taurochenodeoxycholic-acid and Retinal-Diseases

Bile acids are produced in the liver and excreted into the intestine, where their main function is to participate in lipid digestion. Ursodeoxycholic acid (UDCA) and tauroursodeoxycholic acid (TUDCA) have shown antiapoptotic, anti-inflammatory, and antioxidant effects in various models of neurodegenerative diseases. However, little is known about signaling pathways and molecular mechanisms through which these bile acids act as neuroprotectors, delaying translation to the clinical setting. We review evidence supporting a potentially therapeutic role for bile acids in retinal disorders, and the mechanisms and pathways involved in the cytoprotective effects of bile acids from the liver and the enterohepatic circulation to the central nervous system and the retina. As secondary bile acids are generated by the microbiota metabolism, bile acids might be a link between neurodegenerative retinal diseases and microbiota.

Topics: Animals; Cytoprotection; Humans; Nerve Degeneration; Neuroprotective Agents; Retinal Diseases; Taurochenodeoxycholic Acid; Ursodeoxycholic Acid

Diseases that affect the eye, including photoreceptor degeneration, diabetic retinopathy, and glaucoma, affect 11.8 million people in the US, resulting in vision loss and blindness. Loss of sight affects patient quality of life and puts an economic burden both on individuals and the greater healthcare system. Despite the urgent need for treatments, few effective options currently exist in the clinic. Here, we review research on promising neuroprotective strategies that promote neuronal survival with the potential to protect against vision loss and retinal cell death. Due to the large number of neuroprotective strategies, we restricted our review to approaches that we had direct experience with in the laboratory. We focus on drugs that target survival pathways, including bile acids like UDCA and TUDCA, steroid hormones like progesterone, therapies that target retinal dopamine, and neurotrophic factors. In addition, we review rehabilitative methods that increase endogenous repair mechanisms, including exercise and electrical stimulation therapies. For each approach, we provide background on the neuroprotective strategy, including history of use in other diseases; describe potential mechanisms of action; review the body of research performed in the retina thus far, both in animals and in humans; and discuss considerations when translating each treatment to the clinic and to the retina, including which therapies show the most promise for each retinal disease. Despite the high incidence of retinal diseases and the complexity of mechanisms involved, several promising neuroprotective treatments provide hope to prevent blindness. We discuss attractive candidates here with the goal of furthering retinal research in critical areas to rapidly translate neuroprotective strategies into the clinic.

Topics: Animals; Cell Death; Electric Stimulation Therapy; Exercise Therapy; Humans; Nerve Growth Factors; Neurons; Neuroprotective Agents; Retina; Retinal Diseases; Taurochenodeoxycholic Acid; Ursodeoxycholic Acid; Vision Disorders

Retinitis pigmentosa (RP) is a group of genetically diverse inherited disorders characterised by the progressive photoreceptors and pigment epithelial cell dysfunction leading to central vision impairment. Although important advances in the understanding of the pathophysiologic pathways involved in RP have been made, drug delivery for the treatment of ocular disorders affecting the posterior segment of the eye is still an unmet clinical need. In the present study, we describe the development of multi-loaded PLGA-microspheres (MSs) incorporating two neuroprotectants agents (glial cell-line-derived neurotrophic factor-GDNF and Tauroursodeoxycholic acid-TUDCA) as a potential therapeutic tool for the treatment of RP. A solid-in-oil-in-water (S/O/W) emulsion solvent extraction-evaporation technique was employed for MS preparation. A combination of PLGA and vitamin E was used to create the microcarriers. The morphology, particle size, encapsulation efficiency and in vitro release profile of the MSs were studied. Encapsulation efficiencies of GDNF and TUDCA for the initial multiloaded MSs, prepared with methylene chloride (MC) as organic solvent and polyvinyl alcohol (PVA) solution in the external phase, were 28.53±0.36% and 45.65±8.01% respectively. Different technological parameters to optimise the formulation such as the incorporation of a water-soluble co-solvent ethanol (EtOH) in the internal organic phase, as well as NaCl concentration, and viscosity using a viscosizing agent (hydroxypropyl methylcellulose-HPMC) in the external aqueous phase were considered. EtOH incorporation and external phase viscosity of the emulsion were critical attributes for improving drug loading of both compounds. In such a way, when using a methylene chloride/EtOH ratio 75:25 into the inner organic phase and the viscosity agent HPMC (1% w/v) in the external aqueous phase, GDNF and TUDCA payloads resulted 48.86±1.49% and 78.58±10.40% respectively, and a decrease in the initial release of GDNF was observed (22.03±1.41% compared with 40.86±6.66% of the initial multi-loaded formulation). These optimised microparticles exhibited sustained in vitro releases over 91 days. These results suggest that the microencapsulation procedure optimised in this work presents a promising technological strategy for the development of multi-loaded intraocular drug delivery systems (IODDS).

Topics: Emulsions; Glial Cell Line-Derived Neurotrophic Factor; Humans; Lactic Acid; Microspheres; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Retinal Diseases; Taurochenodeoxycholic Acid