FK962 protects retinal ganglion cell under hypoxia/reoxygenation: Possible involvement of glial cell line-derived neurotrophic factor signaling pathway.

Loss of retinal ganglion cells (RGCs) is the cause of visual impairment and blindness in glaucoma. Previously, our studies showed that FK962 (N-[1-acetylpiperidin-4-yl]-4-fluorobenzamide) promoted neurite elongation in rat RGCs and trigeminal ganglion (TG) cells. In TG cells, glial cell line-derived neurotrophic factor (GDNF) is known to be involved in the mechanism.

Calpain-specific breakdown fragment in human drusen.

Purpose: With aging and age-related macular dystrophy (AMD), proteolytic fragments are deposited in extracellular drusen located between the RPE and Bruch's membrane. Localized hypoxia may be a risk factor for AMD. Our hypothesis is that following hypoxia, activation of proteolytic enzymes called calpains may cause proteolysis/degeneration of retinal cells and RPE.

GCL loss in BRAO.

Purpose: Our recent publication used optical coherence tomography (OCT) to follow thinning of the retinal ganglion cell layer (GCL) in central retinal artery occlusion (CRAO). Thinning of the inner layers also occurs in patients with branch retinal artery occlusion (BRAO). The mechanism for such thinning may be partially due to proteolysis by a calcium-activated protease called calpain.

Tear miRNA expression analysis reveals miR-203 as a potential regulator of corneal epithelial cells.

Background: microRNAs (miRNAs) are small noncoding RNAs that negatively regulate gene expression. They are found within cells and in body fluids. Extracellular miRNAs have been shown to associate with the surrounding tissues.

Segmenting OCT for detecting drug efficacy in CRAO.

Purpose: Thinning of the inner layers of the retina occurs in patients with central retinal artery occlusion (CRAO). The mechanism for such thinning may be partially due to proteolysis by a calcium-activated protease called calpain. Calpain inhibitor SNJ-1945 ameliorated the proteolysis in a past series of model experiments.

Cell-Permeable Calpain Inhibitor SJA6017 Provides Functional Protection to Spinal Motoneurons Exposed to MPP.

Extra-nigral central nervous system sites have been found to be affected in Parkinson's disease (PD). In addition to substantia nigra, degeneration of spinal cord motor neurons may play a role in the motor symptoms of PD. To this end, hybrid rodent VSC 4.

NFE2L2 activator RS9 protects against corneal epithelial cell damage in dry eye models.

Oxidative stress may cause ocular surface damage during the development of dry eye. Mammalian cells have defense systems against oxidative stress. A central regulator of the stress response is nuclear factor-erythroid 2-related factor 2 (NFE2L2).

Contribution of Calpain and Caspases to Cell Death in Cultured Monkey RPE Cells.

Purpose: AMD is the leading cause of human vision loss after 65 years of age. Several mechanisms have been proposed: (1) age-related failure of the choroidal vasculature leads to loss of RPE; (2) RPE dysfunctions due to accumulation of phagocytized, but unreleased A2E (N-retinylidene-N-retinylethanolamine); (3) zinc deficiency activation of calpain and caspase proteases, leading to cell death. The purpose of the present study is to compare activation of calpain and caspase in monkey RPE cells cultured under hypoxia or with A2E.

Selecting Fuchs patients for drug trials involving endothelial cell proliferation.

Purpose: Fuchs endothelial corneal dystrophy (FECD) might be managed by drug treatment before becoming severe enough to require surgery. For a clinical trial of such a drug, we hypothesize that selecting an adequate number of patients with FECD with only moderately compromised cell densities will be challenging. Thus, the purpose of the present study was to measure the prevalence of patients with FECD exhibiting moderately decreased corneal cell densities.

FK962 induces neurite outgrowth in cultured monkey trigeminal ganglion cells.

Purpose: Corneal sensation, cell proliferation, and wound healing all depend on adequate corneal innervation. Disruption of corneal innervation can lead to dry eye and delayed wound healing. Our studies in rats and rabbits show that the substituted fluorobenzamide drug FK962 accelerates the extension of neuronal processes and recovery of corneal sensitivity.

Neuron-microglia interaction induced bi-directional cytotoxicity associated with calpain activation.

Activated microglia release pro-inflammatory factors and calpain into the extracellular milieu, damaging surrounding neurons. However, mechanistic links to progressive neurodegeneration in disease such as multiple sclerosis (MS) remain obscure. We hypothesize that persistent damaged/dying neurons may also release cytotoxic factors and calpain into the media, which then activate microglia again.

Calpain inhibition reduces structural and functional impairment of retinal ganglion cells in experimental optic neuritis.

Optic neuritis (ON), inflammation of the optic nerve, is strongly associated with multiple sclerosis. ON pathology is characterized by attack of autoreactive T cells against optic nerve antigens, resulting in demyelination, death of retinal ganglion cells, and cumulative visual impairment. A model of experimental autoimmune encephalomyelitis (EAE) was utilized to study the onset and progression of ON and the neuroprotective efficacy of oral treatment with the calpain inhibitor SNJ 1945.

Loss of calpastatin leads to activation of calpain in human lens epithelial cells.

Purpose: Activation of calpains (calpain 2 and Lp82) in rodent lenses readily causes proteolysis and cataract formation. In contrast, primate lenses are quite resistant to activation of calpains. The hypothesis is that high levels of human endogenous calpain inhibitor, calpastatin (CS), prevent calpain activation in human lenses.

Mechanism for laser-induced neovascularization in rat choroid: accumulation of integrin α chain-positive cells and their ligands.

Purpose: Inhibitors binding to integrins α5 and αv are antiangiogenic in models of choroidal neovascularization (CNV). However, a comprehensive understanding of the accumulation of integrin α isoform-positive cells, their ligands, and associations is limited. The purpose of the present study was to examine the localization of integrin α chain-positive cells and their extracellular matrix (ECM) ligands in the RPE/choroid after laser injury.

Degeneration and dysfunction of retinal neurons in acute ocular hypertensive rats: involvement of calpains.

Purpose: Retinal ischemic diseases primarily lead to damage of the inner retinal neurons. Electrophysiological studies also suggest impairment of the inner retinal neurons. Our recent studies with acute ocular hypertensive rats confirmed damage predominantly in the inner retinal layer along with the ganglion cell layer, changes that are ameliorated by the calpain inhibitor SNJ-1945.

Effects of a novel orally administered calpain inhibitor SNJ-1945 on immunomodulation and neurodegeneration in a murine model of multiple sclerosis.

Multiple sclerosis (MS) pathology is marked by the massive infiltration of myelin-specific T cells into the CNS. Hallmarks of T helper (Th) cells during active disease are pro-inflammatory Th1/Th17 cells that predominate over immunoregulatory Th2/Treg cells. Neurodegeneration, a major factor in progressive MS, is often overlooked when considering drug prescription.

SNJ-1945, a calpain inhibitor, protects SH-SY5Y cells against MPP(+) and rotenone.

Complex pathophysiology of Parkinson's disease involves multiple CNS cell types. Degeneration in spinal cord neurons alongside brain has been shown to be involved in Parkinson's disease and evidenced in experimental parkinsonism. However, the mechanisms of these degenerative pathways are not well understood.

Calpain protease causes hypoxia-induced proteolysis in cultured human retina.

Purpose/aim: Calpain proteases are known to be involved in retinal cell death in animal models. The purpose of the present study was to test for calpain activation in human retinas cultured under hypoxic conditions.

Materials And Methods: Calpain activation was detected by immunoblotting for calpain substrates in human and monkey retinas cultured in gas generating pouches to reduce oxygen.