Papers by Merja Voutilainen
Cell Transplantation, 2012
Cerebral dopamine neurotrophic factor (CDNF) is a recently discovered protein, which belongs to t... more Cerebral dopamine neurotrophic factor (CDNF) is a recently discovered protein, which belongs to the evolutionarily conserved CDNF/MANF family of neurotrophic factors. The degeneration of dopamine neurons following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment is well characterized, and efficacy in this model is considered a standard criterion for development of parkinsonian therapies. MPTP is a neurotoxin, which produces parkinsonian symptoms in humans and in C57/Bl6 mice. To date, there are no reports about the effects of CDNF on dopamine neuron survival or function in the MPTP rodent model, a critical gap. Therefore, we studied whether CDNF has neuroprotective and neurorestorative properties for the nigrostriatal dopamine system after MPTP injections in C57/Bl6 mice. We found that bilateral striatal CDNF injections, given 20 h before MPTP, improved horizontal and vertical motor behavior. CDNF pretreatment increased tyrosine hydroxylase (TH) immunoreactivity in the striatum and in the substantia nigra pars reticulata (SNpr), as well as the number of TH-positive cells in substantia nigra pars compacta (SNpc). Posttreatment with CDNF, given 1 week after MPTP injections, increased horizontal and vertical motor behavior of mice, as well as dopamine fiber densities in the striatum and the number of TH-positive cells in SNpc. CDNF did not alter any of the analyzed dopaminergic biomarkers or locomotor behavior in MPTPuntreated animals. We conclude that striatal CDNF administration is both neuroprotective and neurorestorative for the TH-positive cells in the nigrostriatal dopamine system in the MPTP model, which supports the development of CDNF-based treatment for Parkinson's disease.
Parkinson s disease (PD) is a neurodegenerative disorder associated with a progressive loss of do... more Parkinson s disease (PD) is a neurodegenerative disorder associated with a progressive loss of dopaminergic neurons of the substantia nigra (SN). Current therapies of PD do not stop the progression of the disease and the efficacy of these treatments wanes over time. Neurotrophic factors are naturally occurring proteins promoting the survival and differentiation of neurons and the maintenance of neuronal contacts. Neurotrophic factors are attractive candidates for neuroprotective or even neurorestorative treatment of PD. Thus, searching for and characterizing trophic factors are highly important approaches to degenerative diseases. CDNF (cerebral dopamine neurotrophic factor) and MANF (mesencephalic astrocyte-derived neurotrophic factor) are secreted proteins that constitute a novel, evolutionarily conserved neurotrophic factor family expressed in vertebrates and invertebrates. The present study investigated the neuroprotective and restorative effects of human CDNF and MANF in rats w...
Parkinsonism & Related Disorders, 2012
European Journal of Pharmaceutical Sciences, 2008
The Journal of Neuroscience the Official Journal of the Society For Neuroscience, Jul 29, 2009
Mesencephalic astrocyte-derived neurotrophic factor (MANF), also known as Arginine-rich, Mutated ... more Mesencephalic astrocyte-derived neurotrophic factor (MANF), also known as Arginine-rich, Mutated in Early Stage of Tumors (ARMET), is a secreted protein which reduces endoplasmic reticulum (ER) stress. Previous studies have shown that MANF mRNA expression and protein levels are increased in the cerebral cortex after brain ischemia, a condition which induces ER stress. The function of MANF during brain ischemia is still not known. The purpose of this study was to examine the protective effect of MANF after ischemic brain injury. Recombinant human MANF was administrated locally to the cerebral cortex before a 60-min middle cerebral artery occlusion (MCAo) in adult rats. Triphenyltetrazolium chloride (TTC) staining indicated that pretreatment with MANF significantly reduced the volume of infarction at two days after MCAo. MANF also attenuated TUNEL labeling, a marker of cell necrosis/apoptosis, in the ischemic cortex. Animals receiving MANF pretreatment demonstrated a decrease in body asymmetry and neurological score as well as an increase in locomotor activity after MCAo. Taken together, these data suggest that MANF has neuroprotective effects against cerebral ischemia, possibly through the inhibition of cell necrosis/apoptosis in cerebral cortex.
Journal of neuroscience research, 2016
Intrastriatal administration of 6-hydroxydopamine (6-OHDA) induces partial degeneration of the ni... more Intrastriatal administration of 6-hydroxydopamine (6-OHDA) induces partial degeneration of the nigrostriatal pathway, mimicking the pathology of Parkinson's disease (PD). Setting up the partial lesion model can be challenging because a number of experimental settings can be altered. This study compares seven experimental settings in a single study on d-amphetamine-induced rotations, tyrosine hydroxylase (TH)-positive neurites in the striatum, dopamine transporter (DAT)-positive neurites in the striatum, and TH-positive cells in the substantia nigra pars compacta (SNpc) in rats. Moreover, we validate a new algorithm for estimating the number of TH-positive cells. We show that the behavior and immunoreactivity vary greatly depending on the injection settings, and we categorize the lesions as progressive, stable, or regressive based on d-amphetamine-induced rotations. The rotation behavior correlated with the degree of the lesion, analyzed by immunohistochemistry; the largest lesio...
