2 neuroprotective role of phosphoserine in glaucoma1

Neuroprotective Role of Phosphoserine in Glaucoma The phosphoserine in glaucoma Sergio Z.Scalinci1-2, Lucia Scorolli3, Marialuisa Lugaresi1 1

Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138

Bologna, Italy.

2

Glaucoma and Low Vision Study Centre, Department of General Surgery and Organ

Transplants, University of Bologna, 40138 Bologna, Italy; 3

Eye Private Clinic Santa Lucia, Department of Ophthalmology, 40137 Bologna, Italy

4

University of Notre Dame, 46556 Notre Dame IN, United States of America.

5

Department of Ophthalmology, Policlinic Umberto I, University of Rome La Sapienza, 00185

Rome, Italy 6

Department of Ophthalmology, University Scientific Institute San Raffaele, 20132

Milan, Italy

Corresponding author: Sergio Z. Scalinci Department of Medical and Surgical Sciences (DIMEC) University of Bologna, Italy Via G. Massarenti 9, 40138 Bologna, ITALY Phone +39.051.6364595

Fax +39.051.6364595

E-mail sergio.scalinci@unibo.it

Formattato: Tipo di carattere: 10,5 pt

DECLARATION OF INTEREST The authors report no conflicts of interest or financial

ABSTRACT

support. The authors alone are responsible for the content and writing of the paper.

1

AIM: To evaluate the neuroprotective role of

CONCLUSIONS: Multiple studies have focused on

phosphoserine and its anti-apoptotic properties in

the effectiveness of the neuroprotective therapy on

glaucoma and to compare the effectiveness of

patients affected by Chronic Simple Glaucoma

phosphoserine therapy to placebo treatment in

(CSG). Improvements experienced in patients treated

patients affected by glaucoma.

with phosphoserine can confirm its anti-apoptotic activity in treating glaucoma.

METHODS: 51patients (24 males and 27 females), between the ages of 35 and 61 years (average age of

Phosphoserine treatments could have significant

46 years ; standard deviation of ± 3.8) each affected

implications in the treatment of glaucoma as well as

by Chronic Simple Glaucoma (CSG) were enrolled in

in association with the traditional hypotonic topical

this study and followed-up for twelve months, before

therapy. However, further large long-term clinical

the treatment, and at 1,3,6, and 12 months. Patients

studies are still required.

were divided in two groups: subjects in group A (28 KEYWORDS:

patients – Experimental study Groupgroup) received

Glaucoma,

Neuroprotection,

Intraocular Pressure, Phosphoserine, Apoptosis

an oral phosphoserine treatment daily for nine months, subjects in group B (23 patients – cControl

INTRODUCTION

gGroup) received an oral placebo treatment daily for nine months. The patients’ selection was based on the

Glaucoma is a chronic, degenerative pathology

following inclusion: IOP<17 mmHg ± sd 2; cup/disc

characterized characterized by peculiar anatomical-

< 0.5; BCVA =20/20 with correction ≤± 3.5 D; no

functional alterations of the optic nerve, and is not

neurologic diseases.

always associated with an elevated intraocular pressure (IOP). In Optic Glaucomatous Neuropathy

RESULTS: Mean Deviation (visual fields analysis

(GON) a progressive slimming down of the retinal

30-2 Full Threshold), Corrected Pattern Standard

nerve fiber layer is created and is evidenced by an

Deviation, Retinal Nerve Fiber Layer thickness, and

accentuation of the excavation of the head of the

IOP Intraocular Pressure were the parameters

optic nerve via physio-pathological mechanisms

considered in order to evaluate phosphoserine

which are still not all individualized individualized

therapy effectiveness in both groups. 28 patients in

today. Within the last few years numerous studies

group A experienced a statistically significant

have been conducted on a large scale which havea

improvement (p<0. 0105) based either on IOP values

large scale which has confirmed the efficacy of this

or on visual fields analysis. The RNFL analysis,

the low-intensive therapy within the sphere of

however, demonstrated stability, compared with

glaucomatous pathology, even in the presence of a

baseline values. 13 patients in group B experienced

normal pressure level [1-2-3-4-5]. The positive action of

stability based either on the visual field analysis or on

hypotonic eye drops on the tropism of retinal

the IOP values, while 10 patients experienced a

structures is due to a reduction of the mechanical

progressive

stress exerted by the intraocular pressure either on

worsening the

values

of all

the

parameters considered.

