The Pharmacological Approaches in NTG Therapy: Comparison
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Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by Marco Zeppieri.

Normal tension glaucoma (NTG) is defined as a subtype of primary open-angle glaucoma (POAG) in which the intraocular pressure (IOP) values are constantly within the statistically normal range without treatment and represents approximately the 30–40% of all glaucomatous cases. NTG first recognized as a clinical entity by von Graefe in 1857 [4], is a subtype of primary glaucoma characterized by open-angle and IOP values constantly within the statistically normal range without treatment.

  • normal tension glaucoma
  • intraocular pressure
  • medical therapy
  • glaucomatous optic neuropathy

1. IOP-Dependent Therapies: The Drugs Used to Reduce the IOP in NTG

The literature data strongly indicate that the mainstay of current NTG treatment is the reduction of IOP [30[1][2],68], and the first-line treatment involves the use of hypotensive eye drops [68][2]. IOP can be lowered medically either by decreasing the aqueous production or by increasing the trabecular or the uveo-scleral outflow pathways.
The drugs currently used in NTG therapy for their pre-eminently IOP-lowering effect are listed in Table 1.
Table 1.
Pharmacological effects of the drugs used to reduce the IOP in glaucomatous patients.
Substances   IOP-Lowering Effect     OBF Modification     Neuroprotection    
  Animal OAG NTG Animal OAG NTG In Vitro Animal OAG NTG
  Models Patients Patients Models Patients Patients Models Models Patients Patients
PGA and prostamide analogs D D D D > D > D > D D    
Latanoprost D D D D > D > D >        
Travoprost D D D D > D > D >        
Bimatoprost D D D D > D > D > D D    
Tafluprost D D D D > D > D > D D    
NO-donating PGA analogs                    
Latanoprostene bunod D D D              
β-adrenergic antagonists                    
Timolol D D D D < D <   D D    
Carteolol D D D D > D >   D D S S
Levobunolol D D D D > D >   D D    
Betaxolol D D D D > D >   D D S S
Carvedilol D     D >     D D    
Nebivolol D     D > D >          
α-2-adrenergic agonists          
[27][28]. Moreover, dorzolamide has demonstrated a neuroprotective effect in reducing the RGCs apoptosis in vitro [91][28].
-Miotics (Pilocarpine): This agent, an alkaloid isolated from a South American plant (Pilocarpus jaborandi), is the first known topical anti-glaucoma medication introduced in 1875. Pilocarpine lowers the IOP by traction of the scleral spur induced by an increased parasympathetic tone of the ciliary muscle, resulting in enhanced trabecular outflow [71,92][3][29]. The mean IOP reduction is approximately 20–25% [71,92][3][29].
Possible side effects are increased myopia, decreased vision, cataracts, periocular contact dermatitis and ocular congestion [71,92][3][29]. Moreover, treatment with pilocarpine requires administration four times daily, resulting in low patient compliance. Pilocarpine is deemed to have a neuroprotective effect by maintaining calcium homeostasis and mitochondrial membrane integrity [25][22].
Previous authors, investigating the IOP-lowering effect of pilocarpine as monotherapy in NTG patients, have shown modest efficacy, with an IOP reduction of at least 30% from baseline in only 13% to 27% of cases [93][30].
-Rho-associated protein kinase (ROCK) inhibitors: The ROCK inhibitors, many of which are actually under phase II and phase III studies, reduce IOP by disrupting the cytoskeleton and relaxing the smooth-muscle-like cells of the trabecular meshwork and Schlemm’s canal tissues, thus increasing the aqueous humor trabecular outflow [77,94,95][10][31][32]. The mean IOP reduction induced by the ROCK inhibitors is approximately 10–20% [94,95][31][32].
ROCK inhibitors have shown a high incidence of local adverse effects, including conjunctival hyperemia, eye pain, irritation, pruritus and discharge, whereas no systemic side effects are reported [77,94,95][10][31][32].
The ROCK inhibitors have also been shown to increase the ONH blood flow via vasodilatation of the ciliary arteries [94][31]. Moreover, they have demonstrated a neuroprotective effect on the RGCs and a regenerative effect on the ONH axons through the modulation of the RGC apoptosis in both in vitro and animal models [25][22].
A prospective, multicenter, randomized, double-masked, placebo-controlled phase II study evaluating the hypotensive efficacy and safety of the sovesudil, a novel ROCK inhibitor, in NTG patients, showed that a 0.5% ophthalmic solution of sovesudil administered three times daily has a statistically significant IOP-lowering effect as compared with placebo, with mild adverse events, including conjunctival hyperemia in 25% of cases [95][32].
Netarsudil is a potent Rho kinase/norepinephrine transporter inhibitor that has recently received approval from both the FDA and the European Medicines Agency (EMA) for treating patients with OAG and OHT, and it will be shortly available on the market [77][10].
It acts by decreasing the aqueous production, increasing the trabecular outflow and possibly decreasing the episcleral venous pressure [96][33]; moreover, it has the convenience of a once-daily dosage.
Multicenter, double-masked phase III clinical trials have demonstrated the non-inferiority of netarsudil when compared to timolol in the treatment of OAG and OHT patients [96][33]. Moreover, netarsudil has shown to be more effective in subjects with baseline IOP ≤ 26 mmHg, likely because of its ability to decrease the episcleral venous pressure [96][33], suggesting a rationale role in the NTG therapy.
The reported local side effects of netarsudil include conjunctival hyperemia (50–60% of cases), subconjunctival hemorrhages, cornea verticillata, eyelid erythema, increased lacrimation, instillation-site pain and blurred vision, whereas no systemic adverse effects were observed [96][33].
-Combination therapy: The use of more than one drug is needed in NTG patients in which a 30% reduction in IOP is not achieved with monotherapy, leading to an increased frequency of eye-drop administrations and possible side effects and higher costs. Fixed drug combinations have the advantage of combining substances with additive mechanisms of action and reducing the number of drops administered, showing therefore higher efficacy and better compliance than mono- or multiple drugs.
Fixed combinations of dorzolamide/timolol and brimonidine/timolol have been demonstrated to be safe and effective IOP-lowering drugs in NTG patients, without affecting the ocular perfusion [71][3].
The fixed combination of netarsudil and latanoprost has been recently approved by the FDA for the treatment of OAG and OHT patients with only one daily administration [77][10]. This drug combination is the only glaucoma medication that acts on all IOP-reduction mechanisms, i.e., increasing both trabecular and uveo-scleral outflow and decreasing aqueous production and episcleral venous pressure. Recent multicenter, randomized, double-masked clinical trials on OAG and OHT patients have demonstrated that the fixed combination of netarsudil and latanoprost provides an IOP-lowering effect of ≥30% and local side effects similar to its individual components [77][10].

