Borneol, a messenger agent, improves central nervous system drug delivery through enhancing blood–brain barrier permeability: a preclinical systematic review and meta-analysis

Figures & data

Figure 1. Summary of the process for identifying candidate studies.

Table 1. Summary the efficacy of borneol for improving central nervous system drug delivery.

Study	Species (sex, n = experimental / control group)	Weight	Anesthetic + methods to establish animal models	Method of administration (drug, dose, mode, frequency)		Outcome measures and samples	Efficacy result
(author, years)				Treatment group	Control group
Wang et al., 1992	New Zealand rabbits, NS (NS/NS)	2.0–2.5 kg	2% pentobarbital sodium (30 mg/kg, iv)	Synthetic borneol, 1.5 g/kg, ig, once	Same volume of normal saline, ig, once	CT	Increased
Liang et al., 1993a	New Zealand rabbits, male and female (6/6)	1.8–2.4 kg	NS	Synthetic borneol, 1.5 g/kg, ig, once	Same volume of normal saline, ig, once	The brain concentration of EB	Increased?
Liang et al., 1993b	Wistar rats, male and female (20/20)	150–180 g	NS	Synthetic borneol, 1 g/kg, ig, once	Same volume of normal saline, ig, once	The brain concentration of EB	Increased?
Liu et al., 1994	Wistar rats, male and female (14/12)	180–200 g	NS	Synthetic borneol, 1 g/kg, ig, once before administration of the drug	Same volume of normal saline, ig, once before administration of the drug	The brain concentration of Gentamycin (Gentamycin, 3.5 mg/kg, CVI)	Increased
Xu & Wang, 1995a	SD rats, NS (8/8)	250–350 g	NS	Borneol, 1.5 g/kg, ig, once before administration of the drug	Same volume of liquid paraffin, ig, once before administration of the drug	The brain to serum concentration ratio of Sul (Sul, 200 mg/kg, iv)	Increased
Xu & Wang, 1995b	Kunming mice, NS (10/10)	22–26 g	NS	Borneol, 1.5 g/kg, ig, once before administration of the drug	Same volume of liquid paraffin, ig, once before administration of the drug	The brain concentration of EB	ND
Xu & Wang, 1995c	Kunming mice, NS (10/10)	22–26 g	NS	Borneol, 0.5 g/kg, ig, once daily for 4 d before administration of the drug	Same volume of liquid paraffin, ig, once daily for 4 d before administration of the drug	The brain concentration of EB	Increased
Dong et al., 2002a	Wistar rats, male (6/6)	200 ± 5.25 g	NS	Synthetic borneol, 0.3 g/kg, ig, once daily for 4 d before administration of the drug	Same volume of liquid paraffin, ig, once daily for 4 d before administration of the drug	The brain concentration of Pt^2+ (Cisplatin, 7 mg/kg, ip)	Increased
Dong et al., 2002b	Kunming mice, male (6/6)	19.0 ± 0.54 g	NS	Synthetic borneol, 0.125, 0.25, 0.50, 1.00 g/kg, ig, once daily for 4 d before administration of the drug	Same volume of liquid paraffin, ig, once daily for 4 d before administration of the drug	The brain concentration of Pt^2+ (Cisplatin, 15 mg/kg, ip)	Increased
Lin et al., 2003	SD rats, male and female (9/10)	280 ± 32 g	NS	Synthetic borneol, 0.4, 0.8 g/ kg, AI at GV 15, once	No adjunctive intervention	The brain concentration of EB	Increased
Jia et al., 2004	Wistar rats, NS, (10/10)	200 ± 20 g	NS	Borneol, NS, ig, once at 1 h before administration of the drug	Same volume of liquid paraffin, ig, once at 1 h before administration of the drug	The brain concentration of Cisplatin (Cisplatin, 1 mg/kg, ip)	Increased
Wu et al., 2004	Mice, male (5/5)	20–25 g	NS	Synthetic borneol, 0.6 g/kg, ig, once at 15 min before administration of the drug	Same volume of 1% CMC-Na, ig, once at 15 min before administration of the drug	The brain concentration of Rif (Rif, 182 mg/kg, ig )	Increased
Zhang et al., 2005	Guinea pigs, male and female (10/10)	200 ± 20 g	3% pentobarbital sodium (NS, ip)	Synthetic borneol 0.0005, 0.001, 0.002 g per animal, in, once	Same volume of liquid paraffin, in, once	The brain concentration of EB	Increased
Chen, 2005	ICR mice, male and female (5/5)	25 ± 2 g	NS	L-Borneol, 0.0003, 0.0006 g/kg, ig, once	No adjunctive intervention	The brain concentration of paeonol (paeonol, 100 mg/kg, ig)	ND
Zhou et al., 2005	Japanese white rabbits, male and female (5/5)	2.6 ± 0.22 kg	Urethane (NS, NS)	Synthetic borneol,0.75 g/kg, ig, once before administration of the drug	Same volume of 20% CMC-Na, ig, once before administration of the drug	The CSF to serum concentration ratio of CBZ, ECBZ (CBZ, 40 mg/kg, ig)	Increased
Wang, 2006	ICR mice, male and female (6/6)	22 ± 2 g	NS	Synthetic borneol, 0.15, 0.3, 0.6 g/kg, ig, once before administration of the drug	Same volume of PEG 400, ig, once before administration of the drug	1. The brain concentration of Clindamycin (Clindamycin, 40 mg/kg, CVI)	Increased
						2. The brain concentration of amantadine hydrochloride (amantadine hydrochloride, 10 mg/kg, CVI)	Increased
						3. The brain concentration of fentanyl citrate (fentanyl citrate, 1 mg/kg, CVI)	Increased
Wang et al., 2006	Wister rats, NS (6/6)	300 ± 50 g	Pentobarbital sodium (NS, NS)	Borneol, 1 g/kg, iv, once	Same volume of 95% ethanol, iv, once	The brain concentration of TMP (TMP, 10 mg/kg, iv)	Increased
Zheng et al., 2007	New Zealand rabbits, male and female (6/6)	2.0–2.2 kg	Urethane (NS, NS)	Borneol, 0.18 g/kg, ig, once	Same volume of 2% CMC-Na, ig, once	The CSF to serum concentration ratio of Danshensu (Salvia miltiorrhiza, 10 g/kg, ig)	Increased
Xiao et al., 2007	Wistar rats, male (8/8)	250 ± 20 g	NS	Borneol, 1.5 g/kg, ig, once at 1 h before administration of the drug	Same volume of liquid paraffin, ig, once at 1 h before administration of the drug	The brain concentration of As2O3 (As2O3, 0.9 mg/kg, ia)	Increased
Chen et al., 2007	Rabbits, male and female (6/6)	2.5 ± 0.2 kg	20% choral hydrate (800 mg/kg, ip)	Natural Borneol, 0.7 g/kg, ig, once after administration of the drug	No adjunctive intervention	The CSF concentration of SV (SV, 40 mg/kg, ig and 14 mg/kg, ivgtt)	Increased
