Site-based customized surgical approaches for orbital lesion and their outcomes - A case series.

INTRODUCTION AND IMPORTANCE: The orbit is a complex region of the body that is susceptible to several diseases. The term "anterior orbitotomy" describes access to the orbit through the conjunctiva or eyelid from the front. This includes transconjunctival, medial, inferior, and superior approaches. The superior and lateral regions of the posterior orbit can be adequately exposed using a frontotemporal orbitozygomatic approach. The main aim of orbital surgery is to preserve vision. We discuss numerous surgical procedures for ocular tumours in this case series, along with the results of those procedures. CASE PRESENTATION: In this case series, various surgical procedures for ocular tumours are discussed, along with their results postoperatively. Meningioma, cavernous hemangioma, dermoid, and Erdheim Chester disease were among the diagnoses. The early surgical outcome parameters in this case series were increased ocular motility and decreased proptosis. CLINICAL DISCUSSION: A medial orbitotomy was done as the lesion was in the medial orbit in our first case. In the second, third, and fourth cases, lateral orbitotomies were done because the lesion was in the lateral orbit. The frontotemporal orbitozygomatic approach was used in the fifth and sixth cases with the lesion reaching the orbital apex. Patients with symptoms should consider surgical excision, which involves completely removing the tumour while maintaining the functionality of the muscles and optic nerve. Having a good surgical view and exposure is essential to understand the anatomical relationships in a small area. CONCLUSION: The surgical strategy should be used in a manner that maintains visual acuity, limits injury to nearby objects, lowers postoperative morbidity, and is cosmetically acceptable.

Varicella Zoster Reactivation Manifesting as Serpiginous Peripheral Keratitis and Disciform Keratitis Occurring After Necrotizing Fasciitis in an Immunocompromised Male: A Case Report.

Reactivation of herpes zoster ophthalmicus (HZO) can present as corneal involvement without any precedent neuralgia or characteristic herpetic rash. This form of HZO can be the first manifestation of reactivation of varicella zoster virus and can masquerade as peripheral ulcerative keratitis. A 45-year-old male treated for necrotizing fasciitis (NF) one month back presented with painful diminution of vision in the right eye (RE) for two weeks without any associated vesicular rash or neuralgia. On examination, best-corrected visual acuity in RE was 2/60 with non-marginal upper lid defect, and multiple linear contracture scars involving the upper lid, right temple, and preauricular region. There were associated peripheral corneal ring infiltrates, disc-shaped central stromal edema, and reduced corneal sensation. The patient had a history of chicken pox in childhood and was recently diagnosed with seropositive rheumatoid arthritis (RA). Though corneal scrapings were negative on Tzanck smear, a presumptive clinical diagnosis of herpetic disciform keratitis was made, and the patient was started on oral and topical acyclovir with steroids. This was confirmed with improving clinical course and detection of herpes zoster DNA on polymerase chain reaction from corneal scrapings. Lid reconstruction for associated lid defect was performed using paramedian forehead flap, which was remodeled at 16 weeks. Our case, a seropositive RA patient, had reactivation of varicella zoster manifesting as peripheral serpiginous and disciform keratitis activated after NF. There are a few case reports of periorbital NF following HZO in immunocompromised patients. However, till date, no case of HZO occurring after periorbital NF has been reported. Also, in our case, reactivation of HZO presented as disciform and serpiginous keratitis without any precedent herpetic rash or neuralgia.

Surgical Outcomes of Levator Resection in Moderate and Severe Ptosis With a Good Levator Function: A Retrospective Study.

