Neurotrophic factor small-molecule mimetics, including ciliary neurotrophic factor (CNTF) small-molecule peptide mimetics and peptide 021 (P021), are the subject of many ongoing preclinical research studies. CNTF, a member of the IL-6 family of cytokines, is considered by researchers to play a key role in hippocampus and subventricular area neurogenesis and the differentiation of neural stem cells gives rise to its significance. Studies suggest that its potentially neuroprotective properties may be significant.
Neural progenitor cells, hippocampal neurons, and many other brain areas (such as the motor cortex and cerebellum) express the CNTF receptor (CNTFR). In contrast, CNTF itself is expressed in astrocytes in neurogenic niches. Recombinant CNTF has been suggested to improve cognitive function and maintain healthy levels of synaptic proteins in preclinical investigations of AD transgenic mice.
P021, a neurogenic and neurotrophic molecule, has been suggested to improve neurogenesis and memory functions in the dentate gyrus. The research study examined a triple-transgenic mouse model of AD (3xTg-AD). It purported that P021 may potentially block the leukemia inhibitory factor (LIF) signaling pathway and increase BDNF expression. Furthermore, Kazim et al. speculated that compound P021 might restore cognitive decline in old Fisher rats by boosting neurogenesis through enhanced BDNF expression and lowering tau levels.
CNTF-Induced Neurogenesis
Ciliary neurotrophic factor (CNTF) is expressed in astrocytes in the subventricular zone and has been suggested to stimulate neurogenesis in the forebrain of adult mice. These findings all point to a possible connection between dopamine, CNTF, and neurogenesis. Research published in The Journal of Neuroscience by Yang et al. supports this connection by identifying CNTF as an endogenous regulatory component of dopamine D2-receptor-dependent neurogenesis in the hippocampus’s subventricular zone and dentate gyrus.
Because an imbalance in dopaminergic signaling is a pathological hallmark of several neurological diseases, such as Parkinson’s disease, Huntington’s disorder, and amyotrophic lateral sclerosis, pharmacologically modulating CNTF may be an attractive strategy for further studies aiming to normalize dopaminergic and neurogenic deficits.
Dopaminergic stimulation by the selective D2 receptor agonist quinpirole increases cell proliferation in the subventricular and subgranular zones, as speculated by acute BrdU incorporation to identify proliferating neural progenitor cells. Because of its dependence on CNTF, this effect appeared to be lost in CNTF null mutant mice. Research suggests that dopaminergic stimulation of CNTF may increase proliferation and neuroblast production, as speculated by the observation of a CNTF-dependent increase in doublecortin-positive neuroblasts after quinpirole presentation.
P21 Peptide and Dopamine
Dopaminergic neurons are protected by ciliary neurotrophic factor (CNTF). In two animal models of Parkinson’s disease, Nam et al. speculated that astrocyte-expressed capsaicin receptor TRPV1 may have mediated the creation of endogenous CNTF to prevent the loss of dopaminergic neurons.
There is presently no remedy for Parkinson’s disease that is either neuroprotective or neurorestorative. Here, researchers suggest that astrocyte transient receptor potential vanilloid 1 (TRPV1) may mediate endogenous production of ciliary neurotrophic factor (CNTF), which inhibits the active degeneration of dopamine neurons and promotes behavioral recovery via CNTF receptor alpha (CNTFR) on nigral dopamine neurons in the MPP+-lesioned and adeno-associated virus -synuclein rat models of Parkinson’s disease.
Post-mortem substantia nigra from PD was analyzed by Western blotting and immunohistochemistry, and the results suggest that this endogenous neuroprotective mechanism (TRPV1 and CNTF on astrocytes and CNTFR on dopamine neurons) may be relevant to PD. Findings point to astrocytic TRPV1 as a potential target in the context of Parkinson’s disease by stimulating endogenous neuroprotective machinery.
It is becoming widely accepted that non-neuronal cells, such as astrocytes, may have a role in producing neuropathological or neuroprotective properties in Parkinson’s disease.
Regarding Parkinson’s disease, astrocytes, the most numerous glial cells in the brain, may have both protective and negative effects. By secreting neurotrophic elements such as glial cell line-derived neurotrophic factor (GDNF), mesencephalic astrocyte-derived neurotrophic factor (MANF), and ciliary neurotrophic factor (CNTF), astrocytes protect neurons.
TRPV1 has been hypothesized to be found in the brain, where it may have a role in influencing neuronal function, directing motor behavior, and regulating neuroinflammation. Systemic presentation of capsaicin, which is believed to be able to cross the blood-brain barrier, may activate TRPV1. Here, researchers propose that capsaicin-induced TRPV1 activation on astrocytes may produce CNTF, which acts via CNTF receptor alpha (CNTFR) on dopamine neurons to halt their degeneration in PD animal models.
Targeting of this endogenous neuroprotective mechanism (TRPV1 and CNTF on astrocytes and CNTFR on dopamine neurons) may potentially prove successful in mitigating certain symptoms of Parkinson’s disease.
Many experimental studies suggested that TRPV1 activation by capsaicin (CAP) may prevent the degeneration of nigrostriatal dopamine neurons in the 1-methyl-4-phenylpyridinium- (MPP+-) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- (MPTP-) or 6-hydroxy dopamine (6-OHDA-) lesioned rodent model of PD via inhibiting glial-derived inflammatory responses and producing ciliary neurotrophic factor (CNTF).
Investigations purport that TRPV1 may be a potential target in the context of PD since scientists recently hypothesized that TRPV1 activation by CAP may have boosted the survival of nigral dopamine neurons by modifying the M1/M2 microglia/macrophage phenotype in lipopolysaccharide- (LPS-).
References
[i] Nam, Jin H., et al. “TRPV1 on Astrocytes Rescues Nigral Dopamine Neurons in Parkinson’s Disease via CNTF.” Brain, vol. 138, no. 12, 21 Oct. 2015, pp. 3610–3622, www.ncbi.nlm.nih.gov/pmc/articles/PMC4840550/
[ii] Mori, M., et al. “CNTF: A Putative Link between Dopamine D2 Receptors and Neurogenesis.” Journal of Neuroscience, vol. 28, no. 23, 4 June 2008, pp. 5867–5869, www.ncbi.nlm.nih.gov/pmc/articles/PMC6670321/
[iii] Hagg, T., and S. Varon. “Ciliary Neurotrophic Factor Prevents Degeneration of Adult Rat Substantia Nigra Dopaminergic Neurons in Vivo.” Proceedings of the National Academy of Sciences, vol. 90, no. 13, 1 July 1993, pp. 6315–6319, 10.1073/pnas.90.13.6315.
[iv] Jeong, Kyoung Hoon, et al. “Activation of CNTF/CNTFRα Signaling Pathway by HRheb(S16H) Transduction of Dopaminergic Neurons in Vivo.” PLOS ONE, vol. 10, no. 3, 23 Mar. 2015, p. e0121803, 10.1371/journal.pone.0121803.
[v] Wi, Rayul, et al. “Functional Crosstalk between CB and TRPV1 Receptors Protects Nigrostriatal Dopaminergic Neurons in the MPTP Model of Parkinson’s Disease.” Journal of Immunology Research, vol. 2020, 28 Sept. 2020, pp. 1–11, 10.1155/2020/5093493.