Zhang et al., 2007	Japanese white rabbits, male and female (10/10)	2.5 ± 0.4 kg	20% choral hydrate (1.2 g/kg, ip)	Borneol, 0.7 g/kg, ig, once after administration of the drug	Same volume of 75% ethanol, ig, once after administration of the drug	1. The CSF concentration of Vs (Vs, 40 mg/kg, iv and ivgtt)	Increased
						2. The ultrastructure of BBB
Liu & Gao, 2007	Japanese white rabbits, male and female (NS/NS)	2.5 ± 0.4 kg	20% choral hydrate (NS, NS)	Natural Borneol, 0.7 g/kg, ig, once after administration of the drug	Same volume of 75% ethanol, ig, once after administration of the drug	The CSF concentration of SV (SV, 40 mg/kg, iv)	Increased
Lin et al., 2008	Kunming mice, NS (5/5)	25 ± 5 g	NS	Borneol, 0.002, 0.010, 0.050 g/kg, ig, once	No adjunctive intervention	The brain concentration of SF (SF, 200 mg/kg, ig)	Increased
Liu et al., 2008	SD rats, male and female (5/5)	190–210 g	NS	Borneol, 0.009 g/kg, ie, once	No adjunctive intervention	The brain concentration of ligustrazine (ligustrazine, 50 mg/kg, ie)	Increased
Zhou et al., 2008	ICR mice, male and female (6/6)	NS	NS	Synthetic borneol, 0.75 g/kg, ig, once daily for 5 d before administration of the drug	Same volume of corn embryo oil, ig, once daily for 5 d before administration of the drug	The brain concentration of CBZ, ECBZ (CBZ, 760 mg/kg, ig)	Increased
Shi & Zhao, 2008	Japanese white rabbits, male and female (8/8)	3.0 ± 0.5 kg	20 % urethane (1.0–1.6 g/kg, iv)	Natural Borneol, 0.7 g/kg, ig, once at 1 h before administration of the drug	Same volume of 75% ethanol, ig, once at 1 h before administration of the drug	The CSF to serum concentration ratio of ACNU (ACNU, 4 mg/kg, iv)	Increased
Li et al., 2008	Japanese white rabbits, Male and female (16/14)	2.5 ± 0.5 kg	20% choral hydrate (1.0–1.2 g/kg, ip)	Natural Borneol, 0.7 g/kg, ig, once at 1 h before administration of the drug	Same volume of 75% ethanol, ig, once at 1 h before administration of the drug	The CSF to serum concentration ratio of TMZ (TMZ, 12 mg/kg, ig)	Increased
Liu et al., 2008	Rabbits, male and female (6/6)	1.8–2.5 kg	NS	Natural Borneol, 0.18 g/kg, ig, once	Same volume of 2% CMC-Na, ig, once after administration of the drug	The brain concentration of Danshensu (Salvia miltiorrhiza, 10 g/kg, ig)	Increased
Ge et al., 2008	SD rats, male and female (5/5)	260–310 g	NS	Synthetic borneol, 1.5, 1.95 g/kg, ig, once	Same volume of liquid paraffin, ig, once	The ultrastructure of BBB	Increased
Gao et al., 2009	Japanese white rabbits, male and female (6/6)	2.5 ± 0.5 kg	20% choral hydrate (700–800 mg/kg, ip)	Natural Borneol, 0.7 g/kg, ig, once at 1 h before administration of the drug	Same volume of 75% ethanol, ig, once at 1 h before administration of the drug	The CSF concentration of methotrexate (methotrexate, 100 mg/kg, iv)	Increased
Wu et al., 2009	Kunming mice, male and female (3/3)	20 ± 2 g	NS	Borneol, NS, iv, once	No adjunctive intervention	1. The brain concentration of AZT (AZTP-CL, 30 mg/kg, NS)	Increased
						2. The blood concentration of AZT (AZTP-CL, 30 mg/kg, NS)	ND
Wang et al., 2009	Rabbits, male and female (6/6)	1.8–2.2 kg	Phenobarbitone (45 mg/kg, ip)	Borneol, 0.085 g/kg, ig, once	No adjunctive intervention	The brain concentration of Notoginsenoside R1, ginsenoside Rg1 and Re (Panax notoginseng 15.0 g/kg, ig)	Increased
Xiao & Ping, 2009	Mice, NS (6/6)	NS	NS	Borneol, 0.03 g/kg, ig, once	No adjunctive intervention	The brain concentration of TMPP (TMPP, 37.5 mg/kg, ig)	Increased
Chai et al., 2009	SD rats, male (5/5)	320 ± 20 g	Pentobarbital sodium (45 mg/kg, ip)	Borneol, 0.00011 g/kg, ie, once	No adjunctive intervention	The brain concentration of NT-NP (NT-NP, 60 µg/kg, ie)	Increased
Zhu, 2009	SD rats, male and female (10/10)	250–300 g	10% chloral hydrate (350 mg/kg, CVI)	Synthetic borneol, 0.125, 0.25, 0.50, 1.00 g/kg, ig, once daily for 4 d	Same volume of liquid paraffin, ig, once daily for 4 d	1. The brain concentration of EB	Increased
						2. The concentration of drug (VCR, 1 mg/kg,CVI)	Increased
Wei et al., 2010	Wistar rats, male (4/4)	260–300 g	10% choral hydrate (3.45 g/kg, ip)	Borneol, 27 g/kg, ig, once daily for 7 d	No adjunctive intervention	The CSF concentration of ceftriaxone (ceftriaxone, 180 g/kg, im, once daily for 7 d)	Increased
Zhang et al., 2011 (1)a	Balb/c mice, male (3/3)	18–22 g	10% chloral hydrate (0.4 g/kg, ip)	Borneol, 0.006 g per animal, ig, once after administration of the drug	No adjunctive intervention	Immunofluorescence image	Increased
Zhang et al., 2011 (1)b	SD rats, male (3/3)	200 ± 10 g	NS	Borneol, 0.001 g/kg, ig, once after administration of the drug	No adjunctive intervention	The brain concentration of Hup (NP-Hup A or Apr-NP-Hup A,, 500 µg/kg, once)	Increased
Wu et al., 2011	SD rats, male (6/6)	220–260 g	NS	Borneol, 0.028 g/kg, ig, once	No adjunctive intervention	The brain concentration of HSYA (HSYA, 20.0 mg/kg, ig)	Increased
Zhang et al., 2011 (2)	Wistar rats, male (3/3)	200 ± 20 g	NS	Borneol, 0.2 g/kg, ig, once daily for 7 d before administration of the drug	Same volume of 50% ethanol, 2.0 ml/kg, ig, once daily for 7 d before administration of the drug	The brain concentration of CBZ (CBZ, 120 mg/kg, ig)	Increased
Wang et al., 2011	Kunming mice, male and female (9/9)	20 ± 5 g	NS	Borneol, 0.375 g/kg, ig, once	No adjunctive intervention	The brain concentration of jujuboside A (CSJD, 37.5 g/kg, ig)	Increased
Yu et al., 2011	Kunming mice, male and female (10/10)	18–22 g	NS	Synthetic borneol 0.2, 0.4 g/kg, ig, once daily for 14 d	No ajunctive intervention	1. The brain concentration of EB	Increased
						2. The brain concentration of Rh 123	Increased
						3. The permeation index Kp
						4. The ultrastructure of BBB
Wu, 2011	Kunming mice, male and female (10/10)	20 ± 2 g	NS	Synthetic borneol, 1 mmol/kg, respectively, ig, once	Same volume of liquid paraffin, ig, once	The brain concentration of EB	Increased
