A snapshot on introspection of autism spectrum disorder.

Autism spectrum disorder is a neurodevelopmental condition marked by restricted interests and difficulty with social communication. ASD is characterized by heightened neuroinflammation and irregular neuronal connections. ASD is more frequent in male than female with male-female ratio of around 4:1. ASD affects 2.8% or 1 in 36 8-year-olds, based on the CDC's Morbidity and Mortality Weekly Report. Various factors like Environmental, Genetic, Epigenetic and Developmental factors are linked with genesis of ASD. Repetitive behaviors, Impaired communication skills, difficulty with social interaction are some of the clinical features of ASD. Current Pharmacotherapy of ASD limits to management of symptoms only, not cure. The stem cell therapy has a promising potential to be a breakthrough in treating ASD. Various types of stem cells have been successfully tested in children with ASD. AI has a potential to emerge as a tool for early detection of ASD. Robotics can assist the children with ASD to overcome the challenges associated with ASD.

Triphala Ameliorates Nephropathy via Inhibition of TGF-ß1 and Oxidative Stress in Diabetic Rats.

INTRODUCTION: Advanced glycation end products, oxidative stress, and TGF-ß expression play a crucial role in pathophysiology of diabetic nephropathy. Inhibition of oxidative stress and TGF-ß expression by natural traditional medicines may give an economic and safe alternative treatment option. Triphala churna, a traditional medicine, has been proved to have potent antioxidant activity, and individual components of it have shown significant antidiabetic activity. Hence, the present study was designed to study the effect of Triphala churna in diabetic nephropathy in rats. METHODS: Diabetes was induced in rats by administration of streptozotocin (55 mg/kg i.p.). Four weeks after induction of diabetes, the animals were treated with Triphala churna at the doses of 250, 500, and 1,000 mg/kg for next 4 weeks. Various biochemical and urine parameters such as glucose, creatinine, blood urea nitrogen (BUN), total protein, and albumin were assessed at the end of study. Creatinine clearance, BUN clearance, and glomerular filtration rate were determined. Oxidative stress parameters such as malondialdehyde, catalase, reduced glutathione, and superoxide dismutase were determined in kidney tissues. TGF-ß1 expression was measured with ELISA, immunohistochemistry, and western blot techniques. Histopathology study was carried out with haemotoxylin and eosin, periodic acid-Schiff, and Masson's trichrome staining to determine histological changes. RESULTS: Treatment with Triphala churna significantly improved urine parameters. Triphala churna treatment also improved plasma proteins, albumin, creatinine, and BUN levels. The oxidative stress was reduced in the kidney with the treatment of Triphala churna. Histopathological studies revealed that Triphala churna reduced kidney damage. Immunohistochemistry, ELISA, and western blotting study revealed that treatment with Triphala decreased the expression of TGF-ß in kidney tissues. CONCLUSION: From the results, it can be concluded that Triphala churna has a significant nephroprotective effect because of its capability of inhibiting oxidative stress and TGF-ß in diabetes.

Development of collateral vessels: A new paradigm in CAM angiogenesis model.

The chorioallantoic membrane (CAM) assay is one of the most widely used models to study angiogenesis. In this study, collateral vessel development is reported in CAM assay useful in analysis of angiogenesis. Four days old white Leghorn fertilized chicken eggs were inoculated with vehicle, standard or test angiogenesis inhibitor using standard protocol. Central vessel growth was seen tapering down and collateral vessels were developed from the lower side of the chorioallantoic membrane moving upward in 12 days old standard or test treated CAMs. In the absence of the central vessel, collateral blood supply helped in survival of embryos. Hence, development of collateral vessels was used for ranking of blood vessels and angiogenesis in addition to well-known standard parameters related to central vessel. The finding could differentiate molecules inhibiting angiogenesis with or without collateralization which is crucial in anti-angiogenic therapy used for cardiovascular diseases and cancer. This study proposes a new avenue to distinguish pro-angiogenic molecules from anti-angiogenic ones as well as anti-angiogenic molecules which may or may not support alternative vascularization pathway that would have great impact on future angiogenic and anti-angiogenic therapy.

Impact of pre-exposure of tail suspension on behavioural parameters like locomotion, exploration, and anxiety in mice.