2. The IOP-Independent Therapies

The IOP-independent strategy for NTG therapy is a relatively new concept that includes two main purposes:
(1)
Maintenance and/or increase of the ONH blood perfusion and/or oxygenation;
(2)
Neuro-protection, i.e., prevention and/or reduction of the degeneration and death of the RGCs, and/or RGCs regeneration.
Substances targeting the axonal damage and the RGCs apoptotic cascade, having therefore antioxidant, anti-inflammatory, anti-apoptosis or vaso-active properties, may therefore represent an alternative approach to the NTG treatment [23,24,25,36,40,41,97,98,99,100,101,102][22][25][34][35][36][37][38][39][40][41][42][43].
The following section summarizes the drugs and dietary supplements that have shown the ability to increase OHN perfusion or to have neuroprotective properties on RGCs in vitro, in glaucoma animal models in vivo, or in preclinical or clinical trials on glaucomatous patients.

2.1. Dietary Supplements in the NTG Treatment

The “dietary supplements” are defined by the FDA as substances, including vitamins, minerals, botanicals, herbs or dietary elements, used to supplement the diet by increasing the total dietary intake, in order to correct nutritional deficiencies, maintain an adequate intake of certain nutrients or to support specific physiological functions [98,99,100,102][39][40][41][43]. In contrast to drugs, which are designed to treat illnesses or diseases, dietary supplements cannot provide any pharmacological, immunological or metabolic actions [89,90,91,92,93,94,95,96,97,98,99,100,102][24][27][28][29][30][31][32][33][38][39][40][41][43]. On the basis of this regulatory definition, the producers cannot therefore claim any clinical effect of dietary supplements on glaucoma unless these substances have been investigated and registered for use as a drug. Some of these substances are currently in phase II or III of drug development.
The dietary supplements that could have a rationale in the NTG treatment are summarized in Table 2 and are as follows:
Table 2.
Biological effects of the dietary supplements used in glaucomatous patients.
Substances   IOP Changes     OBF Changes     Neuroprotection    
  Animal OAG NTG Animal OAG NTG In Vitro Animal OAG NTG
  Models Patients Patients Models Patients Patients Models Models Patients Patients
Flavonoids       D > D >   D D    
Ginkgo biloba extract       D > D > D > D D S S
Camelia sinensis or Green tea       D >     D D S S
Anthocyanins   D <     D > D > D D S S
Epigallocatechin-3-gallate             D D S  
Resveratrol             D D    
Citicoline             D D D * S
Coenzyme Q10 (ubiquinone) D <           D D S  
Forskolin D < D <         D D S  
Panax Ginseng         D > D > D D S  
Curcumin             D D    
Cannabinoids D < D <         D      
Palmitoylethanolamide (PEA)   D < D <         D S S
Nitric oxide (NO) D < D < D <              
         