Dong et al., 2012	SD rats, female (5/5)	180–220 g	10% choral hydrate (3.5 g/kg, ip)	Synthetic borneol, 0.05, 0.1, 0.2, 0.4 g/kg, ig, once at 15 min before administration of the drug	No adjunctive intervention	The brain concentration of geniposide (geniposide, 300 mg/kg, iv)	Increased
Yu et al., 2012	SD rats, female (5/5)	180–220 g	10% choral hydrate (3.5 g/kg, ip)	Synthetic borneol, 0.2 g/kg, ig, once at 5 min, 15 min or 30 min before administration of the drug	No adjunctive intervention	1. The brain concentration of geniposide (geniposide, 300 mg/kg, iv)	Increased
						2. The blood concentration of geniposide (geniposide, 300 mg/kg, iv)	ND
Wang et al., 2012	Kunming mice, NS (6/6)	20 ± 3 g	NS	Synthetic borneol, 0.2 g/kg, ig, once daily for 3 d before administration of the drug	No adjunctive intervention	1. The brain concentration of QUE (QUE, 50 mg/kg, ig)	Increased
						2. The blood concentration of QUE (QUE, 50 mg/kg, ig)	ND
Cao, 2013	SD rats, male (5/5)	300 ± 20 g	10% choral hydrate (NS, ip)	Synthetic borneol, 0.125 g/kg ig, once at 30 min before administration of the drug	Same volume of corn embryo oil, ig, once at 30 min before administration of the drug	1. The brain concentration of CPT-11 (CPT-11, 40 mg/kg, CVI)	Increased
						2. The blood concentration of CPT-11 (CPT-11, 40 mg/kg, CVI)	ND
Yu et al., 2013	SD rats, male (10/10)	180–220 g	Chloral hydrate (0.3 g/kg, ip)	L-Borneol,0.1, 0.2 g/kg, ig, once daily for 7 d	Same volume of normal saline, ig, once daily for 7 d	1. The brain concentration of Rh 123	Increased
						2. The permeation index Kp
						3. The ultrastructure of BBB
Diao et al., 2013	SD rats, NS (5/5)	250 ± 20 g	10% chloral hydrate (300 mg/kg, ip)	Borneol, 0.7 g/kg, ig, once at 1 h before administration of the drug	Same volume of 75% ethanol, ig, once at 1 h before administration of the drug	The CSF concentration of 131I-MnTBAP (131I-MnTBAP, 1.85MBq per animal, CVI)	Increased
Huang et al., 2013	Kunming mice, male (8/10)	18–22 g	5% chloral hydrate (NS, NS)	Synthetic borneol, 0.2 g/kg, ig, once daily for 5 d	Same volume of 5% tween and 0.2% CMC-Na, ig, once daily for 5 d	1. The brain concentration of EB	Increased
						2. The blood concentration of EB	ND
Zhang, 2014	SD rats, male (6/6)	280 ± 25 g	Chloral hydrate (300 mg/kg, ip)	Synthetic borneol,0.015, 0.030 g/kg, CVI, once	No adjunctive intervention	The brain concentration of kaempferol (kaempferol, 25 mg/kg, CVI)	Increased
Xin et al., 2014	Wistar rats, male (6/6)	245 ± 10 g	10% choral hydrate (345 mg/kg, ip)	Synthetic borneol,0.186 g/kg, ig, once daily for 7 d before administration of the drug	No adjunctive intervention	1. The brain concentration of Meropenem (Meropenem, 0.208 g/kg, ip)	Increased
						2. The blood concentration of Meropenem (Meropenem, 0.208 g/kg, ip)	ND
Liu, 2015	Male and female, New Zealan white (10/10)	2.0–2.5 kg	10% choral hydrate (350–400 mg/kg, iv)	Borneol, 0.002, 0.004, 0.008 g/kg, ie, once	Same volume of solvent, ie, once	The CSF concentration of ligustrazine (ligustrazine, 20 mg per animal, ie)	ND
Zhang 2015	Male, SD rats (5/5)	255–305 g	NS	Borneol, 15, 30 mg/kg, CVI	No adjunctive intervention	The brain concentration of Kaempferol	Increased
Guo et al., 2015	Male, SD (5/5)	230–250 g	10% chloral hydrate (3.5 mg/kg, ip) + the mice were injected with 2.5 × 0^6 C6 cells suspended in 25 ul of PBS (C6/SD glioma model)	Natural Borneol, 140, 35 mg/kg, ig, once at 1 h before administration of the drug	Same volume of CMC ig, once at 1 h before administration of the drug	Effect of bonenol on pharmacokinetic parameters of methotrexate in brain	Increased
Yu et al., 2015	Male, NIH rats (10/10)	26–30 g	NS	Borneol, 50, 100, 200 mg/kg, ig, twice daily for 7 d	No adjunctive intervention	1. The brain concentration of Rh 123 (Rh 123, 0.3 mg/kg, CVI )	Increased
						2. The blood concentration of Rh 123 (Rh 123, 0.3 mg/kg, CVI )	ND
Zhao et al., 2015	Female and male, Wistar rats (8/8)	18–22 g	NS	Borneol, 3 mg/kg, ig, once daily for 7 d	No adjunctive intervention	The brain concentration of nerve growth factor	Increased
Ren, 2016	Male, Wistar rats (13/13)	200 ± 20 g	NS	Natural Borneol, 14.28 g/kg, ig, once daily for 10 d	No adjunctive intervention	The brain concentration of phenytoin sodium	Increased
Wei, 2016	Kunming mice, female (5/5)	20–25 g	Ether (NS, NS)	Natural Borneol, 125, 250 mg/kg, ig, 30 min before administration of the drug	Same volume of 75% alcohol 0.01 ml/g, ig, 30 min before administration of the drug	1. The brain concentration of Erlotinib (Erlotinib, 50 mg/kg, ig)	Increased
Wu, 2016	FVB rats, NS (6/6)	NS	1.25% avertin (NS, NS)	Natural Borneol, 2 mg/10g, ig, once at 1 h before measuring	No adjunctive intervention	1. The brain concentration of Rh 123	Increased
						2. The brain concentration of Adriamycin (Adriamycin, 58 ug/10 g, iv)	Increased
Tang et al., 2016	Kunming mice, female and male (54/54)	NS	NS + co-culture of primary brain microvessel endothelial cells and astrocytes in rats	Natural Borneol, 25, 50, 100 mg/kg, ig, once before administration of the drug	Same volume of 50% alcohol, once before administration of the drug	The brain concentration of puerarin	Increased
Hou et al., 2016	SD rats, male (36/36)	180–220 g	Chloral hydrate (NS, ip)	Borneol, 100 mg/kg, ig and iv	No adjunctive intervention	The brain concentration of asiaticoside	Increased
Yin, 2017	C57BL/6 mice, male (10/10)	20 ± 2 g	NS + the mice were injected with 5 × 10^4 GL261 cells suspended in 4ul of PBS (mouse GL261 glioma models)	L-Borneol, 0.1, 0.15, 0.3, 0.6, 0.9 g/kg, ig, once at 1 h before administration of the drug	No adjunctive intervention	1. The brain concentration of Cisplatin	Increased
						2. The brain concentration of EB	Increased
						3. Survival of tumor-bearing mice
						4. Gadolinium-enhancement ratio

