Neuroprotection: Herbal Treatment for Glaucomatous Optic Neuropathy
You Qin Jiang, MD
Dept. of Ophthalmology, The Second Xiang Ya Hospital,
Central South University, Changsha, Hunan, 410011,
People's Republic of China
Introduction
Erigeron Breviscapus (vant) Hand-Mazz (EBHM) is a herb that has
often been used by Chinese people over the centuries; it possesses
the ability to inhibit blood coagulation, enhance the microcirculation,
and dilate brain blood vessels, as is evidenced by its clinical
application in the treatment of brain thrombosis and associated
paralysis, myocardial ishemia and coronary arteriosclerosis.
Experience with EBHM as a neuroprotector to treat glaucomatous
optic neuropathy is based on three clinical trials and on several
laboratory studies. Two clinical trials took place in 1990s and
the other one was done by multi center clinical trial recently.
The following is a brief summary of our efforts of trying to use
EBHM for the patients with glaucoma after their IOP were controlled
by surgery or medicine in past fifteen years. The herb had no
side-effect. It was passed by SDA (State Drug Administration)
in China and is commercially available after 2002 in China.
Clinical Trials
In order to evaluate the neuroprotective effect of EBHM on visual
field of the glaucoma patients with controlled IOP after trabeculectomy
and/or medicacine, two prospective, randomized, double-masked,
placebo controlled clinical trials were conducted in the Second
Xiang Ya hospital, Central South University, China from 1991-1993
and 1999-2000. And a multi center clinical trial was done by eight
Eye centers/clinics from 2002-2003 in China.
- The first clinical trail (1991-1993)
Sixty one patients (68 eyes) with primary glaucoma IOP controlled
by trabeculectomy at least more than two months including PACG
44cases (47 eyes), POAG 17 cases (21eyes) were evaluated. The
patients were randomly divided into EBHM group and placebo group.
The remedy of two groups were #2 tablets tid. The IOP was 15.45±4.50mmHg
in EBHM group and 16.20±3.15mmHg in control group(P>0.05).
After six months of treatment, the EBHM group did better than
placebo group as measured by stimulus V/4/e of the Goldmann
perimeter with the Esterman Grid. The improvement of visual
field in EBHM group was 16.62±11.39 grid and 0.76±8.39
grid in the placebo group (P<0.01). The visual field improving
rate was 93.1% in EBHM group and 10.34% in control group (P<0.01).
- The second clinical trial (1999-2001)
A similar study was performed using Oculus Automated Perimeter.
Forty five patients (eyes) with moderate or late stage glaucoma
were randomly assigned to EBHM group ( EBHM tablets #2 t.i.d)
or placebo group ( placebo tablets #2 t.i.d.) matched by age
and IOP. Their IOP were lowered than 21mmHg in diurnal IOP fluctuation
at least more than two months after trabeculectomy with or without
taking antiglaucoma medicine or taking medicine alone at least
two months and had experience with automated perimetry at least
twice to eliminate learning effect. The visual fields improved
significantly in the treatment group (mean sensitivity + 1.42
dB versus – 0.95 dB in the placebo group, P = 0.001) after
six months.
- A multi center clinical trial (2002-2003)
Ninety nine glaucoma patients with POAG and PACG at least three
months after trebuculectomy and/or medicine treatment. The mean
IOP were lower than 15mmHg (range, 8-18mmHg) in both groups.
After 2,4,6 months of treatment, the visual field defect score
(VFDS) in EBHM group were reduced to 0.44±1.60, 1.27±2.16
and 1.42±2.37 respectively. It is revealed that the longer
duration of EBHM taken the visual fields defect decreased gradually.
However, after 2,4,6 months treatment the VEDS in placebo group
decreased to –0.02±1.50, 0.68±1.73, and
0.40±1.57. It demonstrated that the reduction of VFDS
in the same period between two groups showed a significant difference
after two to four months (P<0.05) and highly significant
difference after six months treatment (P = 0.007).
Laboratory studies
1. Study-1 (1992-1993)
The effect of EBHM on the metabolism of retinal ganglion cells
of rats after artificial acute high intraocular pressure
A modified cytochrome oxidase (CO) histochemical and computer
image analysis were used to examine the effect of EBHM injection
on the metabolism of rat RGC after artificial acute high IOP.
75% of the average tail arterial blood pressure of the rats
was used as the perfusing pressure of the anterior chamber of
the right eyes maintained 60min to establish a model of decrease
the numbers of the CO active RGC and their gray values. In EBHM
group 15mg/Kg EBHM intramuscularly injected daily one week prior
to and 21days post to the elevated IOP established. In control
group, the artificial acute high IOP of the right eyes were
performed as EBHM group but no treatment was given. The study
revealed that the data of density and the gray value of CO active
RGC in EBHM group were much higher than those in the control
group. The difference of the density of high active CO retinal
ganglion cells and the high active CO retinal ganglion cells
between EBHM group and control group were both significant (P<0.01).
2. Study-2 (1997-1998)
The effect of EBHM on the axoplasmic flow of the optic nerve
in rats with experimentally elevated intraocular pressure
An acute elevated IOP with 110mmHg/45 min maintained by intra
anterior chamber perfusing with normal saline solution in the
right eyes of 30 SD rats. Then randomly distributed into 3 groups.