INTRODUCTION: An abnormally drooping upper eyelid in comparison with the normal position in primary gaze refers to ptosis. Levator resection should be the procedure of choice in patients with moderate to severe ptosis and a good levator function. METHODS: In this retrospective study, we analysed the surgical outcomes after large and maximal levator resection in patients with moderate and severe ptosis with a good levator function and Bell's phenomenon. All patients had a good levator function; therefore, levator resection was the procedure of choice. We performed levator resection of 20 mm and above and the desired post-operative correction was achieved. RESULTS: One patient had microcornea, and hence, he was undercorrected and his post-operative marginal reflex distance 1 (MRD 1) was 3 mm. Two patients who had severe ptosis pre-operatively had a post-operative MRD 1 of 3 mm. Rest of the patients had a post-operative MRD 1 of 4 mm. CONCLUSION: Levator resection of 20 mm or more should be performed in patients with congenital simple ptosis with a good levator function and Bell's phenomenon to achieve a favourable post-operative outcome.

Screening of BACE1 inhibitors with antiamyloidogenic activity: A study of flavonoids and flavonoid derivatives.

Aggregates of ß-amyloid peptide are found to occur in brains of AD patients and are formed upon sequential cleavage of the amyloid precursor protein by BACE1 and γ-secretase. Strategies inhibiting either peptide aggregation or the rate limiting enzyme BACE1 have been in demand for its implication in AD therapeutics. The present study is undertaken to mine compounds with dual ability. In this context, some natural compounds that were already predicted as BACE1 inhibitors by our group, were further tested for their activity as aggregation inhibitors. A pharmacophore model built with known antiamyloidogenic compounds was then applied for screening the natural compounds previously predicted as BACE1 inhibitors. Subsequently experimental validation by Thioflavin-T and Aß-GFP assay filtered four compounds genistein, syringetin, tamarixetin and ZINC53276039. Out of them, ZINC53276039 showed promising antiamyloidogenic activity to act as a potent inhibitor of aggregation. Interestingly, our previous study revealed syringetin and ZINC53276039 to be good BACE1 inhibitors while tamarixetin to be a moderate BACE1 inhibitor. These good to moderate BACE1 inhibitors with moderate to reasonable antiamyloidogenic activity might show potency in reducing the amyloid load of AD brains.

RAPD as a clinical alert for early evidence of dysthyroid optic neuropathy.

Dysthyroid optic neuropathy (DON) is a serious manifestation of thyroid eye disease (TED) resulting in permanent visual loss. There is controversy regarding the diagnostic features of DON. Relative afferent pupil defect (RAPD) in TED is highly specific for DON. Our first patient, a 42-year-old male presented with proptosis and intermittent blurring of vision with best corrected visual acuity of 6/6 in both eyes and right RAPD as an early sign of DON. Our second patient, a 54-year-old female presented with proptosis and clinical activity score <3 at the time of presentation. She developed intermittent blurring of vision with left RAPD on her second presentation as clue of bilateral asymmetric DON in her eyes, though BCVA was 6/6 both eyes. Both cases of bilateral asymmetric DON had RAPD as early specific sign of DON, which prompted us to do detailed radio-imaging to confirm DON, hence highlighting the importance of RAPD.

Apoptotic and autophagic death union by Thuja occidentalis homeopathic drug in cervical cancer cells with thujone as the bioactive principle.

