Evidence for an Additive Neurorestorative Effect of Simultaneously Administered CDNF and GDNF in Hemiparkinsonian Rats: Implications for Different Mechanism of Action

eNeuro. 2017 Mar 13;4(1):ENEURO.0117-16.2017. doi: 10.1523/ENEURO.0117-16.2017. eCollection Jan-Feb 2017.

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder associated with a progressive loss of dopaminergic (DAergic) neurons of the substantia nigra (SN) and the accumulation of intracellular inclusions containing α-synuclein. Current therapies do not stop the progression of the disease, and the efficacy of these treatments wanes over time. Neurotrophic factors (NTFs) are naturally occurring proteins promoting the survival and differentiation of neurons and the maintenance of neuronal contacts. CDNF (cerebral dopamine NTF) and GDNF (glial cell line-derived NTF) are able to protect DAergic neurons against toxin-induced degeneration in experimental models of PD. Here, we report an additive neurorestorative effect of coadministration of CDNF and GDNF in the unilateral 6-hydroxydopamine (6-OHDA) lesion model of PD in rats. NTFs were given into the striatum four weeks after unilateral intrastriatal injection of 6-OHDA (20 µg). Amphetamine-induced (2.5 mg/kg, i.p.) rotational behavior was measured every two weeks. Number of tyrosine hydroxylase (TH)-positive cells from SN pars compacta (SNpc) and density of TH-positive fibers in the striatum were analyzed at 12 weeks after lesion. CDNF and GDNF alone restored the DAergic function, and one specific dose combination had an additive effect: CDNF (2.5µg) and GDNF (1µg) coadministration led to a stronger trophic effect relative to either of the single treatments alone. The additive effect may indicate different mechanism of action for the NTFs. Indeed, both NTFs activated the survival promoting PI3 kinase (PI3K)-Akt signaling pathway, but only CDNF decreased the expression level of tested endoplasmatic reticulum (ER) stress markers ATF6, glucose-regulated protein 78 (GRP78), and phosphorylation of eukaryotic initiation factor 2α subunit (eIF2α).

Keywords: 6-OHDA; CDNF; ER stress; GDNF; additive effect; rat.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amphetamine / pharmacology
  • Animals
  • Antiparkinson Agents / administration & dosage*
  • Cells, Cultured
  • Central Nervous System Stimulants / pharmacology
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Corpus Striatum / pathology
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / pathology
  • Drug Synergism
  • Drug Therapy, Combination
  • Functional Laterality
  • Glial Cell Line-Derived Neurotrophic Factor / administration & dosage*
  • Male
  • Mice
  • Motor Activity / drug effects
  • Nerve Growth Factors / administration & dosage*
  • Neuroprotective Agents / administration & dosage
  • Oxidopamine
  • Parkinsonian Disorders / drug therapy*
  • Parkinsonian Disorders / metabolism
  • Parkinsonian Disorders / pathology
  • Pars Compacta / drug effects
  • Pars Compacta / metabolism
  • Pars Compacta / pathology
  • Rats, Wistar
  • Recombinant Proteins / administration & dosage
  • Tyrosine 3-Monooxygenase / metabolism

Substances

  • Antiparkinson Agents
  • CDNF protein, human
  • Central Nervous System Stimulants
  • Glial Cell Line-Derived Neurotrophic Factor
  • Nerve Growth Factors
  • Neuroprotective Agents
  • Recombinant Proteins
  • Oxidopamine
  • Amphetamine
  • Tyrosine 3-Monooxygenase