Brimonidine D D D       D D S S
Carbonic anhydrase inhibitors                    
Dorzolamide D D D D > D > D > D      
Brinzolamide D D D              
Acetazolamide D D D              
Miotics                    
Pilocarpine D D D       S      
ROCK inh.                    
Sovesudil D D D D > D >   D D    
Netarsuldil D D D D > D >   D D    
IOP = intraocular pressure; OBF = ocular blood flow; OAG = open-angle glaucoma; NTG = normal tension glaucoma; D = demonstrated, i.e., supported by strong scientific evidence; S = supposed, i.e., supported by weak scientific evidence; > = increase; < = decrease; PGA = prostaglandin; NO = nitric oxide; ROCK = Rho-associate protein kinase.
-Prostaglandin (PGAs)F2α analogs and prostamide analogs (latanoprost, travoprost, bimatoprost and tafluprost): Since the introduction of latanoprost in 1996, these drugs have become the first-line treatment in POAG and NTG medical therapy because they have shown the highest efficacy in reducing IOP with adequate diurnal and nocturnal IOP control, good safety profile and the convenience of only one application per day, which results in higher patient’s compliance [68,71,72,73][2][3][4][5].
These medications induce an IOP reduction of approximately 25–33% by increasing the uveo-scleral outflow secondary to the widening of the ciliary muscle and, to a lesser extent, by enhancing the trabecular meshwork outflow [72,73][4][5].
These medications demonstrated to be able to lower the IOP over 24 h and to reduce the nocturnal IOP peaks [72][4], which are considered to be one of the risk factors in the progression of NTG [35][6]. In particular, latanoprost has been shown to maintain the IOP reduction and the enhancement of the uveo-scleral outflow during the nighttime, whereas the ocular hypotensive effect of the timolol is abolished during the nocturnal/sleep period [71,74][3][7].
PGAs and prostamide analogs have shown good long-term safety profiles. Potential adverse effects include increased eyelash growth, periocular hyperpigmentation, palpebral and conjunctival hyperemia, allergic conjunctivitis, keratitis and herpes virus activation; most importantly, the systemic side effects are rare and minimal. Nonetheless, because of their pro-inflammatory effect, the use of these drugs is discouraged in patients with active ocular inflammation and cystoid macular edema [73][5].
Moreover, PGAs analogs were demonstrated to increase the ocular blood flow in NTG patients [75][8]. Latanoprost, bimatoprost and tafluprost have demonstrated a neuroprotective effect on the RGCs in vitro and in animal models [76][9].
-Nitric-oxide-donating PGAs analogs: Latanoprostene bunod is a nitric-oxide-donating prostaglandin F2α analog that has recently received approval from the Food and Drug Administration (FDA) in the US for reducing IOP in patients with OAG or OHT, which will be available in Europe in the near future [77][10].
This drug increases the aqueous outflow both by uveo-scleral and trabecular pathways [77][10].
Multicenter, randomized, double-masked, phase III clinical trials have demonstrated that the latanoprostene bunod is effective in lowering the IOP in OAG and OHT patients both during the diurnal/wake and nocturnal/sleep periods, showing a lowering effect significantly higher than that of latanoprost and timolol, with a side effect profile similar to that of prostaglandin analogs [77][10].
-Beta-adrenergic antagonists (beta-blockers) (timolol, levobunolol, carteolol, betaxolol, carvedilol and nebivolol): Since the introduction of timolol for glaucoma therapy in 1979, these drugs have been considered as the first-line ocular hypotensive therapy for approximately 25 years [78][11].
Beta-blockers can be divided into nonselective beta-adrenoceptor antagonists, including timolol, carteolol, levobunolol and carvedilol, and selective beta-1-adrenoceptor antagonists, including betaxolol and nebivolol, which have been demonstrated to induce fewer side effects on cardiac and pulmonary functions in comparison with nonselective beta-blockers [78,79][11][12].
Beta-blockers induce a diurnal IOP reduction of 20–25% by decreasing aqueous humor production from the epithelial cells of the ciliary body [78][11]. Sleep laboratory studies have demonstrated that beta-blockers do not have any IOP-lowering effect during the nocturnal/sleep time [42,71,74,78][3][7][11][13]. Due to a decrease in endogenous circulating catecholamine levels, the aqueous humor production is significantly lower during the night, which may explain the decreased nocturnal efficacy of the beta-blockers [42,71,74,78][3][7][11][13].
Potential side effects of the beta-blockers include allergic conjunctivitis, keratitis, bronchospasm, vasospasm, bradycardia, systemic systolic and diastolic hypotension and heart rate reduction [78,79][11][12].
Carteolol is a nonselective beta-adrenoceptor blocker with partial agonist activity [80][14]. These eyedrops, in comparison with those of timolol, although showing comparable IOP-lowering efficacy, lack local anesthetic activity, with consequently less ocular surface irritation, and induce a reduced decline in heart rate or dyspnea, likely due to the partial agonist activity of the carteolol [80][14].
Levobunolol is a nonselective beta-blocker that has shown an IOP-lowering efficacy similar to that of timolol and a concomitant vasodilatory effect on the vascular smooth muscle cells, likely due to the block of calcium channels [81][15].