BBB: the blood–brain barrier; increased: an significantly increasing blood–brain barrier permeability after the administration of borneol; decreased: an significantly decreasing blood–brain barrier permeability after the administration of borneol; ND: no statistical difference between treatment and control group; Increased? or decreased?, the efficacy result was reported as increasing or decreasing blood brain barrier permeability with absence of statistical analysis or available original data; NS: not stated; AI: acupoint injection; EB: Evans blue; Sul: sulfanilamide; ig: intragastric administration; ip: intraperitoneal administration; in: intranasal administration; iv: intravenous injection; Rh 123: rhodamine 123; Kp: the permeation index calculated by the ratio of Rh 123brain/Rh 123blood; VCR: Vincristine; CVI: caudal vein injection; P-gp, P-glycoprotein; TMP: tetramethylpyrazine; CSF: cerebrospinal fluid; NT-NP: neurotoxin nanoparticle; CSJD: Compound Shuyu Jiannao Decoction; TMPP: tetramethylpyrazine phosphate; SF: sodium ferulate; SV: Sodium Valproate; CBZ: carbamazepine; Rif: rifampicin; AZTP-CL: azidothymidine palmitate liposome; AZT: azidothymidine; CPT-11: Irinotecan; HSYA: hydroxysafflor yellow A; ACNU: nimustine; TMZ: Temozolomide; QUE: quercetin; CT: computed tomography; Vs: Valproate sodium; Hup: Huperzine, CMC: carboxymethylcellulose sodium.