Development (Cambridge, England), Jan 30, 2015
Local inhibitory GABAergic and excitatory glutamatergic neurons are important for midbrain dopami... more Local inhibitory GABAergic and excitatory glutamatergic neurons are important for midbrain dopaminergic and hindbrain serotonergic pathways controlling motivation, mood, and voluntary movements. Such neurons reside both within the dopaminergic nuclei, and in adjacent brain structures, including the rostromedial and laterodorsal tegmental nuclei. Compared to the monoaminergic neurons, the development, heterogeneity, and molecular characteristics of these regulatory neurons are poorly understood. We show here that different GABAergic and glutamatergic subgroups associated with the monoaminergic nuclei express specific transcription factors. These neurons share common origins in the ventrolateral rhombomere 1, where postmitotic selector genes Tal1, Gata2, and Gata3 control the balance between the generation of inhibitory and excitatory neurons. In the absence of Tal1, or both Gata2 and Gata3, the GABAergic precursors adopt glutamatergic fates and populate the glutamatergic nuclei in ex...
FEBS Letters, 2015
Parkinson's disease (PD) is a progressive... more Parkinson's disease (PD) is a progressive neurodegenerative disorder where dopamine (DA) neurons in the substantia nigra degenerate and die. Since no cure for PD exists, there is a need for disease-modifying drugs. Glial cell line-derived neurotrophic factor (GDNF) and related neurturin (NRTN) can protect and repair DA neurons in neurotoxin animal models of PD. However, GDNF was unable to rescue DA neurons in an α-synuclein model of PD, and both factors have shown modest effects in phase two clinical trials. Neurotrophic factors (NTFs), cerebral DA NTF (CDNF) and mesencephalic astrocyte-derived NTF (MANF) form a novel family of evolutionarily conserved, endoplasmic reticulum (ER) located and secreted NTFs. CDNF and MANF have a unique structure and an unparalleled dual mode of action that differs from other known NTFs. Both protect cells from ER stress, and regulate the unfolded protein response via interacting with chaperons, and CDNF dissolves intracellular α-synuclein aggregates. By binding to putative plasma membrane receptors, they promote the survival of DA neurons similarly to conventional NTFs. In animal models of PD, CDNF protects and repairs DA neurons, regulates ER stress, and improves motor function more efficiently than other NTFs.
Brain and Behavior, 2013
Cerebral dopamine neurotrophic factor (CDNF) protein has been shown to protect the nigrostriatal ... more Cerebral dopamine neurotrophic factor (CDNF) protein has been shown to protect the nigrostriatal dopaminergic pathway when given as intrastriatal infusions in rat and mouse models of Parkinson's disease (PD). In this study, we assessed the neuroprotective effect of CDNF delivered with a recombinant adeno-associated viral (AAV) serotype 2 vector in a rat 6-hydroxydopamine (6-OHDA) model of PD. AAV2 vectors encoding CDNF, glial cell line-derived neurotrophic factor (GDNF), or green fluorescent protein were injected into the rat striatum. Protein expression analysis showed that our AAV2 vector efficiently delivered the neurotrophic factor genes into the brain and gave rise to a long-lasting expression of the proteins. Two weeks after AAV2 vector injection, 6-OHDA was injected into the rat striatum, creating a progressive degeneration of the nigrostriatal dopaminergic system. Treatment with AAV2-CDNF resulted in a marked decrease in amphetamine-induced ipsilateral rotations while it provided only partial protection of tyrosine hydroxylase (TH)-immunoreactive cells in the rat substantia nigra pars compacta and TH-reactive fibers in the striatum. Results from this study provide additional evidence that CDNF can be considered a potential treatment of Parkinson's disease.
Parkinsonism & Related Disorders, 2011
Journal of Neuroinflammation, 2014
Background: The anti-inflammatory effect of the cerebral dopamine neurotrophic factor (CDNF) was ... more Background: The anti-inflammatory effect of the cerebral dopamine neurotrophic factor (CDNF) was shown recently in primary glial cell cultures, yet such effect remains unknown both in vivo and in 6-hydroxydopamine (6-OHDA) models of Parkinson? s disease (PD). We addressed this issue by performing an intranigral transfection of the human CDNF (hCDNF) gene in the critical period of inflammation after a single intrastriatal 6-OHDA injection in the rat.
Parkinsonism & Related Disorders, 2009
Parkinsonism & Related Disorders, 2012
Although initially thought to be important primarily in neural development, a number of trophic p... more Although initially thought to be important primarily in neural development, a number of trophic proteins have been found to have neuroprotective and neuroregenerative activity in the adult central nervous system, particularly for midbrain dopamine neurons (MDN). Neurorestoration is potentially feasible for MDN since there is an initial loss of phenotype for these neurons in Parkinson's disease (PD) rather than neuronal death. There is a considerable recent literature on trophic properties of TGF-β superfamily proteins for MDN's, including glial cell-derived neurotrophic factor (GDNF), neurturin, and bone morphogenetic proteins (BMPs). This paper will review studies with the factors listed above, as well as describe more recent studies with two newly described trophic proteins, MANF and CDNF. Data will be presented from various animal models of PD suggesting that these trophic proteins may eventually lead to PD therapeutics in man. In addition, some data on small molecules with neuroprotective properties (AP(4)A, retinoic acid and vitamin D(3)) will also be described.