Group-A (0-day group) included six rats for RGC counting via
superior colliculus with horse radish peroxidase retrograde
labeling; Group B (20-day group) 12 rats subdivided into EBHM
and control groups(6 rats in each subgroup) for RGC counting
via left superior colliculus retrograde labeling after 12 days,
and Group-C (40-day group) included 12 rats submitted the same
treatment and procedure as group B after 40 days. The results
showed that after 0 day of acute elevated IOP, no labeled RGCs
were observed. After twenty days of acute elevated IOP, in the
control and EBHM subgroups in group B the density of labeled
RGCs were (423±220)/mm2 and (749±294)/mm2 respectively(P<0.01).
After 40 days of acute elevated IOP, the density of RGCs in
the control and EBHM subgroups in group C were(610±315)/mm2
and (1048±393)/mm2 respectively (P<0.01). The difference
of the density of the labeled RGCs between groups C and B with
EBHM treatment showed significant (P<0.01) also. It is revealed
that EBHM can improve the optic nerve axoplasmic transportation
blocked by acute elevation of IOP in rats.
3. Study-3 (1999-2000)
The effect of EBHM on retinal ganglion cells after partial optic
nerve crush injury
48 S-D rats were randomly divided into 3 groups. Group A: normal
control group had 6 rats. Calibrated optic nerve crush injury
model (ONPCI) was induced in the right eyes of the rest 42 rats
by a clip held on the retrobulbar optic nerve maintaining 4s
to inflicted a crush injury to partial block the optic nerve
axoplamic transportation. The left eyes served as control. Those
42 rats were randomly divided into Group B (injury model) and
Group C (injury model with EBHM treatment). 3% fast blue solution
was injected into bilateral superior colliculi 3 days prior
to sacrifice. After enucleation the whole retina from both eyes
were flat mounted on a slide and observed under a fluorescence
microscope. The labeled RGC rate was used for statistical analyzing.
(The labeled RGC rate = RGC from ONPCI eye/ RGC from control
eye ×100%).
The results showed that the labeled rate of RGC in group A (normal
control) was 99.79±13.05%, in group B(ONPCI) were 77.79%±7.11%,
63.76%±3.79% and 54.66%±4.75% in post to ONPCI
at day 4, day 14 and 21 respectively, and in group C (after
ONPCI treated with EBHM) labeled RGC rate were 80.13%±12.03%,
78.17%±9.19% and 83.59%±12.61% at day 4, day 14
and 21 respectively. It is obvious that after ONPCI treated
with EBHM the labeled RGC rate were significantly higher than
without treated with EBHM at 14 days and 21 days (P<0.05).
4. Study-4 (2001-2002)
The effect of EBHM on NMDA-induced retinal neuron damage in
rats
A retinal neuron loss model in retinal ganglion cell layer(RGCL)
was established by intravitreal injection of a single dose NMDA(1mmol/2µl)
in the rats. The results showed that (1) The mean of neuron
counting from RGCL is statistically significant higher in EBHM+NMDA
group than in normal saline solution + NMDA group at 14 days
after NMDA-treated (P=0.044). (2) EBHM has no effect on neuron
counting from RGCL when administered alone. There was no difference
in the numbers of neurons in RGCL between normal control group
and EBHM group.
Conclusions
Chinese herbs have been used for medical purposes for centuries.
EBHM is extracted from a single natural plant. Both our clinical
trials and laboratory studies showed that this drug has a efficacy
on neuroprotection. Meanwhile it is used clinically for glaucoma
patients with controlled IOP to restore/improve the visual fields.
However, the longer duration is needed to further illustrate in
human glaucoma and the molecular mechanisms for its neuroprotective
effects need to be further investigation.
References
1. Jiang Y, Liu X. New concepts in glaucoma therapy: neuroprotection.
In: Yuan J, Lim ASM, eds. The Frontier of Ophthalmology in the
21st Century, pp 541-554. Tianjin Science and Technology Press
2001
2. Li Jun Jia, You Qin Jiang, Zhen Zhong Wu. Erigeron Breviscapus
(vant) Hand-mazz to treat the patients with intraocular pressure
controlled late stage glaucoma. Journal of Chinese Practical Ophthalmology,
1994; 12(5):269-273
3. Chang Hua Ye, You Qin Jiang. A clinical study of the neuroprotection
effect of Erigeron Breviscapus (vant) Hand-mazz on glaucoma patients.
Chinese Ophthalmic Research, 2003; 21:307-311
4.Li Jun Jia, Zhong Hao Liu, You Qin Jiang, The effect of EBHM
on the metabolism of retinal ganglion cells of rats after artificial
acute high intraocular pressure. 1995; Chin J Ophthalmol, 31:129-132
5. Yi Hua Zhu, You Qin Jiang, Zhong Hao Liu, et al. The effect
of EBHM on the axoplasmic flow of the optic nerve in rats with
experimentally elevated intraocular pressure. Chin J Ophthalmol,
2000; 36(4):289-291
6.Bing Jiang, You Qin Jiang. The effect of erigeron breviscapus
(vant) hand-mazz on retinal ganglion cells after optic nerve crush
injury. Submitted by Chin J Ophthalmol
7. Jing Ming Shi, You Qin Jiang. Neuroprotective effect of EBHM
on NMDA-induced retinal neuron in rats. Submitted by Science of
Ophthalmology
8. Wang Ning-li*, Sun Xing-huai, Li Jing-zhen, Wang Jing-hua,
Chen Xiao-ming, Lin Ding, Lui Jian-hua, Zhong Yi-sheng, Zhang
Chun, Guo Wen-yi: Herbal treatment for glaucomatous optic neuropathy
— A multi center clinical trial on EBHM
*Beijing Tongren Eye Center, Capital Medical University, Beijing
100730, China
Key Words: Erigeron Breviscapus (vant) Hand-Mazz,
Glaucoma, Neuroprotection
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