Translational preclinical research may lead to improved

Translational Preclinical Research May Lead To Improved-Free PDF

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Nicholson et al Preclinical research to treat NA AION. optic disk cup in NA AION patient was oral or intravitreally injected steroids were and inflammation associated with NA. reported 24 carried 2 35 36 but the results were ION one of the best options at present is. disappointing One study compared the to control and correct any vasculopathic. MEDICATIONS outcome of 613 consecutive patients who risk factors such as severe hypertension. In patients with predisposing factors for voluntarily opted for either systemic corti hyperglycemia and hypercholesterolemia. NA AION phosphodiesterase 5 PDE5 costeroid treatment or no treatment 37 Although these measures have not been. inhibitors used to treat erectile dysfunc Among those with visual acuity up to 20 70 proven to prevent a sequential acute event. tion such as sildenafil may disturb optic within 2 weeks of disease onset rates of of NA AION they will likely improve the. nerve autoregulation leading to blood ves visual improvement after 6 months were patients overall health. sel dilatation and ONH edema 25 More 69 8 for the treated patients and 40 5. data are still needed to corroborate this for the untreated patients Among those ANIMAL MODELS OF NA AION THE. finding Moreover it is unclear if these with a moderate to severe initial visual field FUTURE TARGETS OF MEDICAL. effects are incidental or associated with defect corresponding rates were 40 1 and TREATMENT. their effects on the ocular circulation 26 24 5 In another trial patients who were Rodent and primate models of NA AION. Optic neuropathy was also reported treated with intravitreal triamcinolone to have been developed to further under. in 14 of 22 patients being treated with improve ONH edema in the acute phase standing of the mechanisms underlying. the antiarrhythmic drug amiodarone 27 of NA AION exhibited more improve the disease 45 47 The models reproduce. typically bilateral Upon discontinuation of ment in visual acuity and visual field at some signs of NA AION across species. amiodarone only a few cases improved all 6 months than patients who were not 38 namely ONH edema and loss of capillary. of whom had mild optic nerve dysfunction 40 However none of these findings 37 perfusion in the optic nerve immediately. 40 have been confirmed in a large ran behind the globe but not in the retinal. NATURAL HISTORY OF NA AION, domized controlled trial Indeed in a state vessels and all show long term apopto. Up to 40 of NA AION patients, ment on the steroid controversy in NA sis of the retinal ganglion cells RGCs. show spontaneous improvement in vision, AION researchers concluded that the data due to loss of axoplasmic transport in the. whereas 5 29 experience a continued, so far on intravitreal steroid treatment damaged optic nerve 48 49 The appear. deterioration over a few days or weeks 8, are at best anecdotal and at worst poten ance of the fundus after injury in pri.
28 Following this initial phase further, tially dangerous or misleading 41 Clin mates is very similar to that in humans. progression is unusual 28 29 NA AION, icians also need to take into account that with ONH swelling and flame like hemor. recurs in the affected eye in 6 of patients, corticosteroids may have significant sys rhages 49. within 2 years and in up to 7 6 within, temic side effects especially in elderly or Rodent models of AION rAION. 3 years 30 32, vasculopathic patients 41 have so far proved invaluable for test.
TREATMENT OF NA AION The administration of bevacizumab ing potential novel treatments Hyper. Because the pathologic mechanism of NA an anti vascular endothelial growth fac baric oxygen administered during the crit. AION is still unclear suggestions for treat tor antibody to patients with NA AION ical period immediately after induction. ment are wide ranging None of the treat yielded satisfactory results in few cases of injury proved effective in preventing. ments attempted so far has proved effective 42 However there are reports of NA RGC loss 50 Intravenous or intravitreous. in recovering the visual loss ION association with intravitreal beva prostaglandin J2 proffered almost