Changes in Class I and IIb HDACs by δ-Opioid in Chronic Rat Glaucoma Model

Zaidi, Syed; Guzman, Wendy; Singh, Sudha; Mehrotra, Shikhar; Husain, Shahid

doi:10.1167/iovs.61.14.4

Cited by 15 publications

(8 citation statements)

References 52 publications

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“…Pupils were dilated with topical 0.5% tropicamide (Akorn, Lake Forest, IL, USA) and 2.5% phenylephrine HCL (Paragon BioTeck, Portland, OR USA). PERG recording of both eyes was performed simultaneously to investigate RGC function using the Celeris-Diagnosys system (Diagnosys, Lowell, MA, USA) according to a published protocol [ 43 , 44 ]. Briefly, mice were placed on Celeris-Diagnosys system equipped with a feedback-controlled heating pad for maintaining animal core temperature at 37 °C, and small lubricant eye drop (GenTeal Lubricant Eye Gel, Alcon, Ft. Worth, TX) was applied before recording to prevent corneal dryness.…”

Section: Methodsmentioning

confidence: 99%

Calbindin 2-specific deletion of arginase 2 preserves visual function after optic nerve crush

Zaidi,

Xu,

Lemtalsi

et al. 2023

Cell Death Dis

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We previously found that global deletion of the mitochondrial enzyme arginase 2 (A2) limits optic nerve crush (ONC)-induced neuronal death. Herein, we examined the cell-specific role of A2 in this pathology by studies using wild type (WT), neuronal-specific calbindin 2 A2 KO (Calb2cre/+ A2 f/f), myeloid-specific A2 KO (LysMcre/+ A2f/f), endothelial-specific A2 KO (Cdh5cre/+ A2f/f), and floxed controls. We also examined the impact of A2 overexpression on mitochondrial function in retinal neuronal R28 cells. Immunolabeling showed increased A2 expression in ganglion cell layer (GCL) neurons of WT mice within 6 h-post injury and inner retinal neurons after 7 days. Calb2 A2 KO mice showed improved neuronal survival, decreased TUNEL-positive neurons, and improved retinal function compared to floxed littermates. Neuronal loss was unchanged by A2 deletion in myeloid or endothelial cells. We also found increased expression of neurotrophins (BDNF, FGF2) and improved survival signaling (pAKT, pERK1/2) in Calb2 A2 KO retinas within 24-hour post-ONC along with suppression of inflammatory mediators (IL1β, TNFα, IL6, and iNOS) and apoptotic markers (cleavage of caspase3 and PARP). ONC increased GFAP and Iba1 immunostaining in floxed controls, and Calb2 A2 KO dampened this effect. Overexpression of A2 in R28 cells increased Drp1 expression, and decreased mitochondrial respiration, whereas ABH-induced inhibition of A2 decreased Drp1 expression and improved mitochondrial respiration. Finally, A2 overexpression or excitotoxic treatment with glutamate significantly impaired mitochondrial function in R28 cells as shown by significant reductions in basal respiration, maximal respiration, and ATP production. Further, glutamate treatment of A2 overexpressing cells did not induce further deterioration in their mitochondrial function, indicating that A2 overexpression or glutamate insult induce comparable alterations in mitochondrial function. Our data indicate that neuronal A2 expression is neurotoxic after injury, and A2 deletion in Calb2 expressing neurons limits ONC-induced retinal neurodegeneration and improves visual function.

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Section: Methodsmentioning

confidence: 99%

Calbindin 2-specific deletion of arginase 2 preserves visual function after optic nerve crush

Zaidi,

Xu,

Lemtalsi

et al. 2023

Cell Death Dis

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“…One of the proposed mechanisms for the beneficial effects of delta-opioid agonism is epigenetic modification. Histone deacetylase activity has been positively correlated with glaucoma progression, and delta-opioid agonism was demonstrated to suppress this activity in ocular hypertensive animal models ( Zaidi et al, 2020 ). Modification of the epigenetic pathway has also been researched in non-retinal cells, including restoration of cells comprising the trabecular meshwork and Schlemm’s canal system ( Sharif, 2021 ).…”

Section: Therapeutic Approachesmentioning

confidence: 99%

The potential for mitochondrial therapeutics in the treatment of primary open-angle glaucoma: a review

Kuang,

Halimitabrizi,

Edziah

et al. 2023

Front. Physiol.