ganglion cells or on the vascular structures of the

2

cribriform plate [1-2-3-4-5]. Given this, one hypothesizes

commonly associated with other neurodegenerative

hypothesizes that IOP is an important individual

pathologies, such as Alzheimerâ&#x20AC;&#x2122;s disease or

element in the pathological mechanism and the

Parkinsonâ&#x20AC;&#x2122;s disease [17-18-19-20-21]. Experimental studies

pathological conditions which are successively

have shown that nerve fiber damage begins after the

established and which are bound to apoptotic

first acute attack and progresses independently of

mechanisms conditioned with the tropism of the optic

having obtained a successive check of the IOP. This

nerve in both neurogenic and vascular components. It

process seems to be the result of a greater

is noted, in fact, that the survival of a retinal ganglion

susceptibility of the retinal ganglion cells to auto-

cell is largely influenced by the equilibrium between

destructive processes triggered by an initial damage.

anti-apoptotic factors (neurotrophins) and pro-

This process seems to be induced by a toxic action

apoptotic factors, including hyperbaric stress, and

and charged by retinal ganglion cells on the part of

accompanied by genetic and/or metabolic factors [6-7-

some substances with neuro-toxic effects, produced

8-9-10]

by degenerate ganglion cells. These molecules are

. As a consequence of the dis-equilibrium

between cellular survival mechanisms and cellular

represented by glutamate, nitric oxide, and free

death mechanisms we observe, in the first place, the

radicals - all of which favor neuro-degeneration [16-22-

hyper-activation of the enzyme phospholipase-A2

23]

. These signs which regarding the pathogenesis of

(PLP-A2) which is able to catabolize

ganglion cell death with successive subsequent

phosphatidylcholine (PDC), the principal

atrophy of the optic nerve of glaucoma help us to

phospholipid which constitutes the cellular

understand how current research is actually being

membrane of the retinal ganglion cells, and

oriented towards neuro-protection. Neuro-protection

arachidonic acid (AA) and diacylglycerols (DAG)

must therefore be tuned to the salvation of ganglion

which, in physiological concentrations, represent

cells which are still integral in nature and which are

important intracellular messages

[11-12-13-14]

. Once the

not involved or marginally affected by either primary

integrity of the cellular ganglion membrane is

of secondary degenerative effects [24-25]. Beyond the

compromised (as occurs in ischemia15), glutamate,

pharmaceuticalsBesides the medicinal products

the principle excitatory neurotransmitter, is released

already studied, (such as inhibitors of glutamate

and consequently the receptor canal NMDA present

receptors, calico-antagonists, growth factors (NGF,

on the surface of adjacent cells is stimulated [7-10-16-

BDNF, FGF) with neuro-trophic properties [260-271]),

175]

. From this condition follows the depolarization of

new molecules (such as Phosphoserine) deserve

the membrane and a successive consecutive opening

particular deepeningshould be further investigated.

of Ca2+ ion channels. An increment of intracellular

The goal of our study was to evaluate the rationale of

Ca2+ concentration contributes to the activation of

an anti-apoptosis therapy in glaucomatous

apoptotic processes

[186]

. This reaction, which

pathologies through the use of Phosphoserine.

represents a secondary attack, can expand itself in an

Phosphoserine is a constituent of the structural matrix

exponential manner to adjacent cells. The

of all cellular membranes and plays a fundamental

mechanisms of the first attack and of the extension of

role in the synthesis of neurotransmitters, and thus

the secondary attack of the adjacent cells are

contributes to an improvement of the functional state

3

Formattato: Tipo di carattere: 10 pt, Apice Formattato: Tipo di carattere: 10 pt

either of neurons of the central nervous system,

2.

Good tonometric compensation in topical

(amplifying cognitive activity, ) or of ganglion cells,

hypotonic therapy (IOP < 17 mmhg ± 2

which augment neuro-conductance. From hereherein

standard deviation; corrected in function

addition anti-catabolic functions are attributed to

with the corneal thickness- CCT- according

Phosphoserine, as well as the stimulation of immune

to the LALES study);

capacity and a possible improvement of the mood of

3.