equal. cizumab use 43 and data from con protection when administered 5 h before. MEDICATIONS trolled randomized studies are lacking for rAION injury or immediately after sug. Owing to its known anti thrombotic activ this indication gesting that it may have an even longer. ity aspirin has been suggested for the treat therapeutic window in humans in whom. ment of patients after an initial event of SURGERY the injury develops more slowly with. NA AION in order to reduce the poten The ischemic optic neuropathy decom episodes of recurring ONH edema 51 52. tial for hemostasis and inflammation and pression study IONDT prompted by Prostaglandin J2 is currently being tested. thereby prevent a recurrence in the fellow the compartment syndrome theory indi in a primate model Bernstein 2014 per. eye 33 34 However no significant long cated that decompression surgery was sonal communication Others reported. term benefit was found Nevertheless given no better than careful follow up The that subcutaneous granulocyte colony. aspirin s proven role in treating cardiovas 43 improvement in patients with care stimulating factor G CSF had both anti. cular risk factors many clinicians continue ful follow up as compared to 33 in apoptotic effects on the RGCs and anti. to recommend it for secondary prevention the surgery group with visual loss dur inflammatory effects on the optic nerve. of NA AION if not contraindicated 34 ing the 6 months follow up 12 vs 24 53 Experiments in models of optic nerve. In NA AION compression of the optic respectively revealing that decompression crush ONC which induces severe edema. nerve vasculature by the edematous ONH surgery was harmful 44 in the ONH while allowing for exam. is believed to increase the ischemic insult ination of loss of microvascular perfu. and worsen the visual prognosis Therefore CONTROL OF RISK FACTORS sion and RGC death show a protective. attempts to reduce the ONH edema in the Considering the poor results of treat effect of G CSF when administered after. early stages of the disease with aggressive ments directed at the optic disk edema injury 54 55. Frontiers in Neurology Neuro Ophthalmology July 2014 Volume 5 Article 122 2. Nicholson et al Preclinical research to treat NA AION. Clinical findings on the benefit of beva PPAR agonist pioglitazone 69 the sir 5 Hayreh SS Ocular vascular occlusive disorders. cizumab were supported in a murine tuin 1 SIRT1 agonist resveratrol 70 natural history of visual outcome Prog Retin. Eye Res 2014 41C 1 25 doi 10 1016 j preteyeres, model of ONC showing that the drug pre pigment epithelial derived growth fac. 2014 04 001, served the integrity of the microvasculature tor PEDF 71 Toll like receptor 4 6 Steigerwalt RD Jr Cesarone MR Belcaro G Pas. 56 This apparently prevented post ONC TLR4 antagonists 72 valproate 73 carella A De Angelis M Gattegna R et al Arteritic. ischemia from spreading from the site of and endothelin B antagonists 74 There anterior ischemic optic neuropathy treated with. injury to the immediate retrobulbar por is an even larger army of available drugs intravenous prostaglandin E 1 and steroids Int J. Angiol 2010 19 3 e113 5 doi 10 1055 s 0031, tion of the nerve Accordingly experimen for potential pretreatment in ONC injury. tal studies of intravitreal brimonidine a Overall they are directed against reducing 7 Zhang C Guo Y Miller NR Bernstein SL Optic. peripherally acting 2 adrenergic agonist inflammation or its signaling molecules nerve infarction and post ischemic inflammation. reported an increase in short term RGC promoting survival or repair of damaged in the rodent model of anterior ischemic optic neu. survival after ONC 57 However this axons or preserving patency of the blood ropathy rAION Brain Res 2009 1264 67 75. doi 10 1016 j brainres 2008 12 075, effect is paradoxical in glaucoma brimoni supply Almost none have been clinically 8 Hayreh SS Zimmerman MB Nonar. dine was found to reduce aqueous humor tested teritic anterior ischemic optic neuropa. production by inducing vasoconstriction thy natural history of visual outcome. whereas in rAION the decreased RGC Ophthalmology 2008 115 2 298 305. SUMMARY doi 10 1016 j ophtha 2007 05 027, loss would be expected to be secondary to There is still no widely recognized treat 9 Giambene B Sodi A Sofi F Marcucci R Fedi.