Journal of Biological Chemistry, 2012
ABSTRACT The endoplasmic reticulum (ER) stress protein mesencephalic astrocyte-derived neurotroph... more ABSTRACT The endoplasmic reticulum (ER) stress protein mesencephalic astrocyte-derived neurotrophic factor (MANF) has been reported to protect cells from stress-induced cell death before and after its secretion; however, the conditions under which it is secreted are not known. Accordingly, we examined the mechanism of MANF release from cultured ventricular myocytes and HeLa cells, both of which secrete proteins via the constitutive pathway. Although the secretion of proteins via the constitutive pathway is not known to increase upon changes in intracellular calcium, MANF secretion was increased within 30 min of treating cells with compounds that deplete sarcoplasmic reticulum (SR)/ER calcium. In contrast, secretion of atrial natriuretic factor from ventricular myocytes was not increased by SR/ER calcium depletion, suggesting that not all secreted proteins exhibit the same characteristics as MANF. We postulated that SR/ER calcium depletion triggered MANF secretion by decreasing its retention. Consistent with this were co-immunoprecipitation and live cell, zero distance, photo affinity cross-linking, demonstrating that, in part, MANF was retained in the SR/ER via its calcium-dependent interaction with the SR/ER-resident protein, GRP78 (glucose-regulated protein 78 kDa). This unusual mechanism of regulating secretion from the constitutive secretory pathway provides a potentially missing link in the mechanism by which extracellular MANF protects cells from stresses that deplete SR/ER calcium. Consistent with this was our finding that administration of recombinant MANF to mice decreased tissue damage in an in vivo model of myocardial infarction, a condition during which ER calcium is known to be dysregulated, and MANF expression is induced.
Experimental Neurology, 2011
Cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic fac... more Cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) constitute a novel, evolutionarily conserved family of neurotrophic factors (NTF) expressed in vertebrates and invertebrates. The effects of two-week infusions of CDNF, MANF and glial cell line-derived neurotrophic factor (GDNF) were studied in a rat 6-hydroxydopamine (6-OHDA) hemiparkinsonian model. Degeneration of nigrostriatal dopamine nerve tract after toxin injection was assessed by measuring amphetamine-induced rotational behavior, and at the end of the experiment by quantifying tyrosine hydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNpc) and TH-positive fibers in the striatum. The diffusion of the NTFs into the brain tissue following chronic infusion was also studied. Finally, we examined the transportation of intrastriatally injected 125 I-CDNF within the brain. The amphetamineinduced rotational behavior was gradually normalized in rats treated with CDNF for two weeks following the intrastriatal 6-OHDA injection. CDNF was also able to inhibit 6-OHDA-induced loss of TH-immunoreactive cells of the SNpc and TH-positive fibers in the striatum. MANF and GDNF had no statistically significant effect in any of the above measures. The volume of distribution for MANF in the striatum was significantly larger than that of GDNF after 3-day infusions. Both 125 I-CDNF and 125 I-GDNF were retrogradely transported from the striatum to the SN. No behavioral signs of toxicity were observed during treatment with the three NTFs. These results imply that CDNF may have potential as a neuroprotective or even neurorestorative therapy of PD.
European Journal of Pharmacology, 2006
Neuronal nicotinic acetylcholine receptors subserve predominantly modulatory roles in the brain, ... more Neuronal nicotinic acetylcholine receptors subserve predominantly modulatory roles in the brain, making them attractive therapeutic targets. Natural products provide key leads in the quest for nicotinic receptor subtype-selective compounds. Cytisine, found in Leguminosae spp., binds with high affinity to α4β2 ⁎ nicotinic receptors. We have compared the effect of C3 and C5 halogenation of cytisine and methylcytisine (MCy) on their interaction with native rat nicotinic receptors. 3-Bromocytisine (3-BrCy) and 3-iodocytisine (3-ICy) exhibited increased binding affinity (especially at α7 nicotinic receptors; K i ∼0.1 μM) and functional potency, whereas C5-halogenation was detrimental. 3-BrCy and 3-ICy were more potent than cytisine at evoking [ 3 H]dopamine release from striatal slices (EC 50 ∼11 nM), [ 3 H]noradrenaline release from hippocampal slices (EC 50 ∼250 nM), increases in intracellular Ca 2+ in PC12 cells and inward currents in Xenopus oocytes expressing human α3β4 nicotinic receptor (EC 50 ∼2 μM). These compounds were also more efficacious than cytisine. C3-halogenation of cytisine is proposed to stabilize the open conformation of the nicotinic receptor but does not enhance subtype selectivity.
European Journal of Pharmaceutical Sciences, 2008
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Papers by Merja Voutilainen