OBJECTIVE: "Multi-targeting" drugs can prove fruitful to combat drug-resistance of multifactorial disease-cervical cancer. This study envisioned to reveal if Thuja homeopathic mother tincture (MT) and its bioactive component could combat human papillomavirus (HPV)-16-infected SiHa cervical cancer cells since it is globally acclaimed for HPV-mediated warts. METHODS: Thuja MT was studied for its antiproliferative and antimigratory properties in SiHa cells followed by microscopic determination of reactive oxygen species (ROS) generation by 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) staining and loss in mitochondrial membrane potential (MtMP) by rhodamine 123 (Rh123) staining. Apoptosis and autophagy inductions were studied by acridine orange/ethidium bromide (AO/EB) staining and immunoblot analyses of marker proteins. The bioactive component of Thuja MT detected by gas chromatography-mass spectrometry was studied for antiproliferative and antimigratory properties along with in silico prediction of its cellular targets by molecular docking and oral drug forming competency. RESULTS: Thuja MT showed significant antiproliferative and antimigratory potential in SiHa cells at a 50% inhibitory concentration (IC50) of 17.3 µL/mL. An increase in DCFDA fluorescence and loss in Rh123 fluorescence prove that Thuja MT acted through the burst of ROS and loss in MtMP respectively. AO/EB-stained cells under the microscope and immunoblot analyses supported Thuja-induced cellular demise via dual pathways-apoptosis and autophagy. Immunoblots showed cleavage of caspase-3 and poly(adenosine diphosphate-ribose) polymerase-1 (PARP-1) along with upregulation of Beclin-1, microtubule-associated protein 1 light chain 3B (LC3B)-II, and p62 proteins. Hence, the apoptotic cascade followed a caspase-3-dependent pathway supported by PARP-1 cleavage, while autophagic death was Beclin-1-dependent and mediated by accumulation of LC3BII and p62 proteins. Thujone, detected as the bioactive principle of Thuja MT, showed greater anti-proliferative and anti-migratory potential at an IC50 of 77 µg/mL, along with excellent oral drug competency with the ability for gastrointestinal absorption and blood-brain-barrier permeation with nil toxicity. Molecular docking depicted thujone with the strongest affinity for mammalian target of rapamycin, phosphoinositide 3-kinase, and protein kinase B followed by B-cell lymphoma 2, murine double minute 2 and adenosine monophosphate-activated protein kinase, which might act as upstream triggers of apoptotic-autophagic crosstalk. CONCLUSION: Robust "multi-targeting" anticancer potential of Thuja drug and thujone for HPV-infected cervical cancer ascertained its therapeutic efficacy for HPV infections.

Microspherophakia: A clinical approach and mini review with a case report.

Microspherophakia refers to a spherophakic lens with a decreased equatorial diameter. Microspherophakia can be found in systemic or ocular conditions, such as Marfan's syndrome, Weill-Marchesani syndrome, iridocorneal endothelial syndrome, and Axenfeld-Rieger syndrome. A 3-year-old girl was brought with complaints of eyes appearing larger, watering and inability to see bright light for 1 year. On examination, she had megalocornea; the cornea was clear with a shallow anterior chamber, and microspherophakic lens. Her intraocular pressure (IOP) was recorded as 43 and 32 mmHg in the right and left eyes, respectively. This article guides in classifying, categorizing, and managing a case with microspherophakia.

In silico investigation of the role of vitamins in cancer therapy through inhibition of MCM7 oncoprotein.

An overabundance of MCM7 protein, a component of the minichromosome maintenance complex that normally initiates DNA replication, has been reported to cause different types of cancers with aggressive malignancy. Inhibition of MCM7 may lead to a significant reduction in cancer-associated cell proliferation. Despite such significance of MCM7 in cancer, the protein structure is yet to be resolved experimentally. This significantly halts the structure-guided ligand designing for cancer therapy targeting the MCM7. The present study aims to resolve the tertiary structure of MCM7 and repurpose the FDA-approved clinically used drugs for cancer therapy by targeting MCM7 protein. The secondary and 3D structures of MCM7 were generated using multiple bioinformatics tools, including the Self-Optimized Prediction Method with Alignment (SOPMA), SWISS-MODEL, and I-TASSER. The reliability of the modeled structure was assessed using PROCHECK. Initially, a structure-guided virtual screening was performed on the approved drug library to identify potential hits against MCM7. The detailed molecular mechanism of receptor interactions of the identified hits was evaluated using extensive molecular dynamics simulation. The results from this study reveal an intriguing discovery of the potential of ergocalciferol (vitamin D2), cholecalciferol (vitamin D3), ergosterol (precursor of vitamin D2) and menaquinone (vitamin K2) as oncoprotein inhibitors for cancer therapy via inhibition of MCM7.

