Neuroprotective Effects of Fingolimod in a Cellular Model of Optic Neuritis

Candadai, Amritha A.; Liu, Fang; Verma, Arti; Adil, Mir S.; Alfarhan, Moaddey; Fagan, Susan C.; Somanath, Payaningal R.; Narayanan, S. Priya

doi:10.3390/cells10112938

Cited by 9 publications

(3 citation statements)

References 65 publications

(74 reference statements)

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“…In multiple sclerosis, it improved axonal and myelin integrity [ 129 ]; and in mice prevented demyelination [ 130 ]. It increased dendritic spines [ 131 , 132 ], reduced neuronal death from ROS [ 133 ], and improved mitochondrial production of ATP [ 134 ]. In microglia, fingolimod shifted M1 polarization toward M2 [ 135 , 136 ].…”

Section: Eleven Available Drugs Benefit Some or All Of The Five Cell-...mentioning

confidence: 99%

Formulating treatment of major psychiatric disorders: algorithm targets the dominantly affected brain cell-types

Fessel

2023

Discov Ment Health

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Background Pharmacotherapy for most psychiatric conditions was developed from serendipitous observations of benefit from drugs prescribed for different reasons. An algorithmic approach to formulating pharmacotherapy is proposed, based upon which combination of changed activities by brain cell-types is dominant for any particular condition, because those cell-types contain and surrogate for genetic, metabolic and environmental information, that has affected their function. The algorithm performs because functions of some or all the affected cell-types benefit from several available drugs: clemastine, dantrolene, erythropoietin, fingolimod, fluoxetine, lithium, memantine, minocycline, pioglitazone, piracetam, and riluzole Procedures/findings Bipolar disorder, major depressive disorder, schizophrenia, Alzheimer’s disease, and post-traumatic stress disorder, illustrate the algorithm; for them, literature reviews show that no single combination of altered cell-types accounts for all cases; but they identify, for each condition, which combination occurs most frequently, i.e., dominates, as compared with other possible combinations. Knowing the dominant combination of altered cell-types in a particular condition, permits formulation of therapy with combinations of drugs taken from the above list. The percentage of patients who might benefit from that therapy, depends upon the frequency with which the dominant combination occurs in patients with that particular condition. Conclusions Knowing the dominant combination of changed cell types in psychiatric conditions, permits an algorithmically formulated, rationally-based treatment. Different studies of the same condition often produce discrepant results; all might be correct, because identical clinical phenotypes result from different combinations of impaired cell-types, thus producing different results. Clinical trials would validate both the proposed concept and choice of drugs.

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Section: Eleven Available Drugs Benefit Some or All Of The Five Cell-...mentioning

confidence: 99%

Formulating treatment of major psychiatric disorders: algorithm targets the dominantly affected brain cell-types

Fessel

2023

Discov Ment Health

View full text Add to dashboard Cite

show abstract

“…In multiple sclerosis, it improved axonal and myelin integrity [ 95 ] and, in mice, prevented demyelination [ 96 ]. It increased dendritic spines [ 97 , 98 ], reduced neuronal death from ROS [ 99 ], and improved mitochondrial production of ATP [ 100 ]. In microglia, fingolimod shifted M1 polarization toward M2 [ 101 , 102 ].…”

Section: Changes In Brain Cell Types In Ptsd Cte and Tbimentioning

confidence: 99%

Supplementary Pharmacotherapy for the Behavioral Abnormalities Caused by Stressors in Humans, Focused on Post-Traumatic Stress Disorder (PTSD)

Fessel

2023

JCM

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Used as a supplement to psychotherapy, pharmacotherapy that addresses all of the known metabolic and genetic contributions to the pathogenesis of psychiatric conditions caused by stressors would require an inordinate number of drugs. Far simpler is to address the abnormalities caused by those metabolic and genetic changes in the cell types of the brain that mediate the behavioral abnormality. Relevant data regarding the changed brain cell types are described in this article and are derived from subjects with the paradigmatic behavioral abnormality of PTSD and from subjects with traumatic brain injury or chronic traumatic encephalopathy. If this analysis is correct, then therapy is required that benefits all of the affected brain cell types; those are astrocytes, oligodendrocytes, synapses and neurons, endothelial cells, and microglia (the pro-inflammatory (M1) subtype requires switching to the anti-inflammatory (M2) subtype). Combinations are advocated using several drugs, erythropoietin, fluoxetine, lithium, and pioglitazone, that benefit all of the five cell types, and that should be used to form a two-drug combination, suggested as pioglitazone with either fluoxetine or lithium. Clemastine, fingolimod, and memantine benefit four of the cell types, and one chosen from those could be added to the two-drug combination to form a three-drug combination. Using low doses of chosen drugs will limit both toxicity and drug-drug interactions. A clinical trial is required to validate both the advocated concept and the choice of drugs.

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“…[9,16] and optic neuritis. [17] The safety of FTY720 in animal models and in humans and its ability to cross the blood-brain barrier have been well documented. [12] Increasing evidence over the past decade highlighted the involvement of the ocular immune response in LIRD.…”

Section: Introductionmentioning

confidence: 99%

The effect of fingomolid (FTY720) protecting the retina of rats from light-induced retinal degeneration (LIRD)

Zhang,

Chen,

Zhao

et al. 2024

Preprint

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Object: Fingomolid (FTY720), an immunosuppressive agent, was found to protect the retina against light stress in our previous study. In this study, we investigate whether FTY720 has a protective effect on retinal degeneration and whether immune response is involved in photoreceptor apoptosis in light-induced retinal degeneration (LIRD) in rats. Methods: Sprague-Dawley rats raised in cyclic dim light were exposed to 2700 lux white light for 6 hours to build LIRD animal models. FTY720 (10.0 mg/kg) or vehicle was administered intraperitoneally to rats 0.5 h before light exposure. Histology and F-ERGs analysis were used to evaluate the structure and function of retina, respectively. The apoptosis of retinal cells was detected by TUNEL assay. The immune T cells on light-damaged retina were measured by immunofluorescence analysis, and the expression of immune proteins was examined by western blot. Results: After light exposure, significant reductions in ERGs response were observed in vehicle-treated (VLD) group, whereas there was no significant difference between FTY720-treated (FTY-LD) group and normal group. A slight thinning was observed in FTY-LD group, which was not reflected in the full field ERG responses. Pretreatment with FTY720 inhibited light-induced photoreceptor apoptosis and protected retinal structure and function against light damage. CD3+ and CD8+ T molecules were increased in the VLD group, but did not occur on the whole retina in rats treated with FTY720. The expression of CD3+ and CD8+ proteins were up-regulated by light exposure and suppressed by FTY720 pretreatment. Light stress activated the microglial cells, and FTY720 could suppress the activation. Conclusion: FTY720 could inhibit apoptosis and suppress CD3+ and CD8+ T cells and microglial activation in light-damaged retina in rats, showing an obvious protective effect on photoreceptors. These results help to better understand the pathogenesis of LIRD, and FTY720 may provide therapeutic benefit for retinal diseases.

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Neuroprotective Effects of Fingolimod in a Cellular Model of Optic Neuritis

Cited by 9 publications

References 65 publications

Formulating treatment of major psychiatric disorders: algorithm targets the dominantly affected brain cell-types

Formulating treatment of major psychiatric disorders: algorithm targets the dominantly affected brain cell-types

Supplementary Pharmacotherapy for the Behavioral Abnormalities Caused by Stressors in Humans, Focused on Post-Traumatic Stress Disorder (PTSD)

The effect of fingomolid (FTY720) protecting the retina of rats from light-induced retinal degeneration (LIRD)

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