improved perfusion Furthermore a study ment for NA AION Evidence from ani S Abbate R et al Evaluation of traditional and. conducted to evaluate the effects of bri mal models of NA AION generally sug emerging cardiovascular risk factors in patients. monidine on AION revealed worse vision with non arteritic anterior ischemic optic neu. gests that reducing edema and inflamma, in those who received brimonidine 58 ropathy a case control study Graefes Arch Clin Exp. tion in the acute phase might be effective Ophthalmol 2009 247 5 693 7 doi 10 1007. Therefore brimonidine in the ONC setting Intravitreal injections are becoming more s00417 008 0981 6. may promote axonal growth 59 rather commonly used 10 Salomon O Huna Baron R Kurtz S Steinberg DM. than affect vasoactivity protect the RGCs The availability of drugs and the direct Moisseiev J Rosenberg N et al Analysis of pro. in conditions of elevated intraocular pres thrombotic and vascular risk factors in patients. approach into the eye may be the best with nonarteritic anterior ischemic optic neuropa. sure 60 and increase levels of brain approach to therapy during the acute thy Ophthalmology 1999 106 4 739 42 doi 10. derived neurotrophic factor BDNF 61 phase allowing support for the injured 1016 S0161 6420 99 90159 8. There are as yet no studies of the effect RGCs Improving RGC survival and reduc 11 Kawasaki A Purvin VA Burgett RA Hyperhomo. of brimonidine on the oligodendrocytes ing axonal damage after NA AION is cysteinaemia in young patients with non arteritic. which are necessary for optic nerve axonal anterior ischaemic optic neuropathy Br J Oph. an active topic of investigation direct thalmol 1999 83 11 1287 90 doi 10 1136 bjo. health and are directly injured by ONC ing future goals of neuronal regener 83 11 1287. Brimonidine may be generally protective ation or retinal neurogenesis Cellular 12 Biousse V Kerrison JB Newman NJ Is non. when axonal regrowth is required after therapy either by systemic transplanta arteritic anterior ischaemic optic neuropathy. rAION related to homocysteine Br J Ophthalmol 2000. tion or intravitreous administration might, It is noteworthy however that findings 84 5 555 doi 10 1136 bjo 84 5 554c. become the next mode of treatment to 13 Hayreh SS Podhajsky P Zimmerman MB Role. of enhanced RGC survival after rAION improve visual outcome in NA AION of nocturnal arterial hypotension in optic nerve. 62 following pretreatment with brimoni head ischemic disorders Ophthalmologica 1999. dine were not replicated in models of ACKNOWLEDGMENTS 213 2 76 96 doi 10 1159 000027399. NA AION 58 63 Furthermore the sud 14 Archer EL Pepin S Obstructive sleep apnea and. This work was supported in part by the nonarteritic anterior ischemic optic neuropathy. den onset of NA AION and the typi Zanvyl and Isabelle Krieger Fund Balti evidence for an association J Clin Sleep Med 2013. cally delayed diagnosis make brimonidine more MD USA NGC Israel Science 9 6 613 8 doi 10 5664 jcsm 2766. pretreatment for NA AION impractical Foundation 1189 12 NGC 15 Waller EA Bendel RE Kaplan J Sleep disorders and. although translating from bench to clinic the eye Mayo Clin Proc 2008 83 11 1251 61. brimonidine might be used prophylacti doi 10 4065 83 11 1251. cally in the fellow unaffected eye of patients REFERENCES 16 Behbehani R Mathews MK Sergott RC Savino PJ. 1 Hayreh SS Ischemic optic neuropathy Prog Nonarteritic anterior ischemic optic neuropathy in. with NA AION Retin Eye Res 2009 28 1 34 62 doi 10 1016 j patients with sleep apnea while being treated with. High doses of estrogen 64 were found preteyeres 2008 11 002 continuous positive airway pressure Am J Oph. to have no therapeutic value in rAION 2 Hayreh SS Ischemic optic neuropathies where thalmol 2005 139 3 518 21 doi 10 1016 j ajo. compatible with the lack of gender speci are we now Graefes Arch Clin Exp Ophthalmol 2004 11 004. 2013 251 8 1873 84 doi 10 1007 s00417 013 17 Bilgin G Koban Y Arnold AC Nonar. ficity in NA AION outcome although 2399 z teritic anterior ischemic optic neu. women are considered protected until 3 Banik R Nonarteritic anterior ischemic optic neu ropathy and obstructive sleep apnea. menopause ropathy an update on demographics clinical pre J Neuroophthalmol 2013 33 3 232 4. Aside from G CSF 54 55 other exoge sentation pathophysiology animal models prog doi 10 1097 WNO 0b013e31828eecbd. nous compounds were found to have a pro nosis and treatment J Clin Exp Ophthalmol 2013 18 Kolb SD Backhouse O Obstructive sleep apnoea. S3 004 doi 10 4172 2155 9570 S3 004 prevalence in non arteritic anterior ischaemic. tective effect against some aspects of ONC 4 Luneau K Newman NJ Biousse V Ischemic optic optic neuropathy a response Br J Ophthal. when administered after injury includ neuropathies Neurologist 2008 14 6 341 54 mol 2013 97 6 794 doi 10 1136 bjophthalmol. ing crystallin 65 BDNF 66 68 the doi 10 1097 NRL 0b013e318177394b 2013 303179. www frontiersin org July 2014 Volume 5 Article 122 3. Nicholson et al Preclinical research to treat NA AION. 19 Landau K Winterkorn JM Mailloux LU Vetter W 34 Atkins EJ Nonarteritic anterior ischemic optic cells association with axonally transported pro. Translational preclinical research may lead to improved medical management of non arteritic anterior ischemic optic neuropathy James D Nicholson 1 2 Hana Leiba 3 4 and Nitza Goldenberg Cohen 1 2 5 1 The Krieger Eye Research Laboratory Felsenstein Medical Research Center PetachTikva Israel 2 Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel 3 Department of Ophthalmology

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