Structural and functional implications of leucine-rich repeats in toll-like receptor1 subfamily.

Leucine-rich repeats (LRRs) - the protein-protein and protein-ligand interaction motif of proteins participating in a plethora of functions in plants, vertebrates, invertebrates, and prokaryotes - are a fascinating piece of conserved yet versatile structural motif. In toll-like receptors (TLRs), this domain forms the extracellular part that is preceded by an intracellular toll/interleukin-1 receptor (TIR) domain. The extracellular part is crucial for recognizing a structurally diverse set of viral, bacterial, fungal, and parasite-derived components, while the TIR domain is recruited for activation of downstream signaling following recognition. The distinct ability of the paralogs TLR1 and TLR6 to dimerize with TLR2 and recognize different ligands intrigued and motivated us to exchange the dimerizing and ligand-binding residues between TLR1/6 and note the effect on dimer formation and ligand binding. The appreciable sequence modification brought about no significant alteration in the native scaffold of the motif, as revealed from the comparison of simulations with wild-type dimers. Moreover, docking of the exchanged ligands to the variant proteins supported favorable binding. Thus, the structural stability and the functional plasticity offered by the motif might be the reason for its extensive use across cellular functions and life forms, a feature crucial for coevolution and the knowledge essential for therapeutics.

Orbital Venolymphatic Malformation Treated With Sodium Tetradecyl Sulfate: A Case Report.

Orbital and periorbital venolymphatic malformations (VLMs) are benign congenital vascular lesions and constitute 1%-3% of all orbital masses. Widespread facial venous malformations have a high incidence of associated intracranial developmental venous anomalies (DVAs). In such cases, there can be a sudden increase in proptosis following upper respiratory infection or minor trauma. Numerous percutaneous intralesional sclerosing agents like sodium tetradecyl sulfate (STS), bleomycin, doxycycline, ethanol, and OK-432 (Picibanil) have been used for treating VLMs. We hereby report a rare case of retro-orbital VLM treated successfully with STS injection and an isolated dural arterio-venous (AV) fistula in the same patient.

Scope of ß-Secretase (BACE1)-Targeted Therapy in Alzheimer's Disease: Emphasizing the Flavonoid Based Natural Scaffold for BACE1 Inhibition.

Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common form of dementia in the world. Studies report the presence of extracellular amyloid plaques consisting of ß-amyloid peptide and intracellular tangles consisting of hyperphosphorylated tau proteins as the histopathological indicators of AD. The process of ß-amyloid peptide generation by sequential cleavage of amyloid precursor protein by ß-secretase (BACE1) and γ-secretase, followed by its aggregation to form amyloid plaques, is the mechanistic basis of the amyloid hypothesis. Other popular hypotheses related to the pathogenesis of AD include the tau hypothesis and the oxidative stress hypothesis. Various targets of the amyloid cascade are now in prime focus to develop drugs for AD. Many BACE1 inhibitors, ß-amyloid aggregation inhibitors, and Aß clearance strategies using monoclonal antibodies are in various stages of clinical trials. This review provides an in-depth evaluation of the role of BACE1 in disease pathogenesis and also highlights the therapeutic approaches developed to find more potent but less toxic inhibitors for BACE1, particularly emphasizing the natural scaffold as a nontoxic lead for BACE1 inhibition. Cellular targets and signaling cascades involving BACE1 have been highlighted to understand the physiological role of BACE1. This knowledge is extremely crucial to understand the toxicity evaluations for BACE1-targeted therapy. We have particularly highlighted the scope of flavonoids as a new generation of nontoxic BACE1 inhibitory scaffolds. The structure-activity relationship of BACE1 inhibition for this group of compounds has been highlighted to provide a guideline to design more selective highly potent inhibitors. The review aims to provide a holistic overview of BACE1-targeted therapy for AD that paves the way for future drug development.

Flavonoids as BACE1 inhibitors: QSAR modelling, screening and in vitro evaluation.