Table 2. Quality assessment of included studies.

Study	A	B	C	D	E	F	G	H	I	J	Total
Wang et al., 1992	+	–	–	–	–	+	–	–	–	–	2
Liang et al., 1993	+	–	–	–	–	+	–	–	–	–	2
Liu et al., 1994	+	–	+	–	–	+	–	–	–	–	3
Xu & Wang 1995	+	–	+	–	–	+	–	–	–	–	3
Dong et al., 2002	+	–	+	–	–	+	–	–	–	–	3
Lin et al., 2003	+	–	–	–	–	+	–	–	–	–	2
Jia et al., 2004	+	–	–	–	–	+	–	–	–	–	2
Wu et al., 2004	+	–	+	–	–	+	–	–	–	–	3
Zhang et al., 2005	+	–	+	–	–	+	–	–	–	–	3
Chen 2005	–	–	+	–	–	+	–	–	–	–	2
Zhou et al., 2005	+	–	+	–	–	+	–	–	–	–	3
Wang 2006	–	–	–	–	–	+	–	–	+	–	2
Wang et al., 2006	+	–	+	–	–	+	–	–	–	–	3
Zheng et al., 2007	+	–	+	–	–	+	–	–	–	–	3
Xiao et al., 2007	+	–	+	–	–	+	–	–	+	–	4
Chen et al., 2007	+	–	+	–	–	+	–	–	–	–	3
Zhang et al., 2007	+	–	+	–	–	+	–	–	–	–	3
Liu & Gao [40]	+	–	+	–	–	+	–	–	–	–	3
Lin et al., 2008	+	–	+	–	–	–	–	–	–	–	2
Liu et al., 2008	+	–	+	–	–	–	–	–	–	–	2
Zhou et al., 2008	+	–	+	–	–	–	–	–	–	–	2
Shi & Zhao 2008	+	–	+	–	–	+	–	–	–	–	3
Li et al., 2008	–	–	+	–	–	+	–	–	–	–	2
Liu et al., 2008	+	–	+	–	–	–	–	–	–	–	2
Ge et al., 2008	+	–	–	–	–	+	–	–	–	–	2
Gao et al., 2009	+	–	+	–	–	+	–	–	–	–	3
Wu et al., 2009	+	–	–	–	–	+	–	–	–	–	2
Wang et al., 2009	+	–	+	–	–	+	–	–	–	–	3
Xiao & Ping 2009	+	–	–	–	–	+	–	–	–	–	2
Chai et al., 2009	+	+	+	–	–	+	–	–	+	–	5
Zhu 2009	–	–	+	–	–	+	–	–	+	–	3
Wei et al., 2010	+	–	+	–	–	+	–	–	+	–	4
Zhang et al., 2011 (1)		–	+	–	–	+	–	–	+	–	3
Wu 2011	+	–	+	–	–	–	–	–	+	–	3
Zhang et al., 2011 (2)	+	–	+	–	–	+	–	–	–	–	3
Wang et al., 2011	+	–	+	–	–	–	–	–	–	–	2
Yu et al., 2011	+	–	–	–	–	+	–	–	–	–	2
Wu et al., 2011	+	–	+	–	–	–	–	–	–	–	2
Dong et al., 2012	+	–	+	–	–	+	–	–	+	–	4
Yu et al., 2012	+	–	+	–	–	+	–	–	+	–	4
Wang et al., 2012	+	–	+	–	–	–	–	–	+	–	3
Cao 2013	–	–	+	–	–	+	–	–	+	–	3
Yu et al., 2013	+	–	+	–	–	+	–	–	+	–	4
Diao et al., 2013	+	–	+	–	–	+	–	–	–	–	3
Huang et al., 2013	+	–	+	–	–	+	–	–	–	–	3
Zhang, 2014	+	+	+	–	–	+	–	–	+	–	5
Xin et al., 2014	+	–	+	–	–	+	–	–	+	–	4
Liu 2015	–	–	–	–	–	+	–	–	–	–	1
Zhang 2015	+	+	+	–	–	–	–	–	+	–	4
Guo et al., 2015	+	–	+	–	–	+	+	–	–	–	4
Yu et al., 2015	+	–	+	–	–	–	–	–	–	–	2
Zhao et al., 2015	+	+	–	–	–	–	–	–	–	–	2
Ren 2016	–	+	+	–	–	–	–	–	–	–	2
Wei 2016	–	–	+	–	–	+	–	–	–	–	2
Wu 2016	–	–	+	–	–	+	–	–	–	–	2
Tang et al., 2016	+	–	+	–	–	–	+	–	–	–	3
Hou et al., 2016	+	–	+	–	–	+	–	–	–	–	3
Yin 2017	+	+	+	–	–	–	+	–	+	–	5