Betaxolol is a selective beta-1-adrenoceptor antagonist [82][16]. The use of this eyedrop in NTG is controversial. Studies have shown that similar to timolol, betaxolol can induce hypotensive dipping of blood pressure during nighttime, with detrimental effects on the VF damage progression [83][17]. Comparative clinical trials investigating the use of local beta-blocker for managing NTG have shown a greater reduction in IOP with timolol, however, better VF preservation using betaxolol [82][16], suggesting that the decrease in blood pressure due to the systemic effect of nonselective beta-blockers could have a negative effect on the preservation of visual function.
Carvedilol is a relatively new nonselective beta-blocker with multiple other actions, including antioxidant activity, vasodilatation, inhibition of apoptosis, anti-inflammatory activity, calcium channel blocking and mitochondrial protective effects [84][18]. Studies have shown that this drug reduces IOP following both topical and oral administration in vivo in animal models [85,86][19][20].
Nebivolol is a novel beta-1-selective adrenoceptor antagonist that has been shown to decrease IOP following both topical and oral administration in animal models [85][19].
Betaxolol, carteolol and levobunolol eye drops have been associated with increased ONH blood flow in glaucoma patients [78,80,81,82][11][14][15][16]. Carvedilol has shown the ability to improve ocular microcirculation in animal models after topical or oral administration by blocking the alfa-adrenergic receptors [85][19]. Nebivolol has been shown to improve the ocular blood flow in rabbits [85][19] and in glaucoma patients suffering from concomitant arterial hypertension after oral administration [87][21]. The effect of nebivolol on ocular hemodynamics is likely related to its known peripheral vasodilatory effects due to its NO-releasing properties [87][21].
Beta-blockers have shown neuroprotective properties in vitro and in animal models, which have been proposed to be related to their ability to reduce the amount of glutamate entering and damaging the RGCs and to their calcium-channel-blocking properties [25,78,84,86][11][18][20][22].
In general, the use of beta-blockers in NTG is debatable because of their possible negative effect on the ONH blood flow. These drugs have known vasoconstrictive properties. Moreover, the absorption of topical beta-blockers into the systemic circulation and the administration of an evening oral dose of beta-blockers have been demonstrated to increase the physiologic nocturnal arterial systolic and diastolic hypotension and to reduce the heart rate and the blood oxygen saturation [42,71,78][3][11][13]. Supporting these concerns, previous studies have demonstrated that the treatment of NTG patients with timolol or betaxolol increases the risk for VF deterioration [83][17].
Recent clinical trials on NTG patients have shown that betaxolol and carteolol had a protective effect on the VF indices which was IOP-independent [88][23].
-Selective alpha-2-adrenergic-agonist (Brimonidine): Brimonidine has shown the ability to reduce the IOP production and to improve the uveo-scleral outflow consequent to a slight pupil dilatation [78,89][11][24].
The IOP-lowering effect induced by brimonidine is approximately 20–25% [89][24], and it appears to be effective only during the diurnal/wake period, whereas it appears minimal during the nocturnal/sleep period [89][24].
Because of its high selectivity for alfa-2 than for alpha-1 adrenergic receptors, the brimonidine did not induce mydriasis and vasoconstriction of the retinal vessels [78,89][11][24]. Possible side effects are allergic and follicular conjunctivitis, dry mouth and nose and systemic hypotension [89][24]. Quaranta et al. found a greater reduction in mean 24 h systolic and diastolic blood pressure with brimonidine than with timolol [42][13].
Brimonidine has shown the ability to inhibit the apoptosis of the RCGs in vitro and in vivo animal models possibly through the up-regulation of the neurotrophins, in particular, the so-called brain-derived neurotrophic factor (BDNF) [25,40][22][25].
Moreover, the Low-Pressure Glaucoma Treatment Study (LoGTS), a multicenter, prospective, randomized, double-masked clinical trial in which 190 NTG patients were randomized to receive timolol or brimonidine eyedrops as monotherapy, showed that patients treated with brimonidine were less likely to show VF loss progression than those receiving timolol, despite similar IOP reductions in both groups [70][26], suggesting that brimonidine could provide an adjunctive neuroprotective effect beyond IOP-lowering or, alternatively, that timolol could have a neuro-destructive action, likely related to its lowering effect on systemic blood pressure and pulse rate [70,78][11][26]. It is important to note that approximately one-third of the patients receiving brimonidine in the LoGTS stopped the therapy because of side effects, especially allergic conjunctivitis [70][26].
Furthermore, a recent clinical trial on NTG patients showed that brimonidine, and also betaxolol and carteolol, had a protective effect on the VF indices which was independent of the IOP-lowering efficacy [88][23].
-Carbonic anhydrase inhibitors (CAIs) (dorzolamide, brinzolamide and acetazolamide): They inhibit the carbonic anhydrase isoenzyme 2, reducing the IOP production, with a baseline IOP reduction of approximately 15–20% for topical and 20–30% for oral administration [90,91][27][28]. The CAIs have been demonstrated to lower IOP for 24 h, also during the nocturnal/sleep period [74,90,91][7][27][28].
Potential adverse effects include allergic dermatitis, corneal edema, Stevens–Johnson syndrome, malaise, anorexia, depression and renal calculi [90][27].
Topical dorzolamide has been shown to induce a significant improvement in almost all hemodynamic parameters of intraocular and periocular vessels in both normal and glaucomatous eyes [90,91]
Crocus sativus L. or Saffron
 
