Noopept

Noopept (omberacetam, also coded GVS-111) is N-phenylacetyl-L-prolylglycine ethyl ester, a small synthetic dipeptide derivative. Scientists at the V. V. Zakusov Research Institute of Pharmacology in Moscow designed it as a dipeptide analog of piracetam (Gudasheva et al., 2018), and its major metabolite in rat brain is cycloprolylglycine, a cyclic dipeptide that also occurs there naturally (Gudasheva et al., 1997).

Published work on Noopept falls into six areas. Each summary below states the model used. Most of it comes from the Moscow institute that developed the compound and its collaborators.

Design and metabolism

Its developers built Noopept by reproducing the structure of piracetam with a dipeptide (Gudasheva et al., 2018). One hour after rats received 5 mg/kg intraperitoneally, the parent compound was undetectable in brain while cycloprolylglycine had risen 2.5-fold, and plasma and brain enzymes formed cycloprolylglycine from it in vitro, so the authors proposed that Noopept is a prodrug (Gudasheva et al., 1997). A later rat study found that the metabolite differs from Noopept in its pharmacokinetics but has a similar spectrum of action on memory (Boyko et al., 2018). Models: rats and enzyme assays.

Rodent memory and neuroprotection models

Given orally to rats trained in passive avoidance, Noopept at 0.5 to 10 mg/kg kept its antiamnesic activity, and repeated exposure raised the number of initially unsuccessful rats that learned an active avoidance task, unlike cycloprolylglycine or piracetam (Ostrovskaya et al., 2001). After photochemical thrombosis of the rat frontal cortex, 0.5 mg/kg/day intravenously for 9 days from 1 hour after the lesion reduced the passive avoidance deficit and the infarct volume (Ostrovskaya et al., 1999).

An independent Spanish group gave it, as SGS-111, to Ts65Dn mice, a Down syndrome model, in adulthood or from conception to 5 months of age: hyperactivity fell, but cognitive deficits were not reversed, and spatial learning gains appeared only in control mice (Rueda et al., 2008). Models: rats and mice.

BDNF and NGF in rat hippocampus

In rats, Northern blot analysis showed that a single exposure raised hippocampal mRNA for NGF and BDNF and that 28 days of exposure strengthened the effect without tolerance; in the cortex, levels fell after a single exposure, and BDNF rose slightly with chronic exposure (Ostrovskaya et al., 2008). The study measured mRNA, not protein, and came from the developing laboratory. A 2021 rat study linking Noopept to spinal microglial BDNF in persistent inflammation was retracted by its journal three months after publication, so it is not evidence (Taghizadeh et al., 2021). Model: rat brain tissue.

Glutamate and oxidative stress in cell models

In cultured cerebellar granule cells, GVS-111 protected neurons from oxygen and glucose deprivation and from glutamate or oxidative stress, while piracetam did not reduce glutamate toxicity (Andreeva et al., 2000). At the University of Connecticut, with Moscow co-authors, it raised the survival of human cortical neurons exposed to hydrogen peroxide (half-maximal value 1.21 µM), lowered free radicals and lipid peroxidation, protected more than piracetam or vitamin E, and reduced degeneration in Down syndrome cortical cultures (Pelsman et al., 2003). Models: cerebellar and human cortical neuron cultures.

Amyloid models

In PC12 cells, 10 µM Noopept added 72 hours before amyloid beta 25-35 raised viability and mitochondrial membrane potential and reduced apoptosis, reactive oxygen species, intracellular calcium and tau phosphorylation at Ser396 (Ostrovskaya et al., 2014). In NMRI mice after olfactory bulbectomy, a model with Alzheimer's disease-like features, 0.01 mg/kg for 21 days restored spatial memory in the Morris water maze and raised serum antibodies to amyloid beta 25-35 oligomers, but not to lysozyme amyloid or S100b (Ostrovskaya et al., 2007). Models: PC12 cells and mice.

Human studies

The human evidence is small and regional. Nearly all human studies indexed in PubMed come from Russian centers and Russian-language journals, the two abstracts that give a size each describe 60 people, and PubMed indexes no randomized, placebo-controlled trial. The developing institute also compared Noopept with piracetam in mild cognitive disorders of vascular or traumatic origin; PubMed lists no abstract, so its outcome is not summarized here (Neznamov and Teleshova, 2009).

An open prospective study of 60 people with mild cognitive impairment after stroke reported significant gains on the MMSE and word-association tests at 2 months compared with controls (Amelin et al., 2011). A two-group study of 60 people starting tuberculosis chemotherapy reported less anxiety and fewer neurotoxic and cardiotoxic drug reactions in the 30 given Noopept (Mordyk et al., 2009). Model: human clinical studies.