Borneol, a novel agent that improves central nervous system drug delivery by enhancing blood–brain barrier permeability

Figures & data

Figure 1. Molecular structures of borneol.

Table 1. Comparisons of kinetic profile of orally, intranasally and intravenously administered borneol in mice using the noncompartmental model.

	i.v.	i.n.	p.o.
Plasma^a
Cmax (μg/mL)	68.0 ± 8.4	25.9 ± 5.0**	15.6 ± 2.3**
Tmax (min)	1.0	3.0	10.0
AUC0–120 min (μg·mL^−1·min)	632.3 ± 50.8	573.4 ± 77.7	271.8 ± 37.4**
MRT0–120 min (min)	12.2 ± 1.6	28.2 ± 1.4**	17.9 ± 2.1**
F (%)	100	90.7	43.0
Brain
Cmax (μg/g)	43.0 ± 5.1	9.0 ± 1.4**	8.5 ± 2.0**
Tmax (min)	1.0	3.4	10.0
AUC0–120 min (μg·g^−1·min)	505.3 ± 82.9	345.5 ± 70.0*	194.0 ± 23.5**
MRT0–120 min (min)	20.5 ± 8.8	49.0 ± 8.3**	43.6 ± 17.1**
Re (%)	100	68.4	38.4
Te (%)	79.9	60.3	71.4
DTI	1.0	0.8	0.9

This table is modified based on Zhao et al. (2012). Data are expressed as mean ± SD (n = 5). *p < 0.05, **p < 0.01: versus intravenous group, using one-way analysis of variance (ANOVA). i.v.: intravenous administration; i.n.: intranasal administration; p.o.: oral administration; C_max: calculated maximum concentration; T_max: time corresponding to C_max; AUC_{0–120 min}: partial area under the curve from 0 to 120 min; MRT_{0–120 min}: mean residence time from 0 to 120 min; F: absolute bioavailability; Re: relative brain targeted coefficient; Te: brain/blood drug ratio; DTI: drug target index.

Table 2. Borneol improves kinetic profile of co-administered agents in the brain.

			Cmax (μg/g)		AUC (μg/mL/min)
Borneol (mg/kg)	Co-administered agents (mg/kg)	Sample	alone	combined	alone	combined	Ref.
30, i.g.	TMPP, 37.5, i.g.	Mouse brain homogenate	2.83	4.38	103.54	168.15	Xiao et al., (2008)
0.9, i.n.	TMPP, 5, i.n.	Rat brain homogenate	10.92	14.16	1.95^a	2.80^a	Liu et al., (2008)
250, i.g.	Nimodipine, 2, i.v.	Mouse brain homogenate			21.86	28.42	Wu et al., (2014)
400, i.g.	Gastrodin, 200, i.g.	Mouse brain homogenate	0.50	0.63	50.12	104.67	Cai et al., (2008)
200, i.g.	Geniposide, 300, i.v.	Rat brain homogenate	19	37	810	2410	Dong et al., (2012)
600, i.g.	Rifampicin, 182, i.g.	Mouse brain homogenate	2.0	5.1	285.1	569.5	Wu et al., (2004)
300/600, i.g.	Hyperforin, 200, i.g.	Rat brain homogenate	0.13^b	0.23–0.24	13.8	19.5–19.7	Yu et al., (2011b)
300, i.g.	Levodopa, 416, i.g.	Rat CSF	4.29^b	9.00^b	2587.5	2890.4	Xian et al., (2013)
300, i.g.	Puerarin, 62.5, i.v.	Rat cortex			117.6	341.8	Gao et al., (2010)
300, i.g.	Edaravone, 3.75, i.v.	Rat cortex			50.83	70.29	Gao et al., (2010)
30, i.v.	Kaempferol, 25, i.v.	Rat hippocampus	0.11	0.35	13.06	28.57	Zhang et al., (2015)
186, i.g.	Meropenem, 208, i.p.	Rat striatum	1.20	2.25	122.56	233.25	Xin et al., (2014)

AUC: area under the curve; C_max: maximum concentration; CSF: cerebrospinal fluid; i.g.: intragastrical; i.n.: intranasal; i.p.: intraperitoneal; i.v.: intravenous; TMPP: tetramethylpyrazine phosphate (ligustrazine).

^a μg/mL/h.

^b μg/mL.

Figure 2. The permeability-enhancing effects of borneol may be achieved mainly via three mechanisms: the inhibition of efflux protein function; the enhancement of transmembrane tight junction protein; and predominant enhancement of vasodilatory neurotransmitters. (−), inhibitory effects; (+), enhancing effects; (±) biphasic regulatory effects.

Zhao JY, Lu Y, Du SY, et al. (2012). Comparative pharmacokinetic studies of borneol in mouse plasma and brain by different administrations. J Zhejiang Univ Sci B 13:990–6.

 PubMed Web of Science ®Google Scholar

Xiao YY, Ping QN, Chen ZP. (2008). A simple gas chromatographic method for the simultaneous determination and pharmacokinetic study of tetramethylpyrazine phosphate and borneol in mouse plasma and brain tissue after oral Administration of the fufang tetramethylpyrazine phosphate tablets. J Chromatogr Sci 46:395–400.

 PubMed Web of Science ®Google Scholar

Liu YD, Sun HJ, Li R, et al. (2008). Influence of borneol on nasal absorption of Ligustrazine (Chinese). Chin J Chin Mater Med 33:259–61.

 Google Scholar

Wu C, Liao Q, Yao M, et al. (2014). Effect of natural borneol on the pharmacokinetics and distribution of nimodipine in mice. Eur J Drug Metab Pharmacokinet 39:17–24.

 PubMed Web of Science ®Google Scholar

Cai Z, Hou S, Li Y, et al. (2008). Effect of borneol on the distribution of gastrodin to the brain in mice via oral administration. J Drug Target 16:178–84.

 PubMed Web of Science ®Google Scholar

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

 Google Scholar

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

 Google Scholar

Yu B, Ruan M, Sun Y, et al. (2011b). Effect of borneol and electroacupuncture on the distribution of hyperforin in the rat brain. Neural Regen Res 6:1876–82.

 Web of Science ®Google Scholar

Xian JW, Chan CW, Leung WN, et al. (2013). Borneol enhanced permeability of levodopa across blood-brain barrier _ Potential to lower levodopa dosage for Parkinson’s disease treatment. The 11th International Conference on Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders (AD/PDTM 2013), 2013, 288 p.

 Google Scholar

Gao C, Li X, Li Y, et al. (2010). Pharmacokinetic interaction between puerarin and edaravone, and effect of borneol on the brain distribution kinetics of puerarin in rats. J Pharm Pharmacol 62:360–7.

 PubMed Web of Science ®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

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