Table 1.

Experimental models of neuroprotection by limb RIC: molecular and cellular mechanisms underlying RIC-induced neuroprotection in the ischemic brain

Model	Pathway/mechanism researched	Reference
Rat: Sprague–Dawley (m/270-330 g) IS model: 30 min BCCAO post-RIC: directly after IS, 3 h or 6 h 3 cycles: 15 min RIC + 15 min RF	Protein synthesis Afferent nerves	[23]
Rat: Sprague–Dawley (m/250–280 g) IS model: 1 h MCAO post-RIC: after RF 3 cycles: 10 min RIC + 10 min RF	HIF-1α	[24]
Rat: Sprague–Dawley (m/250–330 g) IS model: 1 h MCAO, 48 h RF pre-RIC: before MCAO 3 cycles: 15 min RIC + 15 min RF	Aquaporin-4	[25]
Mouse: CD1 (adult) IS model: 1 h MCAO post-RIC: after MCAO 3 cycles: 5 min RIC + 5 min RF	Nrf2, HO-1, NQO-1 Nrf2-ARE pathway oxidative stress	[26]
Rat: Sprague–Dawley (m/220–280 g) IS model: 2 h MCAO + 24 h RF per-RIC/post-RIC (at RF) 3 cycles: 10 min RIC + 10 min RF	p38 MAPK-ATF2 pathway	[27]
Rat: Wistar (m/220-250 g) IS model: 20 min BCCAO post-RIC: before MCAO 3 cycles: 10 min RIC + 10 min RF	HO-1, BDNF, TNFα oxidative stress nitrite neuroinflammation	[28]
Rat: Wistar (m/220-250 g) IS model: 20 min BCCAO post-RIC: after BCCAO 3 cycles: 10 min RIC + 10 min RF	nitrite, oxidative stress, lipid peroxidation AChE, BDNF, CREB, GSK-3β, TNFα	[29]
Rat: Sprague–Dawley (m/280-320 g) IS model: 1.5 h MCAO, 24 h RF pre-RIC: 1 h before MCAO 4 cycles: 5 min RIC + 5 min RF	AMPK, HSP70, HIF1α, Bcl2, caspase 3 and 9, apoptosis, inflammation, IL-1β, TNFα, IL-6, oxidative damage	[30]
Mouse: C57BL/6 J (m/22-24 g) IS model: 1 h MCAO, 24 h RF post RIC: (after MCAO) 3 cycles: 10 min RIC + 10 min RF	pSTAT3/STAT3 GFAPα, GS	[31]
Rat: Sprague–Dawley (m/280-320 g) IS model: 1.5 h MCAO pre-RIC: 24 h before MCAO 3 cycles: 10 min RIC + 10 min RF	Brain: IL-4, IL-10, IL-1β, IFN𝛾 Blood: HIF-1α Plasma:IL-4, IL-10, IL-1β,IFN𝛾	[32]
Rat: Sprague–Dawley (m/250-280 g) IS model: 1 h MCAO, 24 h RF pre-RIC: daily for 3 days 4 cycles: 5 min RIC + 5 min RF Cell model: Primary hippocampal neurons, 30 min pre-OGD (precondition), 3 h OGD + 24 h recovery	Notch1/NICD/Hes1 IKKβ/NF-kB_p65	[33]
Rat: Sprague–Dawley (m/250-300 g) IS model: MCAO 90 min post-RIC: after MCAO 3 cycles: 5 min RIC + 5 min RF	apoptosis (Bcl-2/Bax) TNF-α, NF-kB, pSTAT3	[34]
Rat: Sprague–Dawley (m/20 mo) IS model: 90 min MCAO pre-RIC: 24 h before MCAO 3 cycles: 10 min RIC + 10 min RF	HIF1A, HIF2A, IL-1β, IL-6, TNFα, IFN-γ, IL-4, IL-10, pAkt, pERK	[22]
Rat: Wistar (m/250-300 g) IS model: global 4-VO + BCCAO 8 min pre-RIC: before IS 3 cycles: 10 min RIC + 10 min RF	Neuroglobin (Ngb), mt membrane potential, mt Na + /K + -ATPase activity	[35]
Rat: Sprague–Dawley (m/280–320 g) IS model: 1.5 h MCAO + 24 h RF per-RIC, post-RIC: 24 h after RF, daily 14d 3 cycles: 10 min RIC + 10 min RF	Ngb, apoptosis, ROS	[36]
