Age-related Macular Degeneration (AMD)

In AMD, the ageing changes described earlier for RPE and Bruch's membrane are severely advanced. The accumulation of lipofuscin within the RPE gives rise to increased fundus autofluorescence. Changes in Bruch's are also advanced with increased thickness and gross alterations of its structure. There is a considerable increase in the size of the surface deposits and these can seen by the ophthalmologist (figure below).

It is the number and size distribution of drusen that determines the stage of the disease. As these druse become larger and coalesce, they severely curtail metabolic support to the overlying RPE and photoreceptors resulting in their death.

The impact of these changes in Bruch's membrane on the delivery of metabolites has also been assessed.





Transport across Bruch's in AMD

Most of the donor eyes from AMD subjects show the very late stages of the disease. Often, the macular region cannot be sampled because of the high level of scar tissue. Nevertheless, peripheral samples can be easily obtained. It should be noted (from previous discussion) that the changes expected in macular regions are likely to be more severe than in the periphery. The changes in hydraulic conductivity (fluid transport) in the peripheral regions of AMD donors are given on the image.

Data points for AMD donors are shown in red. Thus, even in the periphery, AMD donors show a much steeper decline in fluid transport reaching failure thresholds much earlier in life. Because of the faster changes in macular regions, reduction in fluid transport is expected to be much severe.

When the hydraulic conductivity reaches the failure threshold, the fluid pumped out by the RPE cannot be transported out rapidly by Bruch's membrane. The fluid then accumulates on top of Bruch's forcing a RPE-retinal detachment, as shown in the OCT image below. In such a detachment, the distance between Bruch's and the RPE is increased, lowering the diffusional gradients for effective transport of nutrients. If untreated, such a detachment can lead to the death of RPE and photoreceptors. Nearly 20% of AMD patients show these RPE detachments.

The diffusion of carrier sized proteins is also reduced in AMD donors (figure above, right). The decrease in diffusion capacity observed in the periphery of AMD donors is expected to be much severe in macular regions. The inefficient delivery of essential metals, vitamins, and lipids will severely compromise the viability of RPE and photoreceptors. Heavy metals play a key role in the anti-oxidant machinery of photoreceptors and a reduction will compromise their defence against oxidative damage. The deficiency in the delivery of vitamin A is reflected in compromised scotopic (low light level) vision. Again, delivery of essential unsaturated lipids is essential for synthesis of outer segment discs. These reductions in the delivery of essential nutrients is the initial insult that progresses to the death of RPE and photoreceptors of the retina.

Ginseng: Potential treatment modality for AMD

For any treatment to be effective, the decaying curves discussed earlier for transport of fluids and nutrients must be elevated so that they do not meet failure thresholds within the human lifespan.

Ginseng extract has many components that act as antioxidants, surfactactants, metal chelators, etc. It is therefore likely that they may play a role in solubilising lipid deposits, chelating metals that are deposited within the membrane and therefore release bound and trapped material. Scientists at AltRegen have observed beneficial effects of ginseng extract on both the RPE and Bruch's membrane, the former being on the release of MMP enzymes and the latter associated with release of lipids from Bruch's membrane.

Because of our interest in elevating the decaying transport curves in AMD, the present discussion is restricted to the effects of ginseng on fluid transport and diffusion of carrier-sized proteins across Bruch's membrane. The actual mechanisms that underlie the effects of ginseng have also been investigated and will be communicated at a later date.





Effect of Ginseng extract on the hydraulic conductivity of Bruch's membrane

Donor Bruch's membrane was mounted in specialised Ussing chambers (figures below) and basal hydraulic conductivity was determined. Briefly, a hydrostatic pressure was applied and the resulting flow across the preparation allowed the calculation of the hydraulic conductivity of the sample. The tissue was then perfused with a 10% ginseng extract and incubated for 20 hours. Subsequently, the hydraulic conductivity of the preparation was re-assessed.

The resulting change in hydraulic conductivity after incubation with ginseng is shown below:

In the 17 donor preparations (aged 12-87 years), incubation with ginseng improved the hydraulic conductivity of Bruch's membrane by 2.2-fold at a significance level of p<0.001. Semi-log plots of hydraulic conductivities are shown below to compare with the ageing plots shown earlier:

As shown in the figure on the left, incubation with ginseng elevated the decay curve upwards, a key requirement for a potential treatment for AMD. This elevation shows that after ginseng treatment, the hydraulic conductivities obtained were those associated with donors 25 years younger. Such a displacement would delay reaching the failure threshold by 25 years, sufficient to avoid the degenerative consequences of AMD within the human life-span.


Effect of ginseng extract on the diffusional status of Bruch's membrane

Previous studies had utilised FITC-dextran (molecular weight 21.2 kDa) as a test probe to evaluate the diffusional status of Bruch's membrane. However, dextran molecules are not globular and a better test probe would be a globular protein. We have used FITC-labelled albumin as a more physiological probe. Diffusion studies were carried out in standard Ussing chambers. Basal diffusion rates were obtained followed by incubation with ginseng for 24 hours. Diffusion rates were re-assessed over a period of 12 hours.

Incubation with ginseng increased the diffusional status of Bruch's membrane to albumin by 1.9-fold over basal values (p<0.001). Unlike with FITC-dextrans, the decline in diffusional status of Bruch`s with age was found to be exponential. The effect of ginseng on this exponential decline in shown in the following figure.

Ginseng elevated the decaying curve upwards such that the diffusional status of an individual donor was equal to that of a donor 15 years younger. These results clearly show that incubation with ginseng extract improved the diffusional transport of proteins across Bruch's membrane. Thus transport proteins, essential for carrying metals, vitamins and lipids will be able to deliver their cargo for utilisation by both the RPE and photoreceptor cells. This improvement is thus expected to delay the ageing process and delay or prevent the onset of macular degeneration.

Summary

Ginseng improved both the hydraulic conductivity and diffusional status of human Bruch's membrane. The improvement in hydraulic conductivity would diminish the risk of RPE detachments in patients with AMD. Improvement in diffusional status would allow improved nutritional transport to the RPE and photoreceptors thereby removing the metabolic insults that are essential to the degenerative phase of AMD.

The introduction of ginseng therapy in the early stages of AMD would act as a preventive method curtailing the progression of the disease. In advanced forms, ginseng would arrest any further deterioration of the condition and rescue photoreceptors prior to their demise.

Currently, laser, RPE transplantation and stem cell therapies are being investigated for the treatment of AMD. These are unlikely to be of use if the underlying changes in Bruch's are not also addressed. Pre-treatment with ginseng would offer a better outcome for these futuristic therapies.


New vision & New life with AltRegen

Learn more about AMD

Everything you need to know about Age-related Macular Degeneration.

AltRegen Co., Ltd.

FOLLOW ALTREGEN