A: peer-reviewed publication; B: monitoring of physiological parameters such as temperature; C: random allocation; D: blinded conduct of the experiments; E: blinded assessment of outcome; F: use of anesthetic without significant intrinsic neuroprotective activity (e.g. ketamine); G: animal and/or model (brain tumor model, epilepsy, intracranial infection, cognitive dysfunction or Parkinson); H: sample size calculation; I: compliance with animal welfare regulations; J: statement of potential conflict of interests.

Table 3. The classification of drugs transferred into the brain.

Antineoplastic drugs	Antibiotics and Antiviral drugs	Drugs for epileptic, Parkinson, and cognition	Traditional Chinese medicine	Other drugs
Cisplatin	Gentamicin	Carbamazepine	Ligustrazine	^131I-MnTBAP
Dong et al., 2002	Liu et al., 1994	Zhou et al., 2005	Wang et al., 2006	Diao et al., 2013
Jia et al., 2004	Sulfanilamide	Zhou et al., 2008	Li et al., 2008	Nerve growth factor
Yin 2017	Xu & Wang 1995	Zhang et al., 2011 (2)	Xiao & Ping 2009	Zhao et al., 2015
Nimustine	Rifampicin	Sodium Valproate	Liu 2015	Fentanyl
Shi & Zhao 2008	Wu et al., 2004	Chen et al., 2007	Salvia miltiorrhiza	Wang 2006
Methotrexate	Clindamycin	Zhang et al., 2007	Zhang et al., 2007	As2O3
Gao 2009	Wang 2006	Liu & Gao 2007	Liu et al., 2008	Xiao et al., 2007
Guo et al., 2015	Cefatriaxone	Phenytoin sodium	Ginsenoside	Neurotoxin nanoparticle
Vincristine	Wei et al., 2010	Ren 2016	Wang et al., 2009	Chai et al., 2009
Zhu 2009	Meropenem	Amantadine Hydrochloride	Ferulic acid
Irinotecan	Xin et al., 2014	Wang 2006	Lin et al., 2008
Cao 2013	Azidothymidine	Huperzine	Puerarin
Erlotinib	Wu et al., 2009	Zhang et al., 2011 (1)	Tang et al., 2016
Wei 2016			Asiaticoside
Adriamycin			Hou et al., 2016
Wu 2016			HSYA
Quercetin			Wu et al., 2011
Wang et al., 2012			Jujuboside
Kaempferol			Wang et al., 2011
Zhang 2014			Geniposide
Zhang et al., 2015			Dong et al., 2012
			Yu et al., 2012
			Paeonol
			Chen 2005

HSYA: hydroxysafflor yellow A; ¹³¹I-MnTBAP: manganese porphyrin labeled by ¹³¹I.

Figure 2. Subgroup analysis according to brain Evans blue content. (A) animal species; (B) the frequency of borneol administration; (C) the mode of application; (D) the instrument used for quantification; (E) the therapeutic dose of borneol; (F) the quality of studies. The vertical axis represents effect size point estimates for borneol and 95% confidence intervals.

Figure 3. The forest plot: effects of borneol for improving the BBB permeability compared with control group according to brain Rh 123 content.

Wang NS, Xie D, Liang MR, et al. (1992). Effect of borneol on rabbit blood brain barrier function by CT dynamic scanning observation. Tradit Chin Drug Res Pharmacol 8:28–31.

 Google Scholar

Liang MR, Ye SM, Zhang YQ, et al. (1993). The effect of borneol on Evan’s blue staining of rabbit and rat brain tissue. Guangzhou Zhong Yi Xue Yuan Xue Bao 10:211–3.

 Google Scholar

Liu Q, Liang M, Chen Z, et al. (1994). The influence of borneol on the passing of gentamycin through blood-brain barrier. J Guangzhou Univ Tradit Chin Med 11:37–40.

 Google Scholar

Xu W, Wang ZR. (1995). Effect of menthol and borneol on the distribution of sulfadiazine sodium and Evan’s blue in the rat and mouse brain. Pharmacol Clin Chin Mater Clin Med 6:31–3.

 Google Scholar

Dong XZ, Tang XA, Gao QH, et al. (2002). Study on the Auxo-action of Borneol assisting the penetration of DDB across BBB. Chin Pharm J 37:275–7.

 Google Scholar

Lin XM, Chen HD, Yan JW, et al. (2003). Effect of acupoint injection of camphol-fluid on the permeability of blood-brain barrier in rats. Zhen Ci Yan Jiu 28:99–101.

 Google Scholar

Jia YM, Ding Z, Zeng LY, et al. (2004). Borneol on facilitating permeation for cisplatin through blood brain barrier. Sichuan Med J 25:156–7.