D <
 
 
 
 
D D    
Crocin and Crocetin       D >     D D    
Taurine             D D    
Lycium barbarum             D D    
Erigeron Breviscapus Hand. Mazz. D <           D S S  
Hesperidin             D D    
Scutellaria baicalensis Georgi D <           D D    
Diospyros kaki L. D <           D D    
Tripterygium wilfordii Hook F.             D D    
Lutein and Zeaxanthin             D D    
Caffeine D < D </>           D    
Nicotine         D <   D D    
Melatonin D < D <         D D    
Ethilic alcohol   D </>                
Vitamin A (retinol)                 S  
Vitamin B3 (niacine)/nicotinamide             D D S  
Vitamin B6 (pyridoxine)             D   S  
Vitamin B12 (cobalamin)             D     S
Vitamin C (ascorbic acid) D < D <         D D S  
Vitamin D (cholecalciferol) D <             D    
Vitamin E (alpha-tocopherol)         D >   D D S  
Omega-3 PUFAs D < D <           D    
Alfa-lipoic acid             D D    
Apolipoprotein-E             D D    
Zinc             D D    
Magnesium       D >     D D    
Hydrogen sulfide   D <         D      
Creatine             D      
Spermidine             D D    
Nuclear factor-kappa B             D D    
IOP = intraocular pressure; OBF = ocular blood flow; OAG = open-angle glaucoma; NTG = normal tension glaucoma; D = demonstrated, i.e., supported by strong scientific evidence; S = supposed, i.e., supported by weak scientific evidence; > = increase; < = decrease; PFA = polyunsaturated fatty acids; * = also demonstrated in patients affected by neurological disorders, such as Parkinson’s and Alzheimer’s diseases, dementia and stroke.
-Ginkgo biloba extract (GBE): It is a natural chemical compound found in the leaves of a tree indigenous to Korea, Japan and China [98,99,100,102,103][39][40][41][43][44]. Originally used in Chinese traditional medicine as a treatment for different medical conditions, the GBE was first introduced in Europe in 1965 known as EGb761. The commercially available GBE provides 60 bioactive compounds, mainly consisting of flavonoids (24% to 27% of the extract) and terpenoids (5% to 7% of the extract) [103][44].
The GBE has been demonstrated to have several different effects [98,99[39][40][41][43][44],100,102,103], including:
  • Vasodilatation and enhancement of the cerebral blood flow;
  • Antioxidant properties related to its free radical scavenging activity;
  • Anti-inflammatory effect, inducing a decrease in the levels of the pro-inflammatory prostaglandins and cytokines;
  • Regulation of mitochondrial activity, especially by reducing the mitochondria’s oxidative stress;
  • Anti-apoptotic activity by the downregulation of pro-apoptotic genes;
  • Hemorheological regulation effect, by increasing the erythrocyte deformability and because of a fibrinolytic effect;
  • Neuroprotective activity: GBE provides neuroprotection against ROS, calcium overload, nitric oxide and beta-amyloid-induced toxicity and ischemic-reperfusion-inducing toxicity;
  • Neurotransmission regulation, by regulating the gene expression of neurotransmitter receptors;
  • Hormonal regulation: GBE increases the expression of several hormones, such as thyroid, growth hormones and prolactin, which are essential for neuronal proliferation and differentiation, cognitive capacity related to memory, alertness, motivation and working capacity, and it has been proven to be beneficial in the treatment of cognitive disorders, including dementia;
  • Anti-neoplastic activity, by regulating the expression of proteins involved in DNA damage signaling, repair and gene expression.
Within the specific prescribed dosage, the GBE has shown minimal side effects, which include stomach upset, headache, dizziness, constipation, palpitation and allergic skin reactions [102,103][43][44].
GBE has shown neuroprotective capacity in experimental animal models of chronic glaucoma [102,103][43][44]. Several studies have investigated the effects of the GBE on NTG patients [98[39][40][41][43][44],99,100,102,103], showing the following data:
  • Absence of statistically significant effect on the IOP values;
  • Significantly higher peri-papillary blood flow when compared to placebo;
  • Controversial results on the VF indices;
  • Significant delay in the VF loss progression.
Despite promising results, the lack of rigorous registration studies does not allow to draw firm conclusions on the use of GBE in NTG [103][44].
