2l) Diketopiperazines

From: 'Neuroprotection for traumatic brain injury: translational challenges and emerging therapeutic strategies' h<a id="null" class="null" href="https://www.cohenveteransbioscience.org/wp-content/uploads/2015/10/Loane-Trends-Pharmacol-Sci-2010.pdf">ttps://www.cohenveteransbioscience.org/wp-content/uploads/2015/10/Loane-Trends-Pharmacol-Sci-2010.pdf</a>

Diketopiperazines are cyclized dipeptides that were developed through a rational drug design program based on the tripeptide thyrotropin-releasing hormone (TRH) [74]. TRH and TRH analogs inhibit multiple secondary injury factors and processes [74]. They were shown to be highly neuroprotective in experimental neurotrauma across many laboratories and a small clinical randomized study of TRH in human SCI was promising [75]. Four structurally different diketopiperazines demonstrated significant neuroprotective properties both in vitro and in animal TBI studies [76]. One of these (35b) showed effectiveness across TBI models and species. In neuronal cell cultures, 35b provided neuroprotection in multiple models of necrotic and apoptotic cell death [77]. Intravenous administration of 35b reduced both lesion volume and improved functional recovery after fluid percussion injury (FPI) in rats and CCI in mice [77,78]. The therapeutic window was at least 8 hours. Treatment also significantly reduced apoptotic cell death [77]. Effects appeared to be pleiotropic, with treatment reducing multiple potential secondary injury factors (cyclins, calpains, cathepsin), while upregulating various endogenous neuroprotective and neurotrophic factors (BDNF, HSP-70, HIF-1) [76,79]. In addition, data are available regarding pharmacokinetics, brain penetration after systemic administration and preclinical toxicology in the rat. Similar pleiotropic neuroprotective effects were reported with another diketopiperazine - cyclo-L-glycyl-L

treatment improved functional recovery and long-term histological outcomes, and reduced caspase-3 mediated apoptosis and microglial activation [80]. Given their multipotential neuroprotective effects in experimental TBI models, their clinically relevant therapeutic window, and their safety profile, the diketopiperazines are attractive candidates for further clinical investigation.