P21 Peptide: A Scientific Analysis

Several ongoing preclinical investigations are examining small-molecule mimics of neurotrophic elements, including ciliary neurotrophic factor (CNTF) and peptide 021 (P021). CNTF, a member of the cytokine family IL-6, is significant because it plays a vital part in neural stem cell differentiation, hippocampus neurogenesis, and the subventricular zone. Its neuroprotective potential has been well ascertained. According to its position in the central nervous system, CNTF is considered to be found in neurogenic niches expressed by astrocytes. In contrast, its CNTF receptor α (CNTFRα) receptor appears to be mostly found in neural progenitor cells, hippocampal neurons, and several other brain regions, such as the cerebellum and motor cortex.

Further, recombinant CNTF has been suggested to regulate synaptic protein levels and ameliorate cognitive impairment in preclinical investigations using AD transgenic mice. P021, a chemical with possible neurogenic and neurotrophic properties, has also been hypothesized to improve memory functions and dentate gyrus neurogenesis. P021 was suggested to function in the research above by increasing BDNF expression and inhibiting the leukemia inhibitory factor (LIF) signaling pathway in a triple-transgenic mice model of Alzheimer’s disease (3xTg-AD). Furthermore, Kazim et al. speculated that compound P021, when given to elderly Fisher rats, may have improved neurogenesis via enhanced BDNF expression and decreased tau levels, thereby rescuing aging cells.

P21 Peptide and CNTF-Induced Neurogenesis

Prior research purports that astrocytes in the subventricular zone release the cytokine ciliary neurotrophic factor (CNTF), which has been suggested to improve forebrain development in adult mice. Taken as a whole, these findings point to a connection between neurogenesis, dopamine, and CNTF. In a recent issue of The Journal of Neuroscience, Yang et al. presented a series of experiments that implicate CNTF as an endogenous regulatory component of dopamine D2-receptor-dependent neurogenesis in the subventricular area and the dentate gyrus of the hippocampus. This provides further speculation about the link between the two processes. CNTF has been considered by researchers for potentially restoring normal dopaminergic and neurogenic function since an imbalance in dopaminergic signaling is a pathological feature of numerous neurological disorders.

Research conducted by Yang et al. proposes that when the selective D2 receptor agonist quinpirole is induced to activate dopaminergic pathways, there appears to be an increase in cell proliferation in the subventricular and subgranular zones, as labeled by acute BrdU incorporation of proliferating neural progenitor cells. This impact appeared to be CNTF-dependent as it was nullified in CNTF-deficient mutant mice. As scientists suggested, dopaminergic stimulation of CNTF may increase proliferation and neuroblast production, a CNTF-dependent rise in doublecortin-positive neuroblasts after quinpirole.

Investigations purport that the P21 peptide’s parent protein, CNTF, may protect dopamine neurons. Ciliary neurotrophic factor (CNTF) has a neuroprotective action on dopaminergic neurons. In two Parkinson’s disease models in rats, Nam et al. speculated that capsaicin receptor TRPV1 expressed on astrocytes may have mediated the synthesis of endogenous CNTF to block the degeneration of dopaminergic neurons.

Neither a neuroprotective nor a neurorestorative compound or program exists for Parkinson’s disease at this time. In both the MPP+-lesioned and adeno-associated virus α-synuclein rat models of Parkinson’s disease, researchers hypothesize that astrocyte transient receptor potential vanilloid 1 (TRPV1) might mediate endogenous production of ciliary neurotrophic factor (CNTF). This, in turn, may prevent the active degeneration of dopamine neurons and lead to behavioral recovery through CNTF receptor alpha (CNTFRα) on nigral dopamine neurons.

Investigating post-mortem substantia nigra from Parkinson’s disease research models using Western blot and immunohistochemistry techniques implies that the endogenous neuroprotective system, which includes TRPV1 and CNTF on astrocytes and CNTFRα on dopamine neurons, might be relevant to Parkinson’s disease. As implied by further findings, astrocytic TRPV1 activation may trigger natural neuroprotective mechanisms in living organisms, marking it a potential new adjuvant target in the context of Parkinson’s disease.

A growing body of data suggests that astrocytes and other non-neuronal cells may play a role in the neuropathological or neuroprotective potential of Parkinson’s disease.

The most numerous glial cells in a mammalian brain are the astrocytes, which may have positive and negative impacts on Parkinson’s disease. Astrocytes generate neurotrophic factors such as ciliary neurotrophic factor (CNTF), mesencephalic astrocyte-derived neurotrophic factor (MANF), and glial cell line-derived neurotrophic factor (GDNF), which provide neuroprotection.

One of the receptors involved in pain perception is capsaicin, which is transient receptor potential vanilloid 1 (TRPV1). Sensory neurons express this receptor at high levels. It is possible that TRPV1 may regulate neuroinflammation, control motor conduct, and modulate neuronal activity in the brain, where it may be found. Systemic presentation of capsaicin, which is considered permeable across the blood-brain barrier, may activate TRPV1. In animal models of Parkinson’s disease, researchers theorize that capsaicin stimulation of TRPV1 on astrocytes may result in endogenous CNTF, which may inhibit the degeneration of dopamine neurons by activating dopamine neurons via CNTF receptor alpha (CNTFRα). One potential target for managing Parkinson’s disease might be the endogenous neuroprotective system, which includes TRPV1 and CNTF on astrocytes and CNTFRα on dopamine neurons.

Numerous experimental investigations have purported that capsaicin (CAP) activation of TRPV1 may inhibit glial-derived inflammatory responses and produce ciliary neurotrophic factor (CNTF), thereby preventing the relapse of nigrostriatal dopamine neurons in the 1-methyl-4-phenylpyridinium-(MPP+-), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-(MPTP-), or 6-hydroxy dopamine (6-OHDA-) lesioned rodent model of Parkinson’s disease. Recent work by a research group suggests that CAP-activated TRPV1 may enhance nigral dopamine neuron survival in lipopolysaccharide-presented SN via regulating the M1/M2 microglia/macrophage phenotype, suggesting that TRPV1 might be a target for Parkinson’s disease.

Scientists interested in further studying peptides may purchase them from Biotech Peptides.

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.