Protection of dopamine neurons by CDNF and neurturin variant N4 against MPP+ in dissociated cultures from rat mesencephalon

Abstract

Parkinson’s disease is associated with the loss of dopamine (DA) neurons in ventral mesencephalon. We have previously reported that no single neurotrophic factor we tested protected DA neurons from the dopaminergic toxin 1-methyl-4-phenylpyridinium (MPP+) in dissociated cultures isolated from the P0 rat substantia nigra, but that a combination of five neurotrophic factors was protective. We now report that cerebral DA neurotrophic factor (CDNF) and a variant of neurturin (NRTN), N4, were also not protective when provided alone but were protective when added together. In cultures isolated from the substantia nigra, MPP+ (10 μM) decreased tyrosine hydroxylase-positive cells to 41.7 ± 5.4% of vehicle control. Although treatment of cultures with 100 ng/ml of either CDNF or N4 individually before and after toxin exposure did not significantly increase survival in MPP+-treated cultures, when the two trophic factors were added together at 100 ng/ml each, survival of cells was increased 28.2 ± 6.1% above the effect of MPP+ alone. In cultures isolated from the ventral tegmental area, another DA rich area, a higher dose of MPP+ (1 mM) was required to produce an EC50 in TH-positive cells but, as in the substantia nigra, only the combination of CDNF and N4 (100 ng/ml each) was successful at increasing the survival of these cells compared to MPP+ alone (by 22.5 ± 3.5%). These data support previous findings that CDNF and N4 may be of therapeutic value for treatment of PD, but suggest that they may need to be administered together.

Cerebral dopamine neurotrophic factor protects and repairs dopamine neurons by novel mechanism

“…In contrast to classical NTFs, publications demonstrating survival-promoting effects of extracellular CDNF and MANF on naive neurons are limited. Exogenous CDNF was able to support the development and survival of enteric DA neurons originating from enteric neural crest-derived cells in vitro [ 75 ], whereas it did not support the survival of cultured postnatal midbrain DA neurons [ 76 ]. CDNF promoted neither the survival of superior cervical ganglion (SCG) neurons, motoneurons, nor dorsal root ganglion neurons in contrast to nerve growth factor (NGF) [ 20 ].…”

“…This may be very important from the clinical point of view, because it suggests a good safety profile for CDNF. Although CDNF has now been successfully tested in rodent and NHP models of PD [ 20 , 76 , 84 – 86 , 88 , 103 , 109 – 111 , 117 – 119 ], as well as in Phase I-II clinical trial in patients with PD [ 23 , 112 ], several challenges remain. CDNF can regulate UPR pathways, but its receptors and signaling pathways remain poorly described.…”

Catecholaminergic cell type-specific expression of Cre recombinase in knock-in transgenic rats generated by the Combi-CRISPR technology

“…Generation of NE neurons in the hindbrain depends on the roles of some morphologic proteins and transcription factors (Hirsch et al, 1998; Morin et al, 1997; Pattyn et al, 2000; Vogel-Höpker and Rohrer, 2002). In addition, survival of midbrain DA neurons is promoted through multiple neurotrophic factors, including brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, and cerebral DA neurotrophic factor (Jaumotte et al, 2021; Kumar et al, 2015; Palasz et al, 2020), although studies on survival factors for central NE neurons have been limited (Holm et al, 2002; Reiriz et al, 2002). In particular, a better understanding of the mechanisms for development and survival of midbrain DA neurons provides a useful approach for clinical treatments with cell replacement and gene therapy for Parkinson’s disease (Buttery and Barker, 2020).…”