Cholinergic nervous system and glaucoma: From basic science to clinical applications.

The cholinergic system has a crucial role to play in visual function. Although cholinergic drugs have been a focus of attention as glaucoma medications for reducing eye pressure, little is known about the potential modality for neuronal survival and/or enhancement in visual impairments. Citicoline, a naturally occurring compound and FDA approved dietary supplement, is a nootropic agent that is recently demonstrated to be effective in ameliorating ischemic stroke, traumatic brain injury, Parkinson's disease, Alzheimer's disease, cerebrovascular diseases, memory disorders and attention-deficit/hyperactivity disorder in both humans and animal models. The mechanisms of its action appear to be multifarious including (i) preservation of cardiolipin, sphingomyelin, and arachidonic acid contents of phosphatidylcholine and phosphatidylethanolamine, (ii) restoration of phosphatidylcholine, (iii) stimulation of glutathione synthesis, (iv) lowering glutamate concentrations and preventing glutamate excitotoxicity, (v) rescuing mitochondrial function thereby preventing oxidative damage and onset of neuronal apoptosis, (vi) synthesis of myelin leading to improvement in neuronal membrane integrity, (vii) improving acetylcholine synthesis and thereby reducing the effects of mental stress and (viii) preventing endothelial dysfunction. Such effects have vouched for citicoline as a neuroprotective, neurorestorative and neuroregenerative agent. Retinal ganglion cells are neurons with long myelinated axons which provide a strong rationale for citicoline use in visual pathway disorders. Since glaucoma is a form of neurodegeneration involving retinal ganglion cells, citicoline may help ameliorate glaucomatous damages in multiple facets. Additionally, trans-synaptic degeneration has been identified in humans and experimental models of glaucoma suggesting the cholinergic system as a new brain target for glaucoma management and therapy.

Meditation enhances brain oxygenation, upregulates BDNF and improves quality of life in patients with primary open angle glaucoma: A randomized controlled trial.

BACKGROUND: Glaucoma (POAG) is a kind of neurodegenerative disease known to be closely associated with stress and adverse quality of life (QOL). Stress has also been shown to be involved in etiopathogenesis of primary open angle glaucoma (POAG). Complementary treatment in form of Meditation has been reported to improve QOL, brain oxygenation and decrease markers of stress. With this premise, a randomized controlled trial was carried out to assess the effect of Meditation on intraocular pressure, subjective QOL and objective markers of stress and brain oxygenation in patients with POAG. METHODS: Sixty patients were randomized into intervention and control groups. Intervention group underwent 45 minutes of Meditation daily for 6 weeks in addition to standard medical treatment while controls received only standard medical treatment. Inclusion criteria were patients with POAG, age >45 years, best corrected visual acuity >6/60. Patients with other ocular co-morbid conditions contributing to vision loss, systemic diseases, patients already practicing meditation in any form were excluded. An assessment of IOP, brain oxygenation using functional near infrared spectroscopy (fNIRS), QOL (WHO-BREF QOL) and stress markers in serum (cortisol, ß-endorphins, interleukin-6, brain derived neurotrophic factor (BDNF), reactive oxygen species) was made at baseline and at 6 weeks. RESULTS: 21 female and 39 male patients were enrolled with a mean age of 57.28±9.37 years. All parameters were comparable between two groups at baseline. At 6 weeks mean level of IOP decreased significantly in intervention group (15.9±1.8 mmHg to 14.4±1.21 mm Hg, p-value 0.0001) as compared to control group (15.7±1.4 mmHg to 15.65±1.41, p-value 0.41). fNIRS showed significant improvement in oxygenated hemoglobin change (ΔHbO) in intervention group in the prefrontal cortex (p-value <  0.0001) as compared to control group (p-value 0.52). WHO-BREF QOL score increased significantly in intervention group (86.6±6.16 to 93.3±5.66, p-value 0.0001) as compared to control (89±7.25 to 89.07±3.24, p-value 0.74).Mean serum cortisol decreased significantly in intervention group (497±46.37 ng/ml to 447±53.78 ng/ml, p-value 0.01) as compared to control group (519.75±24.5 to 522.58±26.63 ng/ml, p-value 0.64). Mean ß-endorphin levels increased significantly (33±5.52pg/ml to 43.27pg/ml, p-value <  0.0001) as compared to control group (34.78±4.1pg/ml to 36.33pg±4.07pg/ml p-value 0.27). Interleukin-6 decreased significantly in intervention group (2.2±0.5 ng/ml to 1.35±0.32 ng/ml, p-value <  0.0001) as compared to control group (2.03±0.37 to 2.17±0.34 ng/ml p-value 0.25). BDNF increased significantly in intervention group (52.24±6.71 to 63.25±13.48 ng/ml p-value 0.004) as compared to control group (53.23±5.82 to 54.42±5.66 ng/ml p-value 0.54). ROS decreased significantly in intervention group (1596.19±179.14 to 1261±244.31 RLU/min/104 neutrophils p-value 0.0001) as compared to control group (1577.5±172.02 to 1662.5±84.75 RLU/min/104 neutrophils p-value 0.16). CONCLUSIONS: A short term course of Meditation was associated with significant improvement in brain oxygenation and QOL along with a reduction in IOP and stress markers. Meditation may be a useful as an adjunct to standard treatment in patients with POAG and potentially decrease the risk of glaucoma progression.

Mindfulness Meditation Reduces Intraocular Pressure, Lowers Stress Biomarkers and Modulates Gene Expression in Glaucoma: A Randomized Controlled Trial.

BACKGROUND: Reducing intraocular pressure (IOP) in primary open-angle glaucoma (POAG) is currently the only approach to prevent further optic nerve head damage. However, other mechanisms such as ischemia, oxidative stress, glutamate excitotoxicity, neurotrophin loss, inflammation/glial activation, and vascular dysregulation are not addressed. Because stress is a key risk factor affecting these mechanisms, we evaluated whether mindfulness-based stress reduction can lower IOP and normalize typical stress biomarkers. MATERIALS AND METHODS: In a prospective, randomized trial 90 POAG patients (180 eyes; age above 45 y) were assigned to a waitlist control or mindfulness meditation group which practiced daily for 21 days. We measured IOP (primary endpoint), quality of life (QOL), stress-related serum biomarkers [cortisol, ß-endorphins, IL6, TNF-α, brain-derived neurotrophic factor (BDNF), reactive oxygen species (ROS), total antioxidant capacity (TAC)], and whole genome expression. RESULTS: Between-group comparisons revealed significantly lowered IOP in meditators (OD: 18.8 to 12.7, OS 19.0 to 13.1 mm Hg) which correlated with significantly lowered stress-biomarker levels including cortisol (497.3 to 392.3 ng/mL), IL6 (2.8 to 1.5 ng/mL), TNF-α (57.1 to 45.4 pg/mL), ROS (1625 to 987 RLU/min/104 neutrophils), and elevated ß-endorphins (38.4 to 52.7 pg/mL), BDNF (56.1 to 83.9 ng/mL), and TAC (5.9 to 9.3) (all P<0.001). These changes correlated well with gene expression profiling. Meditators improved in QOL (P<0.05). CONCLUSIONS: A short course of mindfulness-based stress reduction by meditation in POAG, reduces IOP, improves QOL, normalizes stress biomarkers, and positively modifies gene expression. Mindfulness meditation can be recommended as adjunctive therapy for POAG.