P-21 / P021

In simple words

P-21 is a short peptide of six amino acids created on the basis of a natural nerve cell growth factor; it enters the brain and works when taken by mouth. It is studied in mice as an agent against brain changes in Alzheimer's disease, Down syndrome, and a rare form of epilepsy.

What this molecule is

Ac-Asp-Gly-Gly-Leu-Ala-Gly-NH₂ — 6 aa. ~487 Da. CNTF-derived, Ministry of Education university (Kuwait + King's College). BBB-permeable. Orally active.

Why it is studied

Neurotrophic mimetic of BDNF/CNTF. ↓tau, ↓Aβ, ↑neurogenesis in 3xTg-AD transgenic mice. Studied in Down syndrome (prenatally) and CDKL5 deficiency (epileptic encephalopathy). Orally active — a rarity.

How it works

↑BDNF transcription (promoter IV via the HAT pathway) → TrkB → pCREB → PLC/PKC/ERK/Akt → neurogenesis + synaptogenesis. ↓STAT3 → ↓tau hyperphosphorylation (AD mechanism). Prenatal administration normalizes neurogenesis in offspring.

Doses used in studies

Studies used it only in animal models (in feed or SC). No clinical data. Orally active in vivo in mice.

Combined with in studies

• Dihexa — HGF + BDNF — a double neurotrophic hit
• Cerebrolysin — additive, PMID: 21860085
• Semax — BDNF via a different pathway

Level of evidence

Level C Animal studies. Effects have been shown in animals. Whether they carry over to humans has not been proven. transgenic mice only. No clinical data.

Important to know

⚠️ >200 drugs that succeeded in AD mice failed in humans. Orally active = an advantage, but there are no clinical data. Phase I has not started. Research only.

Studies in PubMed

1. Prevention of dendritic and synaptic deficits and cognitive impairment with a neurotrophic compound. (Alzheimers Res Ther, 2017)
2. Prenatal to early postnatal neurotrophic treatment prevents Alzheimer-like behavior and pathology in mice. (Alzheimers Res Ther, 2020)
3. Neurotrophic Treatment Initiated During Early Postnatal Development Prevents the Alzheimer-Like Behavior and Synaptic Dysfunction. (J Alzheimers Dis, 2021)
4. Effects of a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic in an in vitro and in vivo model of CDKL5 deficiency disorder. (J Neurodev Disord, 2024)
5. Alzheimer's Disease: Challenges and a Therapeutic Opportunity to Treat It with a Neurotrophic Compound. (Biomolecules, 2022)
6. Beneficial effect of a CNTF tetrapeptide on adult hippocampal neurogenesis, neuronal plasticity, and spatial memory in mice. (J Alzheimers Dis, 2010)