-Resveratrol: It is a polyphenol commonly found in fruits such as berries and nuts and in the skin of red grapes and red wine, having many properties, including cardioprotective, neuroprotective, antioxidative, anti-inflammatory, antidiabetic and anti-tumoral effects [98,100,102,104][39][41][43][45]. Also, it has shown a neuroprotective effect on RGCs and their axons in cell culture and animal models [104][45].
-Citicoline: It is an endogenous compound crucial for cellular functioning, which undergoes rapid metabolism to form cytidine and choline [105,106][46][47]. It acts as an intermediate in the biosynthesis of cell membrane phospholipids and as a precursor for the neurotransmitter acetylcholine [106][47]. Furthermore, it increases the levels of acetylcholine, dopamine, noradrenaline and serotonin in several brain regions and the dopamine release in the retina [105][46].
Citicoline has a neuroprotective effect, due to the protection of the cell membranes, in particular the mitochondrial ones [105][46].
As a dietary supplement, citicoline has been used in many neurodegenerative diseases, including Parkinson’s and Alzheimer’s diseases, dementia, stroke and glaucoma [105[46][47],106], showing negligible toxicity [106][47].
Citicoline has demonstrated neuroprotective properties on the RGCs both in vitro and in glaucoma animal models [106][47].
Although previous studies failed to show any evidence of citicoline deficiency in glaucomatous patients [106][47], the intramuscular or oral administration of citicoline for at least 2 months in OAG patients has been associated with an improvement in all pattern electroretinogram (PERG) and pattern visual evoked potential (VEP) indices [98][39], whereas the treatment with citicoline eyedrops was associated with a significant slowing down of the VF damage progression [107][48].
Based on these results, citicoline has been approved by the European Union and the Italian Ministry of Healthy as a dietary food supplement for special medical purposes in glaucoma patients [106][47].
-Coenzyme Q10 or Ubiquinone-10: It is an important cofactor of the mitochondrial electron transport chain and a potent antioxidant [41,98,99,102,108][37][39][40][43][49]. It is predominantly present in animal organs, especially in the heart, liver and kidney, and it is also found in several foods, like meat, fish, soy oil and peanuts [98,102,108][39][43][49]. Due to the large molecular weight and lipid-solubility, ubiquinone-10 has poor intraocular penetration, and for these reasons, it is usually used in combination with vitamin E, which increases its bioavailability [98,102,108][39][43][49].
Several in vivo and in vitro studies have demonstrated its anti-apoptotic effect on the RGCs in glaucoma models [25,40,108][22][25][49].
OAG patients treated with a topical combination of coenzyme Q10 and vitamin E for at least 6 months have shown a significant enhancement of both PERG and VEP responses [109][50].
-Camellia sinensis (L.) Kuntze or Green tea: Green tea beverage is made from the infusion of the leaves of Camellia sinensis and contains flavonoids, especially catechins, and alkaloids (such as caffeine and theobromine). The major catechin present in green tea is epigallocatechin-3-gallate (EGCG), which is also found in high concentrations in red wine, dark chocolate, legumes and nuts.
Both EGCG and the green tea extract in toto have shown anti-apoptotic, antioxidant and anti-inflammatory properties on the RGCs in vivo and in vitro models [98,99,100,102][39][40][41][43].
A clinical study showed that the oral administration of EGCG induced an increase in the PERG indices in OAG patients [110][51].
-Panax Ginseng: It is one of the most used medical herbs in Asia [98,100,102][39][41][43].
It has demonstrated antioxidative and anti-apoptotic properties on the RGCs in vitro and in animal models [98,100,102][39][41][43].
The diet supplementation of OAG patients with Panax Ginseng showed significant retinal peripapillary blood flow improvement [98,100,102][39][41][43].
-Anthocyanins: They are a kind of polyphenols abundant in berries, currants, grapes and some tropical fruits, which have been demonstrated to have antioxidant, anti-inflammatory, anti-cancer, anti-angiogenesis, anti-diabetic, anti-obesity and anti-microbial effects [100,102,111][41][43][52].
They have been shown to increase the survival of RGCs in both in vitro and in vivo models [102][43] and to be able to normalize the serum endothelin-1 levels in glaucoma patients [100][41].
A pilot study found that the administration of black currant anthocyanin in NTG patients for 6 months induced a significant increase in ONH and peripapillary retina blood flow, with no significant IOP and VF changes, and that the intake for 2 years reduces the VF deterioration in NTG patients compared to placebo, with no IOP changes [111][52].
