Table 2.

Bioactive molecules in human platelet lysate (HPL) with diverse roles in brain repair and neurogenesis

HPL bioactive factors		Reported biological effects	Experimental model	References
Growth factors, cytokines	BDNF	Supports NSC proliferation, migration, and differentiation	Neuronal precursors	[75, 76]
		Favors synaptic plasticity and facilitates synapse maturation	Neuronal precursors	[77, 78]
		Supports hippocampal neurogenesis	In rodents	[79, 80]
	EGF	Induces NSC proliferation and migration	NSC culture	[81]
		Supports cortical tissue regeneration and motor function recovery	In vivo stroke model	[82–84]
	FGF	Promotes proliferation and differentiation of NSCs	Cell culture and in vivo	[85]
		Stimulates neurogenesis	Focal ischemia model in rats	[82, 86]
		Regulates Schwann cell proliferation, axonal growth, and remyelination	Nerve injury in mice	[87]
	GSN	Inhibits apoptosis and is neuroprotective in murine stroke	Hippocampal neuron culture, in vivo stroke model	[88, 89]
	HGF	Protects dopaminergic neurons, motor neurons, and sympathetic neurons	Neuron culture	[90, 91]
	IGF	Promotes NSC growth and differentiation, stimulates adult hippocampal neurogenesis, has neuroprotective activity	Neuronal cell culture, in vivo administration	[31, 92–95]
	LGALS1	Prevents microglial activation and promotes neuroprotection	Culture of microglia and astrocytes; in mice	[96, 97]
		Promotes astrocyte maturation but inhibits proliferation	In vitro cell culture	[98]
	MANF	Protects rat embryonic nigral dopaminergic neurons	Rat model of PD	[99]
		Is neuroprotective and neurorestorative	Rat model of PD	[100]
		Supports the development and sprouting of dopaminergic axonal terminals	In vitro cell culture	[99]
		Decreases stress and activates the PI3K/Akt/mTOR pathway	In vitro cell culture	[101]
		Activates the PI3K/Akt/GSK3β pathway and Nrf2 nuclear translocation	In vitro	[102]
		Inhibits apoptosis	In vitro cell culture	[103]
		Inhibits autophagic via activation of the AMPK/mTOR pathway and ameliorates ROS by maintaining mitochondrial function	In vitro cell culture	[104]
	NENF	Promotes neurotrophic activity and neuronal cell proliferation and stimulates differentiation	Mouse neural precursor cells	[105]
		Is a novel player in the maintenance of the anxiety circuitry	Neudesin-null mice	[106]
	PDGF	Regulates NSC proliferation, migration, differentiation, and survival processes, and reduces apoptosis	Cultured NSCs	[107, 108]
		Protects cells against MPP+-induced cell death	SH-SY5Y cell culture	[109]
		Has restorative effects	Rodent model of PD	[110, 111]
	PF4	Promotes neuronal differentiation in DBA/2 mice	Mouse primary cells and in vivo infusion	[112]
	TGF-β	Triggers differentiation of precursor cells	In vitro and in vivo mouse mesencephalic progenitors	[113]
	VEGF	Promotes proliferation and migration of endothelial cells, and the formation of new blood vessels in vivo, and enhances vascular permeability	In vitro endothelial cell culture	[114]
		Slows progression of amyotrophic lateral sclerosis in mice by stimulating motoneuron functions	Rat model of amyotrophic lateral sclerosis	[115, 116]
		Protects cultured motoneurons against death in conditions of hypoxia, oxidative stress, and serum deprivation	Neuronal cell culture	[117, 118]
		Exerts protective effects on primary hippocampal neurons against glutamate toxicity	In vitro neuronal culture	[119]
Chemicals	Vit B12	Prevents cognitive decline	Clinical trials	[120, 121]
	Serotonin	Modulates neural activity	Ex vivo using rat brains	[122]
Chemokines	RANTES	Can be neuroprotective	Primary cortical neuron culture, AD and stroke models	[123, 124]
		Contributes to neuronal synaptic activity and memory formation	Primary neuron culture and WT and CCL5-/- mice	[125, 126]
		Reduces neuronal degeneration and memory dysfunction after mTBI	Primary neuron culture, mTBI mouse model	[127]
	MIF	Mediates neuroprotective effects in Parkinson’s disease	Mouse model of PD, SH-SY5Y in vitro model of PD	[128]
Antioxidants	CAT	Protects against dopaminergic neuronal cell death	Mesencephalic neuronal–glial culture, rat stroke model	[129, 130]
	CP	Inhibits lipid peroxidation and ROS	CP−/− mouse model	[131]
		Exerts protective activity against iron-induced oxidative damage in Alzheimer’s disease and TBIs	CP −/−, AD, focal cortical contusion injury mouse models	[131–133]
	GPX	Protects mammalian cells against oxidative damage	Human cell line cultures	[134]
		Is protective in Huntington’s disease models (inhibits the activity of ROS-producing enzymes)	In vitro cell culture and Drosophila Huntington’s disease model	[135]
	SOD	Inhibits lipid peroxidation, is neuroprotective	In vitro primary cultured cortical neurons and rat stroke model	[130, 136, 137]
	Trx (TXN)	Protects against oxidative stress-associated diseases Modulates microtubule polymerization kinetics in vivo	PC12 cell culture	[138, 139]
		Is involved in cell–cell communication, transcriptional regulation, cell signaling, and DNA synthesis	Focal brain ischemia in rats	[140]
		Exerts a cytoprotective effect in the nervous system	RASMC and raw cell culture	[141]
	GCLM	Is associated with glutathione synthesis	In vivo	[142, 143]
Interleukins	TIMP-1	Regulates neuroinflammation and neuropathic pain	In vivo in mice and rats	[144–147]
		Modulates astrocyte function and myelination	In vivo	[148, 149]
	IL-4	Has anti-inflammatory properties	Human monocytes, murine bone marrow-derived macrophage culture	[150]
Platelet-EVs	GFs	Stimulates angiogenesis and neurogenesis	Rat ischemia model	[151]
	miR-126-3p	Exerts anti-inflammatory effects	Primary human macrophages	[152]

AMPK Adenosine monophosphate-activated protein kinase, AD Alzheimer disease, BDNF brain-derived neurotrophic factor, CAT catalase, CCL5 CC chemokine ligand 5, CP ceruloplasmin, EGF epidermal growth factor, EV extracellular vesicle, FGF fibroblast growth factor, GAL-1 or LGALS1 galectin 1, gsn gelsolin, GCLM glutamate-cysteine ligase regulatory subunit, GPX glutathione peroxidase, GSK3β glycogen synthase kinase 3β, GF growth factor, HGF hepatocyte growth factor, IGF‐1 insulin‐like growth factor‐1, MANF mesencephalic astrocyte-derived neurotrophic factor, MIF macrophage migration inhibitory factor, mTOR mammalian target of rapamycin, mTBI mild traumatic brain injury, MPP myelin protein peripheral, NSC neural stem cell, NENF neuron-derived neurotrophic factor or neudesin, Nrf2 nuclear factor erythroid 2-related factor, PI3K phosphatidylinositol 3-kinase, PD Parkinson’s disease, PDGF platelet-derived growth factor, ROS reactive oxygen species, SOD superoxide dismutase, TIMP-1 tissue inhibitors of metalloproteinases 1, TXN thioredoxin, TGF-β transforming growth factor β, WT wild type