Alzheimer's disease (AD) is marked by the presence of amyloid plaques, neurofibrillary tangles, oxidatively damaged neuronal macromolecules and redox sensitive ions. Reduction of amyloid plaques and oxidative stress emerge as a convincing treatment strategy. Plaque reduction is achieved by inhibition of BACE1, the rate limiting enzyme generating the prime constituent of plaques, Aß, through proteolysis of the amyloid precursor protein. Here, we report a QSAR model with five descriptors, developed to screen natural compounds as potent BACE1 inhibitors. Seven compounds out of which five flavonols namely isorhamnetin, syringetin, galangin, tamarixetin, rhamnetin and two flavanonols namely dihydromyricetin, taxifolin were screened. The ability of these compounds were validated using the BACE1 activity assay. The antioxidant property were estimated by the DPPH and ABTS assay. Although inhibition assay implied syringetin to be a promising BACE1 inhibitor, its poor antioxidant activity leaves it less effective as a multitarget ligand. Exhibiting moderate dual ability, isorhamnetin and taxifolin qualified as multi-target scaffolds for AD therapeutics. Our study reveals the importance of 4'-OH in the B ring of flavonols and the lack of any effect of 5'-OH in flavanonols for BACE1 inhibition. In case of antioxidant activity favourable association of 3'-O-methylation derivatives was observed in flavonols.

Hybrid approach to sieve out natural compounds against dual targets in Alzheimer's Disease.

Excess Aß production by the key protease BACE1, results in Aß aggregation, forming amyloid plaques, all of which contribute to the pathogenesis of Alzheimer's disease. Besides the multi-factorial nature of the disease, the diversity in the size and shape of known ligands that bind to the active site of BACE1, that is the flexibility of the enzyme, pose a serious challenge for the identification of drug candidates. To address the issue of receptor flexibility we have carried out ensemble docking with multiple receptor conformations. Therein, two representative structures each from closed and semi-open BACE1 conformations were selected for virtual screening to identify compounds that bind to the active site of both the conformations. These outperformed compounds were ranked using pharmacophore models generated by a ligand-based approach, for the identification of BACE1 inhibitors. The inhibitors were further predicted for anti-amyloidogenic activity using a QSAR model already established by our group thus enlisting compounds with dual potency. BACE1 inhibitory and anti-amyloidogenic activity for the commercially available compounds were validated using in vitro studies. Thus, incorporation of receptor flexibility in BACE1 through ensemble docking in conjunction with structure and ligand-based approach for screening might act as an effective protocol for obtaining promising scaffolds against AD.

Flavanone glycosides inhibit ß-site amyloid precursor protein cleaving enzyme 1 and cholinesterase and reduce Aß aggregation in the amyloidogenic pathway.

Alzheimer's disease (AD) is a slow but progressive neurodegenerative disease. One of the pathological hallmarks of AD is the progressive accumulation of ß-amyloid (Aß) in the form of senile plaques, and Aß insult to neuronal cells has been identified as one of the major causes of AD onset. In the present study, we investigated the anti-AD potential of four flavonoids, naringenin, didymin, prunin, and poncirin, by evaluating their ability to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and ß-site amyloid precursor protein cleaving enzyme 1 (BACE1). All four flavonoids displayed promising inhibitory activity against AChE, BChE, and BACE1. Structure-activity relationships suggested that glycosylation of naringenin at sugar moieties, and at different positions of the glycosidic linkage, might be closely associated with anti-AD potential. Kinetic and docking studies showed the lowest binding energy and highest affinity for the mixed, competitive, and non-competitive type inhibitors didymin, prunin, and poncirin. Hydrophobic interactions and the number of hydrogen bonds determined the strength of the protein-inhibitor interaction. We also examined the neuroprotective mechanisms by which flavonoids act against Aß25-35-induced toxicity in PC12 cells. Exposure of PC12 cells to 10 µM Aß25-35 for 24 h resulted in a significant decrease in cell viability. In addition, pretreatment of PC12 cells with different concentrations of flavonoids for 1 h significantly reversed the effects of Aß. Furthermore, treatment with the most active flavonoid, didymin, significantly reduced BACE1, APPsß, and C99 expression levels in a dose-dependent manner, without affecting amyloid precursor protein (APP) levels in the amyloidogenic pathway. Together, our results indicate that flavonoids, and in particular didymin, exhibit inhibitory activity in vitro, and may be useful in the development of therapeutic modalities for the treatment of AD.