Papillary excavation with cup/disk < 0.5;

some subjects with neurosis28-29-30. With the

4.

BCVA = 10/10 with a correction not

administration of Phosphoserine in the left

superior to ± 3.5D;

randomized single eye of the glaucomatous patient,

5.

PEV with increased latency (p > 100);

one can inquire as to the base of a therapeutic

6.

Absence of concomitant neurological and/or

rationale with positive effects in the slowing down of

systemic ocular pathologies;

apoptotic processes charging the optic nerve [22].

Exclusion criteria were the following: 1.

Patients affected by retinal vascular pathologies;

MATERIALS AND METHODS 2.

A prospective randomized controlled randomized

Patients affected by either type I or type II Diabetes Mellitus.

double blind study of a 12 month duration was carried out (May 2009-May 2010) with a total of 51

In phase zero of the study, all of the selected patients

patients between the ages of 35 and 61 years (average

were subjected to a complete ocular check-up

age of 46 years; standard deviation of ± 3.8) of which

including a measurement of visual acuity, a

there were 24 males and 27 females, each affected by

biomicroscopic exam, a tonometric exam with

Chronic Simple Glaucoma (CSG) and each

Goldmann applanation, and an optic disk exam (with

undergoing topical hypotonic therapy (a combination

+90D Volk lens). All patients underwent a

of timolol, carbonic anhydrase inhibitors and

computerized perimetric examination at 30-2 full

prostaglandin inhibitors: maximal medical therapy

threshold, an analysis of optic nerve fibers via GdDx,

for glaucoma). The study was performed with

and the staging of glaucoma according to the

informed consent and following all the guidelines for

Glaucoma Staging System.

experimental investigations required by the The patients included in our study were randomly

Institutional Review Board or Ethics Committee of

subdivided into two groups:

which all authors are affiliated. All patients were selected in relation to the following “inclusion

-Group A: 28 patients (12 males; 16 females)-

criteria”:

experimental study group;

1.

Initial parametric alterations of the

-Group B: 23 patients (12 males; 11 females)-) -

computerized visual field;

control group.

4

Formattato: Tipo di carattere: 10 pt, Apice Formattato: Tipo di carattere: 10 pt

All patients, of both group A and group B, signed an

measurements. A p value less than 0.05 was

informed consent agreement at the beginning of the

considered statistically significant (Ttable 1). MD

study.

values, CPSD values, nerve fiber thickness values, and IOP values of group A (at the beginning of

We have used Phosphoserine at a concentration of

treatment and during follow-up) were reported in

60mg/100ml on the basis of Visually Evoked

Table 2, while group B values were reported in Table

Potential (VEP) in different dosages evaluating the

3. Pairwise comparisons were performed with the

critical threshold of response. Increasing the dose

Borferroni test (the mean deference is significant at

above the 60mg/100ml we had a reduction of the

the 0.05 level, Table 4).

P100 wave's latency, instead the dose of 60mg/100ml we obtained a constant response.

RESULTS

A daily preparation of Phosphoserine at a

All patients were checked after 1, 3, 6, and 12 months

concentration of 60mg/100ml was administered in

via the same exams used pre-administration. The

oral solution to all of the patients in group A (study

Mean Deviation (MD) and the Corrected Pattern

group). Said The oral solution was administered at an

Standard Deviation (CPSD) were separately

elevated bioavailability in cycles of 14 consecutive

evaluated for all visual fields. All data underwent

days per month (not more, to avoid toxicity), for nine

statistical analysis using the computer program oneway ANOVA in order to study variance while the

months.

program x2 was used to evaluate statistical All of the patients in group B (control group)

significance (a p value less than 0.01 was considered

underwent a placebo treatment (in the left eye) in

statistically significant). Similar static analysis was

cycles of 14 consecutive days per month, for nine

applied in order to evaluate the variation of the

months.

thickness of nerve fibers (RNFL thickness) and of the

Both treatments were carried out maintaining a

IOP. MD values, CPSD values, nerve fiber thickness

hypotonic topical therapy (a combination of timolol,

values, and IOP values of group A (at the beginning

carbonic anhydrase inhibitors and prostaglandin

of treatment and during follow-up) were reported in

inhibitors: maximal medical therapy for glaucoma).

