P-21

P-21 is a small lab made molecule built on four amino acids, the little units that proteins are made from. Those four are a piece of human ciliary neurotrophic factor, a protein the body makes that helps nerve cells survive and grow. Onto the tail of that piece the laboratory hung an adamantane, a rigid ball of carbon borrowed from the Parkinson's drug amantadine, to make it greasier, help it into the brain and slow the enzymes that break peptides apart. It is sold as a derivative of Cerebrolysin and it is not one. It was designed in a single laboratory on Staten Island, and the shorthand every source prints, Ac-DGGLAG-NH2, looks like six amino acids without being six, because the last letters are the carbon cage rather than two more building blocks.

The laboratory's proposal is that P-21 releases a brake on the birth of new nerve cells. The protein it is a fragment of shares a docking assembly on those cells with another signal that suppresses their birth, and the idea is that P-21 blocks the suppressing arm, so the part of the brain where memories are laid down starts making new cells again. Everything downstream of that runs through brain derived neurotrophic factor, the growth signal most closely tied to memory, and through it to an enzyme that tags the tau protein with the chemistry that makes it clump in Alzheimer's disease. That downstream step has been tested against a hard case and failed: in mice bred without the Cdkl5 gene, given the compound by mouth for 70 days and by injection into the abdominal cavity for 30, that growth signal did not rise, and learning, memory, social behaviour and most motor measures were unchanged. The only direct measurement behind the first step that I found is one experiment in cells in a dish, and I found no independent repeat of it.

It is bought for memory and thinking, on the strength of a claimed link to Cerebrolysin, a licensed medicine whose forty years of clinical argument the framing borrows for a compound with no human record at all. What the animal work actually looked at is something else: mouse and rat models of Alzheimer's disease, Down syndrome, ageing and a severe childhood epilepsy syndrome. I found no record of it being given to a person, for that or for anything.

That P-21 is a piece of Cerebrolysin. It is not. Cerebrolysin is a mixture made by digesting animal brain protein with enzymes, and P-21 is a defined molecule of four amino acids with a carbon cage on the end. The real connection is that the inventing laboratory reported finding ciliary neurotrophic factor activity inside Cerebrolysin in 2007 and went off to work on that factor, which is a lineage of attention rather than a chemical derivation, and the licensed medicine's clinical record does not transfer to this molecule. The second mistake stacks on top: several of the most quotable results belong to Peptide 6, the eleven amino acid parent, and a traumatic brain injury result credited to P-21 is that molecule's.

The Alzheimer's Drug Discovery Foundation's reviewers state that safety in humans has not been assessed, and I found no human safety data of any kind and no dedicated toxicology study. What exists is tolerability watched alongside efficacy experiments in rodents: 18 months of chow in triple transgenic mice with no weight loss, no tumours and no signs of pain. The literature raises one theoretical risk, antibodies forming against the compound, and the review that raises it adds that no immune reaction has been reported to date, which means little for something I found no record of anyone taking. The warning I did find belongs to the full length parent protein: given under the skin to 730 patients with motor neurone disease in 1996, it did not slow their decline and its side effects were enough to limit dosing in many of them.