Rat: Sprague–Dawley (m/280-320 g) IS model: MCAO 2 h pre-RIC: 1 h before MCAO 3 cycles: 5 min RIC + 5 min RF	adenosine, adenosine A1 receptor (ADORA1), lipid peroxidation, mitochondrial stress, oxidative stress, TNFα	[37]
Mouse: C57BL/6 J (m/12wo) Bmal1 KO IS model: 60 min MCAO pre-RIC: before MCAO 2 cycles: 10 min RIC + 10 min RF	sleep circadian system	[38]
Rat: Wistar (m/250–300 g,11-12wo) IS model: 4-VO + BCCAO 8 min pre-RIC: before IS 3 cycles: 10 min RIC + 10 min RF	adenosine adenosine A1 receptor p-p38 MAPK pERK	[39]
Rat: Sprague–Dawley (m/260-280 g) IS model: 1.5 h MCAO per-RIC 3 cycles: 10 min RIC + 10 min RF	pial collateral flow	[40]
Rat: Sprague–Dawley (m/16–18 mo) IS model: MCAO per-RIC: 1 h after MCAO 3 cycles: 15 min RIC + 15 min RF	collateral flow	[41]
Rat: Sprague–Dawley (m/age NA) IS model: 1 h MCAO, 24 h RF per-RIC: immediately after MCAO 3 cycles: 15 min RIC + 15 min RF	Apoptosis, MMP-9, MMP-2, p-AMPK, eNOS	[42]
Rat: Sprague–Dawley (m/280-320 g) IS model: 1.5 h MCAO per-RIC, post-RIC: 1d after, daily 7-14d 3 cycles: 10 min RIC + 10 min RF	arteriogenesis, focal CBF, collateral circulation, Notch signaling	[43]
Rat: Sprague–Dawley (m/220-260 g) IS model: 2-VO (3d hypoperfusion) chronic Post-RIC: after VO, daily 28d 3 cycles: 10 min RIC + 10 min RF	p-eNOS/eNOS, CBF, angiogenesis	[44]
Mouse: C57BL/6 J (m/10 wo) IS model: BCAS (30 min + 30 min) post RIC: 1w after BCAS, daily 3w, 1-4mo 4 cycles: 5 min RIC + 5 min RF	Endothelium, VEC (NO), EPC, Macrophages, Angiogenesis, Arteriogenesis	[45]
Rat: Sprague–Dawley (m/250-300 g) IS model: 1.5 h MCAO, 21d RF post-RIC: 2d after MCAO 3 cycles: 10 min RIC + 10 min RF	Kallikrein 1 bradykinin B2 receptor	[46]
Mouse: C57BL/6 (m/9-10wo) IS model: 3-VO post-RIC: immediately after 3-VO 3 cycles: 10 min RIC + 10 min RF	leptomeningeal collateral flow, granulocyte colony‐ stimulating factor (G‐CSF), monocytes/macrophages	[47]
Rat: Sprague–Dawley (m/270-330 g) IS model: 30 min left CCAsO & dMCAO pre-RIC: before CCAsO & dMCAO 3 cycles: 15 min RIC + 15 min RF	LCN2 Bim BOCT	[48]
Rat: Sprague–Dawley (m/260-280 g) IS model: 1.5 h MCAO post-RIC: after MCAO 3 cycles: 10 min RIC + 10 min RF	synaptogenesis PSD95 GAP43 Synapsin1	[49]
Rat: Wistar (m/adult) IS model: Modified 2-VO post-RIC: 1w after IS, 4x/day for 2 weeks 4 cycles: 5 min RIC + 5 min RF	Autophagolysosomal pathway, TFEB, Apoptosis	[50]
Mouse: C57BL/6 (sex NA/adult 8-9wo) IS model: 90 min MCAO, 48 h RF pre-RIC: 48 h before MCAO 3 cycles: 3 min RIC + 5 min RF	COX-IV, HSP60, EndoG/AIF Apoptosis, MDV	[51]
Rat: Wistar (m/200-250 g) IS model: 4-VO + 8 min BCCAO pre-RIC: before IS 3 cycles: 10 min RIC + 10 min RF	hippocampus CA1 apoptosis (DNA fragmentation, apoptotic bodies)	[18]
Rat: Wistar (m/280-320 g) IS model: global 4-VO + BCCAO 8 min pre-RIC: before IS 3 cycles: 10 min RIC + 10 min RF	hippocampus CA1, CA3/DG MEK-1/pERK1/2 neural cell death	[52]