Multi-targeting Strategies for Alzheimer's Disease Therapeutics: Pros and Cons.

Alzheimer's Disease (AD) is a single major cause of dementia in middle to old age individuals involving several different etiopathological mechanisms that are yet to be properly characterized. Major invariant and characteristic features consist of the progressive cerebral deposition of the Amyloid ß-protein (Aß) and the neurofibrillary degeneration through Neurofibrillary Tangles (NFT) formed by hyperphosphorylation of the tau proteins in the regions of the brain that deal with memory and cognition. There are at least five subgroups of AD that can be identified by determining Cerebrospinal Fluid (CSF) levels of Aß1-42, tau and ubiquitin. This multifactorial nature of the disease thus demands promising approaches for the development of rational disease-modifying drugs. A large number of agents have been discovered against individual targets but the success rate is very low and the number of compounds progressing to regulatory review is among the lowest found in any therapeutic area. A very promising modern approach solicits the design of Multi-Target-Directed Ligands (MTDLs) based on the "one molecule multiple targets" paradigm that has been specifically adopted for the treatment of disorders with complex pathological mechanisms. AD is one such disorder in which MTDL has found applicability. This review aims at providing an overview of the research carried out in discovering more efficient treatment against AD using MTDL, with a goal to ascertain safer drugs.

Valvular heart disease and anaesthesia.

Valvular heart disease presents as mixed spectrum lesion in healthcare settings in the third-world and developing countries. Rheumatic heart disease still forms the bulk of the aetiopathology of valve lesions. Mitral and aortic valve lesions top the list of valvular pathology. A thorough understanding of the pathophysiology of valvular heart disease is essential while planning anaesthesia and perioperative care for such patients. Meticulous use of optimal fluids, close monitoring of the changing haemodynamics and avoidance of situations that can cause major reduction of cardiac output and fluid shifts are mandatory to achieve good clinical outcome. We searched MEDLINE using combinations of the following: anaesthesia, aortic, mitral, regurgitation, stenosis and valvular heart disease. We also hand searched textbooks and articles on valvular heart disease and anaesthesia. This article mainly focuses on the understanding the pathophysiology of valvular heart disease in patients presenting for non-cardiac surgeries in secondary and tertiary care setting.

Thyromental height test for prediction of difficult laryngoscopy in patients undergoing coronary artery bypass graft surgical procedure.

BACKGROUND: Patients undergoing coronary artery bypass graft (CABG) procedures have higher incidence of difficult laryngoscopy and intubation than general surgery population. Accurate prediction of difficult laryngoscopy in CABG patients is desirable to reduce the hemodynamic response and myocardial oxygen requirements. Recently, thyromental height test (TMHT) has been proposed as one of the highly sensitive and specific bedside tests to predict difficult airway. We, in our prospective observational study, evaluated the accuracy of the TMHT in predicting difficult laryngoscopy. METHODOLOGY: A total of 345 patients undergoing CABG of either sex, in the age group of 35-80 years, American Society of Anesthesiologists 111, undergoing CABG, were studied. Airway assessment was performed with modified Mallampati test with the addition of thyromental distance, sternomental distance, and TMHT. Intraoperatively, direct laryngoscopy was done in accordance with Cormack and Lehane grade of laryngoscopy. The preoperative data and laryngoscopic findings were used together to evaluate the accuracy of TMHT. The sensitivity, specificity, positive and negative predictive values of other three tests were calculated according to standard formula. RESULTS: A total of 345 patients were in the group with mean age of study population at 56.7 (standard deviation 9.1) years (35-80 years). This study showed that almost all tests had good specificity, but sensitivity was poor. However, sensitivity of TMHT was 75% with accuracy of 95%. Receiver operating characteristic curve analysis of TMHT-derived cutoff was 52.17 which increased sensitivity to 81.25% and specificity to 92.3%. CONCLUSION: TMHT had a higher sensitivity compared to other tests along with good positive and negative predictive value and a very high specificity.