Table 1, while group B values were reported in Table 2. From critical evaluation of the perimetric data, a

Statistical Analysis

slight improvement of the visual field emerged which was statistically significant (p < 0.051) for the

All patients were checked after 1, 3, 6, and 12 months

subjects included in group A and which was

via the same exams used pre-administration. The

evaluated in terms of MD and CPSD after an daily

Mean Deviation (MD) and the Corrected Pattern

oral administration with a concentration of

Standard Deviation (CPSD) were separately

60mg/100ml of Phosphoserine for a complete cycle

evaluated for all visual fields. All data underwent

of 9 months. Such an improvement was an evident

statistical analysis using the analysis of variance

result after only the first 30 days of treatment of the

(ANOVA) computer program ANOVA for repeated

5

Formattato: Tipo di carattere: 10 pt, Sottolineato Formattato: Tipo di carattere: 10 pt

subjects included in group A and remained constant

ganglion cells on the part of some substances with

for the 3, 6, and 12 month check-ups after the

neuro-toxic effects, produced by degenerate ganglion

beginning of the treatment. A different trend was

cells. These molecules are represented by glutamate,

recorded in the evaluation of the perimetric data of

nitric oxide, and free radicals - all of which favor

group B, where the MD did not undergo statistically

neuro-degeneration [15-23-24].

significant variations (p < 0.051, where no Neuro-protection must therefore be tuned to the

statistically significant p>0.05) with respect to the

salvation of ganglion cells which are still integral in

data recorded at the beginning of the study as

nature and which are not involved or marginally

reported in Figure 1. The substantial stability of the

affected by either primary of secondary degenerative

CPSD data, in all patients, indicates the

effects [25-26].

trustworthiness of the perimetric test performed and also indicates that the damage detected from the

The evidence that, after the administration of

exam is the result of a persistent localized defect as

Phosphoserine, (a substance with an anti-oxidant

reported in Figure 2. From the analysis of data

activity and which reduces extracellular

obtained from the measurement of the nerve fiber

concentrations of glutamate) can improve the MD of

layer, a greater stability of the values of group A

visual fields with a slight tomild-to- moderate defect,

patients with respect to the values of group B patients

probably by acting on cells which have not

was found to be statistically significant (p < 0.051) as

undergone an irreversible damage, supports the

reported in Figure 3. The IOP measurement in pre-

theory of neuro-protection301. Thus neuro-protection

treatment and during follow-up showed a statistically

is proposed as an area of research with a leading role

significant reduction (p < 0.051) of the pressure

in glaucomatous patient management. Phosphoserine,

values of patients treated with Phosphoserine, a result

in conjunction with hypotonic topical therapy, could

Formattato: Tipo di carattere: 10 pt, Apice

which was not evidenced by the patients treated

be of usea useful tool in the management of the

Formattato: Tipo di carattere: 10 pt

solely with placebo as reported in Figure 4. None of

glaucomatous patient. However, even given the good

the patients treated with Phosphoserine showed

reliability of the results of this study, the limited

adverse effects to the treatment.

number of patients examined and the possible influence of a learning factor make additional studies

DISCUSSION

necessary in order to confirm the true neuroExperimental studies have shown that nerve fiber

protective role of the substance Phosphoserine. Given

damage begins after the first acute attack and

our understanding, this is the first documentation of

progresses independently of having obtained a

the effect of Phosphoserine on Chronic Simple

successive check of the IOP. This process seems to

Glaucoma (GCS).

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Table 4: Pairwise comparisons with the Borferroni test (the mean deference is significant at the 0.05 level).

Figure 1: Evaluation of the Mean Deviation (visual fields analysis 30-2 Full Threshold) of the subjects included in group A and B. Figure 2: Evaluation of the Corrected Pattern Standard Deviation (CPSD) of the subjects included in group A and B. Figure 3: Evaluation of the variation of the Retinal Nerve Fiber Layer thickness (RNFL) of the subjects included in group A and B. Figure 4: Evaluation of the variation of the Intraocular Pressure (IOP) of the subjects included in group A and B.

10