 Google Scholar

Wu SR, Cheng G, He YX, et al. (2004). Studies on the effects of borneol on the distribution of rifampicin in mice. Chin Pharmacol J 39:289–91.

 Google Scholar

Zhang RT, Wang H, Chen L, et al. (2005). Study on the effect of borneol nasal drops on the vasopermeability of nasal mucosa and cerebral vessel of guinea pigs. J Chin Pharm 16:1291–3.

 Google Scholar

Chen Q. (2005). Study on pharmacokinetics of paeonol influenced by borneol and the distribution of paeonol in mice [MD dissertation]. Zhejiang, Hangzhou: Zhejiang University.

 Google Scholar

Zhou HY, Wang P, Lin D, et al. (2005). Studies on the effects of borneol on the pharmacokinetics of carbamazepine in rabbits. Chin Pharmacol Bull 21:1263–6.

 Google Scholar

Wang W. (2006). Study on the auxo-action of borneol accelerating transportation of drug through the BBB [MD dissertation]. Zhejiang, China: Zhejiang University.

 Google Scholar

Wang Y, Zhang ZY, Xu F, et al. (2006). Effects of borneol on concentration of tetramethylpyrazine in blood and distribution in brain of rat. Zhongguo Yaoye 15:30–1.

 Google Scholar

Zheng XH, Zhao X, Fang M, et al. (2007). Pharmacokinetic effects of shi herb-borneol on jun herb-Salvia miltiorrhiza. J Xi’an Jiaotong Univ Med Sci 28:170–3.

 Google Scholar

Xiao YQ, Zhang LY, Tang HT, et al. (2007). Study on the role of borneol in improving permeability of arsenic through blood brain barrier. Chin J Neurosurg Dis Res 6:244–6.

 Google Scholar

Chen RL, Zhao ZG, Zhang XH, et al. (2007). Effect of Borneol on sodium valproate passing blood-brain barrier. Chin J Rehabil Theory Pract 13:151–3.

 Google Scholar

Zhang XH, Liu FQ, Zhao ZG. (2007). The opening effect on the blood-cerebrospinal fluid barrier induced by borneol (Bn, Bingpian) and its improvement of antibiotic treatment in rabbits with experimental bacterial meningitis. Chin J Neuroimmunol Neurol 14:93–6.

 Google Scholar

Liu N, Gao XC. (2007). The study of blood-brain barrier opening by Borneol. Acta Acad Med Weifang 29:398–400.

 Google Scholar

Lin ZZ, Yao MC, Lan MX, et al. (2008). Effects of borneol on distribution of sodium ferulate in plasma and brain regions of mice. Chin Tradit Herb Drugs 39:551–6.

 Google Scholar

Liu YD, Sun HJ, Li R, et al. (2008). Influence of borneol on nasal absorption of Ligustrazinee. Zhongguo Zhong Yao Za Zhi 33:259–61.

 PubMedGoogle Scholar

Zhou HY, Chen XY, Huang CK, et al. (2008). Effect of borneol on the distribution of carbamazepine in mice. Wenzhou Yi Xue Yuan Xue Bao 38:300–5.

 Google Scholar

Shi WZ, Zhao ZG. (2008). Pharmacokinetics study of nimustine (ACNU) through blood brain barrier after intragastric administration of borneol. Chin J Hosp Pharm 28:1933–6.

 Google Scholar

Li H, Huang J, Shi W, et al. (2008). The pharmacokinetics of temozolomide in rabbits after intragastric administration of Borneol. Proceedings of the Eighth Chinese Conference on Pharmacoepidemiology; Beijing Tiantan Hospital Affiliated to Capital Medical University; Beijing.

 Google Scholar

Ge C, Han M, Bai R, et al. (2008). Effect of borneol on the ultrastructure of promoting blood brain barriar open. Chin J Integr Med Cardio-/Cerebrovasc Dis 6:1183–4.

 Google Scholar

Gao C, Gao M, Shi WZ, et al. (2009). Experimental study on the effect of borneol for methotrexate penetrating across blood brain barrier. Chin J Clin Pharmacol 25:134–7.

 Google Scholar

Wu HB, Wang SN, Shi L, et al. (2009). Effects of borneol on the distribution of azidothymidine palmitate liposomes in mice. Chin Pharmacol J 44:590–3.

 Google Scholar

Wang SX, Miao WL, Fang MF, et al. (2009). Effect of borneol on the tissue distribution of notoginseng R1, ginsenoside Rg1 and Rein rabbits. J Fourth Mil Med Univ 30:2750–2.

 Google Scholar

Xiao YY, Ping QN. (2009). Effects of Borneol-β-cyclodextrin inclusion complex on the plasma and brain concentrations of tetramethylpyrazine phosphate in mice. J Chin Pharm Univ 40:412–5.

 Google Scholar

Chai G, Pan Y, Li F. (2009). Effect of borneol/mentholum eutectic mixture on nasal-brain delivery of neurotoxin loaded nanoparticles. Zhongguo Zhong Yao Za Zhi 34:698–701.

 PubMedGoogle Scholar

Zhu GD. (2009). Study on the auxo-action of borneol accelerating the penetration of BBB and P-glycoprotein-mediated mechanism [MD dissertation]. Guangdong, China: Guangzhou Medical University.

 Google Scholar

Wei Y, Liu P, He X, et al. (2010). Microdialysis and HPLC method for determination of concentration of pantoprazole in rat striatum after combined administration with borneol. Zhongguo Zhong Yao Za Zhi 35:2605–8.