-Cannabinoids: They are compounds found in the Cannabis sativa plant, commonly known as marijuana, and represent one of the most used psychoactive substances in the world. Cannabinoid-like substances released by the neurons and referred to as endocannabinoids have been discovered in 1992 [102,112][43][53].
The cannabinoids exert their effects by interacting with specific endocannabinoid receptors present in the central nervous system [112][53] and, depending on the brain area involved, include alteration of memory, cognition, psychomotor performances, pleasure responses and pain perception.
In both in vitro and in vivo studies, the cannabinoids have been demonstrated to decrease IOP by both reducing the production and increasing the aqueous humor outflow and also protecting the RGCs against glutamate-induced excitotoxicity [40,113][25][54].
Furthermore, a significant transient IOP reduction from 30 min to 4 h after the cannabinoid inhalation has been demonstrated in both OAG patients and healthy subjects [40,102,112,113][25][43][53][54].
-Palmitoylethanolamide (PEA): It is a lipid mediator synthesized during inflammation and tissue damage, with neuroprotective, anti-inflammatory and analgesic properties [98,114][39][55]. It is present in various foods (eggs, soybeans, peanuts, etc.), and it is marketed as a medical food at the dosage of 600/12,000 mg/day in several European countries, including Italy [114][55].
Based on its pharmacological properties, it is speculated that PEA can act by increasing the aqueous humor trabecular outflow, inducing vaso-relaxation in the ophthalmic arteries and stimulating the cannabinoid system [115][56].
PEA has demonstrated neuroprotective efficacy on the RGCs in animal models [114][55]. Previous authors have demonstrated that the systemic administration of PEA for at least 6 months in NTG patients reduced IOP and improved the PEV and PERG indices, without side effects [115][56].
-Vitamins supplementation: Vitamins are organic compounds and essential micronutrients found in plants and animals. The potential neuroprotective effect of vitamins is thought to be mainly related to their antioxidant activity [25,41,98,99,100,102][22][37][39][40][41][43].
Several previous studies have shown that, in comparison with healthy subjects, NTG patients have significantly lower levels of vitamin E, vitamin B3 (nicotinamide or niacin), retinol (vitamin A) and vitamin C [41,98,99,100][37][39][40][41].
The vitamins B3, B6, B12, C, D and E have shown a neuroprotective effect on the RGCs in vitro and in glaucoma animal models [24,41,98,99,100,102][35][37][39][40][41][43]. Previous authors have demonstrated that diet supplementation with 300 mg/day of vitamin E induced a statistically significant improvement in VF indices and blood flow in the ophthalmic and posterior ciliary arteries. On the other hand, the oral B12 supplementation in NTG patients did not show any significant reduction in VF damage progression during a 4-year follow-up [25,98,102][22][39][43].
-Hydrogen sulfide (H2S): It is a gas-transmitter with several endogenous functions in mammalian tissues. It has been demonstrated to reduce the IOP by increasing the humor aqueous outflow, to scavenger ROS species and to increase the glutathione levels, protecting the RGCs from excitotoxicity [116][57]. Despite its potential, its use is limited by the delivery challenges related to its unique physiochemical properties [116][57].
-Other substances: Several other compounds have shown a neuroprotective effect on RGCs and their axons in cell culture or in animal models, in addition to beneficial biological properties in glaucomatous patients, which include lutein and zeaxanthin; nitric oxide; flavonoids; Crocus sativus L. or saffron; hesperidin; nicotine; ethylic alcohol; crocin and crocetin; zinc; magnesium; curcumin, spermidine; creatine; alfa-lipoic acid; apolipoprotein-E; nuclear factor-kappa B; omega-3 polyunsaturated fatty acids; melatonin; taurine; forskolin; Lycium barbarum; Erigeron breviscapus Hand. Mazz.; Scutellaria baicalensis Georgi; Diospyros kaki L.; Tripterygium wilfordii Hook F; caffeine [23,25,41,98,99,100,102][22][34][37][39][40][41][43].
-Caloric restriction: It has been shown to promote the RGCs cell survival in a mouse model of NTG likely by increasing the synthesis of neurotrophic factors, catalase and anti-apoptotic proteins and by decreasing the oxidative stress levels [117][58].