Lipopolysaccharide and cyclic AMP regulation of CB(2) cannabinoid receptor levels in rat brain and mouse RAW 264.7 macrophages.

CB(2) cannabinoid receptors exist in immune cells including macrophages. Affinity-purified antibodies against the CB(2) receptor identified a 45 kDa protein in rat brain, human tonsil and rat and mouse microglia, but not mouse N18TG2 neuroblastoma cells. Intracerebroventricular lipopolysaccharide (LPS) increased immunoreactive CB(2) receptors in brain membranes detected by Western blot. LPS increased immunodetectable CB(2) receptors in cultured RAW 264.7 macrophages, and this was partially attenuated by cyclohexamide or the protein kinase A and C inhibitors H8 and bis-indolylmaleimide. Forskolin or dibutyryl cyclic AMP increased CB(2) receptor immunoreactivity, suggesting the involvement of the cyclic AMP-protein kinase A-Cyclic AMP response element pathway in the regulation of CB(2) receptor levels.

Fragment-based designing for the generation of novel leads against BACE1.

BACE1, the aspartate protease that generates amyloid-ß peptide (Aß) in the brain of AD (Alzheimer's disease) patients, has emerged as a pharmaceutically relevant target. Here, a fragment-based in silico approach has been adopted to design novel compounds with increased ligand efficiency for BACE1, before screening for brain permeability and toxicity. Fragments docked to the active site of BACE1 and sorted into two groups using binding energy cut-off, were joined to create novel ligands with binding energy lying in the range between -11.36 kcal/mol and -8.56 kcal/mol. Interestingly, QIN, a known inhibitor of BACE1 with an IC50 of 11nM, when docked to BACE1, shows a binding energy (-9.43 kcal/mol) lying within the range of the novel ligand-BACE1 complexes. The present strategy thus enabled the design of four novel inhibitors of BACE1 with favourable binding energy, brain permeability and no toxicity that might show promise as leads in future.

A prodrug of a selective inhibitor of inducible nitric oxide synthase is neuroprotective in the rat model of glaucoma.

PURPOSE: To test the hypothesis that nitric oxide, synthesized by inducible nitric oxide synthase, causes degeneration of retinal ganglion cells in an animal model of glaucoma. METHODS: Rats with unilateral, chronic, moderately elevated intraocular pressure were treated orally with L-N(6)-(1-iminoethyl)lysine 5-tetrazole amide, a prodrug of an inhibitor of inducible nitric oxide synthase. The loss of retinal ganglion cells was quantitated as an indicator of glaucomatous damage. RESULTS: At the end of seven months, rat eyes with chronic, moderately elevated intraocular pressure lost approximately 20,000 retinal ganglion cells. Treatment with L-N(6)-(1-iminoethyl)lysine 5-tetrazole amide for seven months completely prevented the loss of retinal ganglion cells in eyes with chronic, moderately elevated intraocular pressure. When treatment with L-N(6)-(1-iminoethyl)lysine 5-tetrazole amide was delayed and started after three months of chronic, moderately elevated intraocular pressure, further loss of retinal ganglion cells was prevented. CONCLUSION: Pharmacological neuroprotection with a selective inhibitor of inducible nitric oxide synthase may be useful for the treatment of glaucoma.