 PubMedGoogle Scholar

Zhang JQ, Wei YH, Duan HG, et al. (2011). Effects of borneol on the pharmacokinetics and brain tissue distribution of carbamazepine. Chin J Hosp Pharm 31:747–50.

 Google Scholar

Wu X, Ouyang L, Xiang D, et al. (2011). Enhancing effect of borneolum syntheticum and acori talarinowii rhizoma on penetrating blood-brain barrier of hydroxysafflor yellow A. China Tradit Herb Drugs 42:734–7.

 Google Scholar

Wang P, Wang C, Lou Y. (2011). Borneol and rhizome of chuanxiong on facilitating permeation for compound Shuyu Jiannao decoction through blood brain barrier. J Hubei Univ Chin Med 13:21–3.

 Google Scholar

Yu B, Lv GH, Sun Y, et al. (2011). Effect of electroacupuncture combined with intragastric administration of borneol on the permeability of blood-brain barrier in the mouse. Zhen Ci Yan Jiu 36:335–40.

 PubMedGoogle Scholar

Dong X, Ruan M, Yu B, et al. (2012). Effects of borneol at different doses on concentration of geniposide in rat brains. China Tradit Herb Drugs 43:1366–70.

 Google Scholar

Yu B, Ruan M, Dong X, et al. (2012). The influence of borneol treatment interval on the concentration of geniposide in rat brains. Chin Pharmacol Bull 28:862–6.

 Google Scholar

Wang G, Zeng N, Wang J, et al. (2012). Study on the effect of borneol influence on BBB opening for promoting the cerebral absorption of quercetin. Pharmacol Clin Chin Mater Clin Med 28:65–8.

 Google Scholar

Cao Y. (2013). Experimental Study on the effect of borneol for CPT-11 penetrating across BBB in rats [MD dissertation]. Zhejiang, China: Zhejiang Chinese Medical University.

 Google Scholar

Yu B, Ruan M, Dong X, et al. (2013). The mechanism of the opening of the blood-brain barrier by borneol: a pharmacodynamics and pharmacokinetics combination study. J Ethnopharmacol 150:1096–1108.

 PubMed Web of Science ®Google Scholar

Diao Y, Liu XN, Wang OY, et al. (2013). The effect of borneol on penetration of MnTBAP through blood brain barrier in rat. Prog Anat Sci 19:410–2.

 Google Scholar

Huang P, Xia HL, Jia F, et al. (2013). Effect of Benzoinum and Borneo Camphor in different proportion on the mice of cerebral ischemia, anoxia and blood-brain barrier. Pharmacol Clin Chin Mater Clin Med 29:75–8.

 Google Scholar

Zhang Q. (2014). The enhancing effect of borneol on the blood-brain barrier penetration of neuroprotective kaempferol based on blood and cerebral microdialysis [MD dissertation]. Anhui, China: Anhui Medical University.

 Google Scholar

Xin HL, He XR, Li W, et al. (2014). The effect of borneol on the concentration of meropenem in rat brain and blood. J Asian Nat Prod Res 16:648–57.

 PubMed Web of Science ®Google Scholar

Liu BL. (2015). Study of borneol on nasal absorption of ligustrazine and on nasal mucosal mucin expression level influence [MD dissertation]. Guangdong, China: Guangzhou University of Chinese Medicine;.

 Google Scholar

Zhang Q, Wu D, Wu J, et al. (2015). Improved blood-brain barrier distribution: effect of borneol on the brain pharmacokinetics of kaempferol in rats by in vivo microdialysis sampling. J Ethnopharmacol 162:270–7.

 PubMed Web of Science ®Google Scholar

Guo JQ, Zhang R, Duan MM, et al. (2015). Effects of natural borneol on methotrexate penetrating across blood-tumor barrier. Trad Chin Drug Res Clin Pharmacol 1:73–7.

 Google Scholar

Yu H, Zhou GL, Mao BB. (2015). Effect of borneol on the function of P-glycoprotein in blood brain barrier. J Anhui Sci Technol Univ 29:34–8.

 Google Scholar

Zhao TJ, Zhang PL, Zhou Y, et al. (2015). Influences of borneol and muscone on blood-brain barrier permeability of nerve growth factor. Chin J New Clin Med 8:728–31.

 Google Scholar

Ren ZY, 2016. Research on the impact of borneol on blood brain barrier and pglycoprotein [MD dissertation]. Shandong, China: Shandong University of Traditional Chinese Medicine.

 Google Scholar

Wei SJ. (2016). Effect of borneol and quercetin on the penetration of erlotinib across the blood-brain barrier in mice [MD dissertation]. Fujian, China: Fujian Medical University.

 Google Scholar

Wu JB. (2016). The role of chloride channels in the enhanced transport of adiamycin and rhodamine across the blood brain barrier induced by borneol [MD dissertation]. Guangdong, China: Jinan University.

 Google Scholar

Tang DD, Zhang J, Wang JR, et al. (2016). Borneol promotes oral absorption and penetration into brain of puerarin and catalpol. Chin J Chin Mater Med 41:2720–6.

 Google Scholar

Hou TH, Li XB, Peng CS. (2016). Effects of borneol on the penetration of asiaticoside through the blood brain barrier in rats. Chin Pharm 27:3939–41.

 Google Scholar

Yin Y, Cao L, Ge HF, et al. (2017). L-Borneol induces transient opening of the blood-brain barrier and enhances the therapeutic effect of cisplatin. Cell Mol Dev Neurosci 28:506–13.

 Google Scholar