise on tyrosine hydroxylase (TH)- and cerebral dopamine neurotrophic factor (CDNF)-containing spinal-cord neurons. Male Swiss mice were divided into 4 groups: sedentary control (SEDCONT), exercise control (EXERCONT), sedentary Parkinson (SEDPD), and exercise Parkinson (EXERPD). The PD groups were submitted to a surgical procedure for stereotaxic bilateral injection of 6-hydroxydopamine into the striatum. TH- and CDNF-containing spinal-cord neurons were evaluated in all groups, using immunohistochemistry and western-blotting. TH content in the ventral horn differed notably between the SEDPD and EXERPD groups. CDNF content was highest in the EXERPD group. SEDPD and EXERPD groups differed the most, as shown by immunohistochemistry and western-blotting. The EXERPD group showed the most intense labeling in immunohistochemistry compared to the SEDCONT and EXERCONT groups. Therefore, we showed here that exercise increased the content of both TH and CDNF in the spinal-cord neurons of a bilateral PD mouse model. We may assume that the spinal cord is affected in a PD model, and therefore this central nervous system region deserves more attention from researchers dealing with PD.