Rat: Wistar (m/250-300 g) IS model: global 4-VO + BCCAO 8 min pre-RIC: before IS 3 cycles: 10 min RIC + 10 min RF	hippocampus CA1 p38 MAPK neural cell death	[53]
Rat: Wistar (m/250-300 g) IS model: global 4-VO + BCCAO 8 min pre-RIC: before IS 3 cycles: 10 min RIC + 10 min RF	p38 MAPK/HSP 70	[54]
Mouse: C57BL/6 J (m/20wo) IS model: eMCAO (embolic) per-RIC (2 h after eMCAO) 5 cycles: 5 min RIC + 5 min RF Condition: tPA 4 h after eMCAO	Infarct size, CBF, pAkt	[20]
Rat: Sprague–Dawley (m/adult) IS model: 8 min 4-VO post-RIC: after IS 4 cycles: 5 min RIC + 4 min RF	Apoptosis (Bcl-2/Bax), NO, eNOS, p-eNOS, PI3K-pAkt/p-eNOS	[55]
Rat: Sprague–Dawley (m/300-320 g) IS model: MCAO 2 h +  post-RIC: 0 min,10 min, 30 min after IS 3 cycles: 10 min RIC + 10 min RF	Akt/GSK3b-dependent autophagy	[56]
Rat: Sprague–Dawley (m/adult) IS model: focal MCAO 90 min + 72 h RF post-RIC: 3 h-6 h after RF 3 cycles: 5 min RIC + 4 min RF	KATP channels	[57]
Rat: Wistar (m/f, 250-350 g) IS model: global 4-VO 10 min delayed post-RIC: 20 min RIC, 2d after IS	very delayed post RIC	[21]
Rat: C57BL/6 J (ovariectomized f/20wo) IS model: eMCAO (embolic) per-RIC (2 h after eMCAO) 5 cycles: 5 min RIC + 5 min RF	Infarct size, CBF	[19]
Rat: Sprague–Dawley (m/280-320 g) IS model: 120 min MCAO, 3 h and 24 h RF per-RIC (10 min after MCAO) 4 cycles: 10 min RIC + 10 min RF	Apoptosis, Autophagy-lysosome pathway (ALP)	[58]
[66]Rat: Sprague–Dawley (m/300–320 g) IS model: 2 h MCAO + 22 h RF per-RIC/post-RIC (I-30 min, RF-0) 3 cycles: 10 min RIC + 10 min RF	Akt/p-Bcl-2/Beclin activation of autophagy	[59]
Rat: Sprague–Dawley (f/250-280 g) IS model: 1 h MCAO post-RIC: after MCAO 3 cycles: 10 min RIC + 10 min RF	TLR4/NF-кB pathway (…inflammation/cytokine production…)	[60]
Rat: Sprague–Dawley (m/260-280 g) IS model: 1.5 h MCAO post-RIC: after MCAO 3 cycles: 10 min RIC + 10 min RF	neurogenesis	[61]
Rat: Sprague–Dawley (m/300–320 g) IS model: 2 h MCAO, 24 h RF post-RIC: after MCAO, before RF 3 cycles: 10 min RIC + 10 min RF	pAkt, fibulin 5, claudin, occludin, BBB	[62]
Rat: Sprague–Dawley (m/250–280 g) IS model: 2 h MCAO, 24 h RF post-RIC: after MCAO, before RF 3 cycles: 15 min RIC + 15 min RF	mTOR p70S6K	[63]
Mouse: C57BL/6 J (m/20-25 g) IS model: 2 h MCAO post RIC: after MCAO 3 cycles: 10 min RIC + 10 min RF	p-AMPKα, p-mTOR, p-ACC, p-ULK1, autophagy, apoptosis	[64]
Rat: Sprague–Dawley (f/16wo) IS model: 1 h MCAO post-RIC: just after MCAO 3 cycles: 10 min RIC + 10 min RF	BBB permeability, MMP-9, claudin-5, GFAP	[65]
Mouse: C57BL/6 (8–10 wo) IS model: 45 min MCAO pre-, early pre-, per-, post- RIC: 4 cycles 5 min RIC + 5 min RF	collateral circulation	[66]
Rat: Sprague–Dawley (m/250-280 g)) IS model: 90 min MCAO post-RIC: just after MCAO 1–3 cycles: 5/10/15 min RIC + 5/10/15 min RF	BBB permeability, apoptosis	[67]