TABLE 2.

Characteristics of different derivatives of rhEPO. Asialoerythropoietin (Asialo-EPO); carbamylated EPO (CEPO); neuro-EPO; EPOL; Darbepoetin alfa.

Derivatives	Source	Structure	Hematocrit Effects	Therapeutic effects	Doses	Routes	Mechanisms	Model or clinical trials	Half-time	References
rhEPO	Chinese hamster ovary cells	Composed of 166 amino acids, with a globular three-dimensional structure of four amphipathic α helices, two β-sheets, and two intra-chain disulfide bridges	High	Neuroprotective effects and improve cognitive function	500–5000IU/kg in rodents; 5000–4000 IU/dose in patients	Ip, iv, intranasal or subcutaneous or intra-artery injection	Anti-inflammation, anti-apoptosis, angiogenesis, neurogenesis, immunoregulation etc.	Multiple acute brain injuries; neurodegenerative disorders; psychiatric disorders et al	8.5 h	Ibbotson and Goa (2001), Cantarelli et al. (2019), Rey et al. (2019), Jarero-Basulto et al. (2020), Peng et al. (2020), Newton and Sathyanesan (2021)
asialo-EPO	From genetically engineered tobacco plants	Deglycosylated form of EPO	Low	Neuroprotective, cardioprotective, and renoprotective effects	44 μg/kg bw; 80 ng/g	Ip, iv	Inhibited caspase-3/-9 activation; reduced mitophagy and autophagy markers	MCAO	1.4 min	Price et al. (2010), Kittur et al. (2015), Peng et al. (2020), He et al. (2021)
CEPO	A chemically modified derivative of EPO	Replace lysines with homocitrulines	Low	Neuroprotective functions	50 μg/kg		Suppressed the expression of pro-apoptotic protein CC3 in the brain and regulated the Bcl-2/Bax ratio; protected neurons from ischemia through the CD131/GDNF/AKT pathway	MCAO		Villa et al. (2007), Wang et al. (2007), Oh et al. (2012), Ding et al. (2017)
Neuro-EPO	Chinese hamster ovary cells	Low sialic acid content in structure, rapidly degraded in the liver, and must be delivered by an intranasal route	None	Neuroprotective effects and improve cognitive function	249 UI/10 μl for animals; 100 ng/ml for cells; 0.5 or 1 mg for patients	Intranasal injection	Upregulated Bcl-2 and inhibited glutamate-induced caspase-3 activation	Cerebral ischemia, AD, and PD		Teste et al. (2012), Rodríguez Cruz et al. (2017), Fernando et al. (2018), Garzón et al. (2018), Pedroso et al. (2018), Rama et al. (2019), García-Llano et al. (2021)
EPOL	Isolated from skimmed goat milk	A low salivated bi-antennary structure	None	Neuroprotective effect	88 μg/kg for mice; at least 1 ng/ml or 10 ng/ml when treating cultured cells	Iv	Activated intracellular JAK/STAT and upregulated Bcl-2	Oxidative stress and AD model in vitro		Castillo et al. (2018), Castillo et al. (2019)
Darbepoetin alfa	A hyperglycosylated rhEPO analog	Additional sialic acid-containing oligosaccharide chains	Higher than rhEPO	Neuroprotective effects and improve cognitive function	10 mg/kg or 5,000 U/kg for rats; 1 μg/kg or 4 μg/kg for infants; 10 μg/kg for preterm infants; 500 μg for anemia patients every 3 weeks for 24 weeks	Ip, iv, subcutaneous injection		MCAO, four-vessel occlusion, intracerebral hemorrhage, and infants or preterm infants	3-fold longer than that of rhEPO	Egrie et al. (2003), Belayev et al. (2005), Grasso et al. (2009), Samson et al. (2010), Patel and Ohls (2015), Ohls et al. (2016), Ohlsson and Aher (2017), Platzbecker et al. (2017)