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Glaucoma, an age-related neurodegenerative disease, is characterized by the death of retinal ganglion cells (RGCs) and the corresponding loss of visual fields. This disease is the leading cause of irreversible blindness worldwide, making early diagnosis and effective treatment paramount. The pathophysiology of primary open-angle glaucoma (POAG), the most common form of the disease, remains poorly understood. Current available treatments, which target elevated intraocular pressure (IOP), are not effective at slowing disease progression in approximately 30% of patients. There is a great need to identify and study treatment options that target other disease mechanisms and aid in neuroprotection for POAG. Increasingly, the role of mitochondrial injury in the development of POAG has become an emphasized area of research interest. Disruption in the function of mitochondria has been linked to problems with neurodevelopment and systemic diseases. Recent studies have shown an association between RGC death and damage to the cells’ mitochondria. In particular, oxidative stress and disrupted oxidative phosphorylation dynamics have been linked to increased susceptibility of RGC mitochondria to secondary mechanical injury. Several mitochondria-targeted treatments for POAG have been suggested, including physical exercise, diet and nutrition, antioxidant supplementation, stem cell therapy, hypoxia exposure, gene therapy, mitochondrial transplantation, and light therapy. Studies have shown that mitochondrial therapeutics may have the potential to slow the progression of POAG by protecting against mitochondrial decline associated with age, genetic susceptibility, and other pathology. Further, these therapeutics may potentially target already present neuronal damage and symptom manifestations. In this review, the authors outline potential mitochondria-targeted treatment strategies and discuss their utility for use in POAG.

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“…Unfortunately, some patients under IOP-lowering therapy still see progression of the disease, which clearly indicates that better therapeutic options are needed to fully cure the disease. Studies have shown that multiple factors play key roles in RGC degeneration including activation of caspases [ 44 , 141 , 142 , 169 , 208 , 320 ], apoptosis [ 6 , 116 , 226 , 255 , 327 ], oxidative stress [ 56 , 143 , 150 , 198 , 219 , 228 , 272 ], ischemia and hypoxia [ 32 , 57 , 141 , 141 , 142 , 142 , 144 , 234 ], epigenetic changes [ 105 , 206 , 242 , 276 , 353 , 359 , 359 , 360 , 360 ], Crosson 2010 #975, [ 145 ], alteration in the levels of pro-inflammatory cytokines [ 1 , 312 , 316 , 341 , 352 , 357 ], and deprivation of neurotrophic factors [ 240 , 256 ]. There is another opinion with limited evidence, which suggests the neurodegeneration observed in glaucoma could be vascular.…”

Section: Adaptive Immunity and Glaucomamentioning

confidence: 99%

The role of the adaptive immune system and T cell dysfunction in neurodegenerative diseases

DeMaio

Mehrotra

Sambamurti

et al. 2022

J Neuroinflammation

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The adaptive immune system and associated inflammation are vital in surveillance and host protection against internal and external threats, but can secondarily damage host tissues. The central nervous system is immune-privileged and largely protected from the circulating inflammatory pathways. However, T cell involvement and the disruption of the blood–brain barriers have been linked to several neurodegenerative diseases including Parkinson's disease, Alzheimer’s disease, and multiple sclerosis. Under normal physiological conditions, regulatory T cells (Treg cells) dampen the inflammatory response of effector T cells. In the pathological states of many neurodegenerative disorders, the ability of Treg cells to mitigate inflammation is reduced, and a pro-inflammatory environment persists. This perspective review provides current knowledge on the roles of T cell subsets (e.g., effector T cells, Treg cells) in neurodegenerative and ocular diseases, including uveitis, diabetic retinopathy, age-related macular degeneration, and glaucoma. Many neurodegenerative and ocular diseases have been linked to immune dysregulation, but the cellular events and molecular mechanisms involved in such processes remain largely unknown. Moreover, the role of T cells in ocular pathologies remains poorly defined and limited literature is available in this area of research. Adoptive transfer of Treg cells appears to be a vital immunological approach to control ocular pathologies. Similarities in T cell dysfunction seen among non-ocular neurodegenerative diseases suggest that this area of research has a great potential to develop better therapeutic agents for ocular diseases and warrants further studies. Overall, this perspective review article provides significant information on the roles of T cells in numerous ocular and non-ocular neurodegenerative diseases.

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Changes in Class I and IIb HDACs by δ-Opioid in Chronic Rat Glaucoma Model

Cited by 15 publications

References 52 publications

Calbindin 2-specific deletion of arginase 2 preserves visual function after optic nerve crush

Calbindin 2-specific deletion of arginase 2 preserves visual function after optic nerve crush

The potential for mitochondrial therapeutics in the treatment of primary open-angle glaucoma: a review

The role of the adaptive immune system and T cell dysfunction in neurodegenerative diseases

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