2.2. Drugs Used for Their IOP-Independent Effects in NTG Patients

Several drugs, approved for the treatment of other diseases, have shown to be useful in the NTG treatment, being thus suitable candidates for drug repositioning. These substances, listed in Table 32, include the following:
Table 32.
Biological effects of the drugs showing IOP-independent actions in glaucomatous patients.
Substances   IOP-Lowering Effect     Ocular Blood Flow Alteration     Neuro-Protection    
  Animal OAG NTG Animal OAG NTG In Vitro Animal OAG NTG
  Models Patients Patients Models Patients Patients Models Models Patients Patients
Calcium channel blockers       D >/< D >/< D >/< D D S S
Memantine             D S    
ACEIs D D         D      
Anticonvulsants (valproic acid)             D D    
Edaravone               D    
N-acetylcysteine               D    
Statins                 S S
Androgen deprivation therapy                 S S
Minocycline               D    
Azithromycin             D      
cAMP PI               D    
C-PAP                 S S
IOP = intraocular pressure; OBF = ocular blood flow; OAG = open-angle glaucoma; NTG = normal tension glaucoma; D = demonstrated, i.e., supported by strong scientific evidence; S = supposed, i.e., supported by weak scientific evidence; > = increase; < = decrease; PFA = polyunsaturated fatty acids; ACEIs = angiotensin-converting enzyme inhibitors; cAMP PI = cyclic adenosine monophosphate phosphodiesterase inhibitors; C-PAP = continuous positive airway pressure.
-Calcium channel blockers (CCBs) (nifedipine, nimodipine and verapamil): These drugs were introduced in the 1960s for the treatment of systemic hypertension and other cardiovascular diseases [118][59]. Although the CCBs are the only FDA-approved treatment addressing the vascular risk factors in glaucomatous patients, their efficacy for NTG therapy is still debated [25,71,118][3][22][59]. They have several ocular effects [71[3][59],118], including the following:
  • To improve the ONH and choroidal in healthy and glaucoma subjects, especially in NTG patients, by inducing vasodilatation in the posterior ciliary arteries, which has been demonstrated using color Doppler imaging and laser Doppler flowmetry;
  • To slow the progression of VFs defects and ONH damage in NTG, whereas the efficacy in POAG patients is debated;
  • To increase VF indices and color contrast sensitivity in NTG patients;
  • To reduce the glutaminergic neurotoxicity on the RGCs both in vitro and in glaucoma animal models, suggesting neuroprotective properties;
  • To induce systemic hypotension that may theoretically decrease the ONH perfusion. For this reason, the use of CCBs in glaucoma, especially in NTG, is controversial. Many authors suggest avoiding systemic anti-hypertensive medication and local beta-blockers at nighttime, because both beta-blockers and CCBs may have a negative impact on the perfusion and oxygenation of the ocular tissues [42,71,78,118][3][11][13][59].
-Memantine: This agent is a glutamate antagonist approved in Europe and the USA for the treatment of Alzheimer’s disease [24][35]. Although it has been demonstrated to slow the glaucomatous ONH damage progression in macaque monkeys [25][22], large prospective multicenter clinical trials in humans failed to show benefit in glaucomatous patients [119][60].
-Angiotensin-converting enzyme inhibitors (ACEIs): These drugs, widely used for the treatment of systemic hypertension, have shown a significant IOP-lowering effect in both POAG and OHT patients and neuroprotective properties in vitro [23][34].
-Anticonvulsants: Drugs like valproic acid have been approved for clinical use in the treatment of various conditions, such as epilepsy, migraines and neuropathic pain. It has been tested in an experimental mouse model of NTG, showing the ability to protect RGCs from oxidative stress [41,120][37][61].
-Edaravone: It is a drug, acting as a free radical scavenger, used for the treatment of acute brain infarction and amyotrophic lateral sclerosis. It has been demonstrated to be effective in preventing the death of RGCs in an NTG mouse model [121][62].
-N-acetylcysteine: It is a drug historically used as an antidote against paracetamol overdose and more recently used for several medical conditions. It has demonstrated neuroprotective efficacy by its antioxidant properties in NTG animal models [41][37].
-Statins: These are a class of drugs used as anti-cholesterol medication. A prospective clinical trial showed that simvastatin provided a protective effect in NTG patients [23][34].
-Androgen-deprivation therapy: This therapy, used in patients with prostate cancer, has been associated with a lower incidence of newly diagnosed NTG, suggesting a role of testosterone in the pathogenesis of NTG [122][63].
-Minocycline: It is a second-generation tetracycline with well-recognized anti-inflammatory properties. It provided neuroprotection in glaucoma animal models by preventing the microglia activation and blocking the apoptotic cascade of the RGCs [25,57][22][64].
-Azithromycin: It is a macrolide antibiotic with anti-inflammatory activity. It has been shown to reduce the apoptosis of the RGCs in an in vitro experimental model of glaucoma [25,57][22][64].
-cAMP phosphodiesterase inhibitors: Ibudilast has been proposed as a potential therapy for several neurodegenerative diseases and is under investigation for the treatment of multiple sclerosis. It has been demonstrated to promote the survival of RGCs in glaucoma animal models [25,57][22][64].
-Continuous positive airway pressure (C-PAP): Previous studies have demonstrated that the C-PAP therapy, in patients with both NTG and OSAS, is effective in stabilizing the VF defects, likely by improving ONH oxygenation and perfusion [123][65].

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