CDNF Rat
Description
Mechanisms of Action
CDNF exerts neuroprotection through dual mechanisms:
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Endoplasmic Reticulum (ER) Stress Modulation: Activates the IRE1α/XBP1 pathway to mitigate ER stress in QA-induced HD models .
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Anti-inflammatory Effects: Suppresses pro-inflammatory cytokines (e.g., TNF-α, IL-6) .
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Dopaminergic Neuron Survival: Promotes tyrosine hydroxylase (TH)-positive neuron survival in PD models .
Parkinson’s Disease (6-OHDA Rat Model)
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Motor Recovery: Chronic CDNF infusion (14 days) reduced amphetamine-induced rotational asymmetry by 60% .
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Neuron Preservation: Increased TH⁺ neurons in the substantia nigra (SN) by 40% vs. controls .
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Dose Dependency: Higher doses (16 µg) showed superior striatal diffusion and efficacy .
| Parameter | CDNF Effect | Source |
|---|---|---|
| Rotational Behavior | ↓ 60% asymmetry | |
| TH⁺ Neuron Survival | ↑ 40% in SN | |
| Striatal Dopamine Levels | Restored to 70% of baseline |
Huntington’s Disease (QA-Lesioned Rats)
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Motor Coordination: Improved rotarod performance by 35% at 5 weeks post-injection .
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Striatal Neuron Viability: Increased NeuN⁺ cells by 50% vs. QA-only controls .
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Neurogenesis: Stimulated DCX⁺ neuroblast migration to lesioned striatum .
Pharmacokinetics and Delivery
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Diffusion: Covers 90% of striatal volume within 20 minutes .
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Retrograde Transport: Detected in SN after striatal administration .
| Administration Route | Dose | Key Finding |
|---|---|---|
| Intrastriatal | 3.7–16 µg | Optimal neuroprotection at 16 µg |
| Chronic Infusion | 2 weeks | Sustained TH⁺ fiber preservation |
Comparative Analysis with MANF and GDNF
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CDNF vs. MANF: CDNF showed superior retrograde transport to SN and reduced rotational behavior in PD models .
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CDNF vs. GDNF: Unlike GDNF, CDNF does not require continuous infusion for efficacy .
| Factor | CDNF | MANF | GDNF |
|---|---|---|---|
| ER Stress Modulation | Yes | Yes | No |
| Clinical Trial Phase | Phase 1–2 (NCT03295786) | Preclinical | Phase 1–2 (discontinued) |
| Striatal Neurogenesis | ↑ 50% DCX⁺ cells | Not reported | Limited |
Clinical and Therapeutic Implications
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Parkinson’s Disease: Phase 1–2 trials confirmed safety and tolerability in advanced PD patients .
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Huntington’s Disease: Preclinical data support CDNF’s potential to delay MSN degeneration .
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Neuropsychiatric Disorders: Zebrafish cdnf mutants exhibit anxiety-like behaviors, hinting at broader applications .
Challenges and Future Directions
Product Specs
CDNF, a trophic factor for neurons and a member of the ARMET family, has been shown to protect neurons from degeneration induced by 6-hydroxydopamine (6-OHDA). In studies where CDNF administration was controlled following 6-OHDA-induced lesions, it was observed to restore neuronal function and prevent further degeneration in the substantia nigra. CDNF is widely expressed in various tissues, including both neuronal and non-neuronal types. Within the brain, the highest concentrations of CDNF are found in the optic nerve and corpus callosum.
(a) Reverse-phase high-performance liquid chromatography (RP-HPLC) analysis.
(b) Sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis.
Cerebral neurotrophic factor, ARMET-like protein 1, Arginine-rich protein mutated in early stage tumors-like 1, Conserved neurotrophic factor, Cdnf, Armetl1.
Product Science Overview
Cerebral Dopamine Neurotrophic Factor (CDNF) is a neurotrophic factor that has garnered significant attention due to its potential therapeutic applications, particularly in neurodegenerative diseases such as Parkinson’s disease. CDNF is part of a unique family of neurotrophic factors, which also includes Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF). These factors are structurally and functionally distinct from other neurotrophic proteins.
CDNF is primarily localized in the lumen of the endoplasmic reticulum (ER) within cells. Unlike many other neurotrophic factors, CDNF is not a secreted protein and does not have receptors on the cell membrane. Its primary function is to regulate ER stress, a condition that can lead to cell death and is implicated in various neurodegenerative diseases .
CDNF has demonstrated the ability to suppress inflammation and apoptosis (programmed cell death). Due to these functions, CDNF has shown protective and restorative properties in various models of neuropathology associated with ER stress, including Parkinson’s disease .
CDNF promotes the survival of midbrain dopaminergic neurons, which are the neurons that degenerate in Parkinson’s disease. This neurotrophic factor does not cross the blood-brain barrier and is administered directly into the brain via a surgically implanted delivery device . Studies have shown that CDNF can improve motor function and neuron survival in rodent models of toxin-induced dopaminergic cell loss .
In addition to its effects on the dopamine system, CDNF has been found to participate in the maturation and maintenance of other neurotransmitter systems, regulation of neuroplasticity, and non-motor behavior . This broad range of functions makes CDNF a promising candidate for the treatment of various neurodegenerative conditions.
Extensive preclinical work on CDNF has been conducted in rodent models. Single intracerebral doses or chronic brain infusion of CDNF have been reported to improve motor function and neuron survival . CDNF has also been shown to enhance the therapeutic benefit of acute subthalamic deep-brain stimulation (DBS), a current treatment for Parkinson’s disease, in a rat model of late-stage disease .
In rodent models of Parkinson’s disease, CDNF has been shown to inhibit α-synuclein oligomer toxicity in cultured dopaminergic neurons . In 6-OHDA-lesioned marmoset monkeys, CDNF treatment increased dopamine transporter (DAT) binding activity on PET scans, suggesting it protected dopaminergic neurons .