The tail suspension test (TST) is a valid tool for assessing antidepressant activity. Association between depression and lower locomotion and exploration activities is also reported. In the present study, photoactometer, hole board and elevated plus maze tests were performed to evaluate locomotion, exploration and anxiety activities on animals of first and second set, however animals of second set were pre-exposed to TST. The comparison between these two sets will help in understanding the impact of pre-exposure to TST on behavioural parameters. In both sets, swiss albino mice were treated with caffeine (10 mg/kg, ip), bupropion (10 mg/kg, ip), duloxetine (10 mg/kg, ip), nicotine (0.8 mg/kg, sc) and normal saline. Control group of second set showed significant decrease in locomotion, exploration and increase in anxiety when compared against control group of first set. In second set, duloxetine, bupropion, and nicotine treated groups showed significant increase in locomotion when compared against control group of same set. Overall, pre-exposure to TST leads to significant decrease in locomotion, exploration activities and increase in anxiety level. Further studies demonstrating it's time bound impact on brain monoamine levels with correlation to behavioural paradigms may help to validate these outcomes.

Minocycline with aspirin: an approach to attenuate diabetic nephropathy in rats.

Degradation of extracellular matrix (ECM) by enhanced production of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in diabetes leads to nephropathy. Cyclooxygenases (COX) further increase levels of these MMPs. The objective of present study was to inhibit MMP-2 and MMP-9 by combination of minocycline and aspirin to treat diabetic nephropathy. Diabetes was induced in male Wistar rats by streptozotocin (STZ, 55 mg/kg i.p.). Four weeks after diabetes induction, the rats were treated with minocycline (50 mg/kg, p.o.), aspirin (50 mg/kg, p.o.), or minocycline (50 mg/kg, p.o.) plus aspirin (50 mg/kg, p.o.) for a period of 4 weeks. At the end of eighth week fluid input, urine output, and renal function tests were carried out for diagnosis of diabetic nephropathy. Renal hypertrophy was measured and histopathology was done to evaluate renal damage. Diabetes produced significant loss of body weight, polyuria, polydipsia, hyperglycemia, and increase in blood pressure. Serum creatinine, urea, and blood urea nitrogen levels were found to be increased significantly in the STZ group diabetic rats. Treatment with combination of minocycline and aspirin significantly prevented the rise in creatinine, urea, and blood urea nitrogen levels and increased creatinine clearance. Image analysis of kidneys revealed that collagen level was significantly decreased in combined treated group when compared with control. Results of present study suggest that MMP-2 and MMP-9 inhibition in presence of COX inhibitor prevents the development of experimental diabetic nephropathy in rats and can be a potential approach for the treatment.

Triphala Churna-A Traditional Formulation in Ayurveda Mitigates Diabetic Neuropathy in Rats.

Neuropathy is a common complication of diabetes affecting a large number of people worldwide. Triphala churna is a formulation mentioned in Ayurveda-a traditional system of medicine. It is a simple powder formulation consisting of powders of three fruits, Emblica officinalis L., Terminalia bellirica (Gaertn.) Roxb. and Terminalia chebula Retz. Individual components of Triphala churna have anti-diabetic and antioxidant activities. Hence, this study was designed to evaluate the effect of Triphala churna on diabetic neuropathy. Diabetes was induced with streptozotocin (STZ, 55 mg/kg, i. p.) in rats. Animals were grouped and treated orally with Triphala churna at a dose of 250, 500, and 1,000 mg/kg after 6 weeks of diabetes induction for the next 4 weeks. At the end of study, parameters such as body weight, plasma glucose level, motor nerve conduction velocity were determined. The effect of Triphala churna on thermal hyperalgesia, mechanical hyperalgesia, and mechanical allodynia was also determined at the end of study. The plasma cytokine levels like TGF-ß1, TNF-α, and IL-1ß were determined by ELISA assay. Histopathology study of the sciatic nerve was studied. Western blotting was performed to study the expression of neuronal growth factor.Treatment with Triphala churna showed a significant reduction in plasma glucose and a significant rise in body weight. Triphala treatment significantly increased the motor nerve conduction velocity and decreased the thermal and mechanical hyperalgesia, as well as mechanical allodynia. The treatment significantly inhibited levels of circulatory cytokines like TGF-ß1, TNF-α, and IL-1ß. Histopathology study confirmed the neuroprotective effect of Triphala churna. The expression of NGF was significantly increased in sciatic nerves after treatment with Triphala churna. From the results, it can be concluded that Triphala churna delays the progression of neuropathy in diabetic rats.

The effect of bupropion augmentation of minocycline in the treatment of depression.

The aim of the current study was to analyse the augmentation of minocycline with bupropion in treating depression. 'Saline' (10 ml/kg), 'minocycline per se' (25 mg/kg), 'minocycline per se' (50 mg/kg), 'bupropion per se' (5 mg/kg), 'bupropion per se' (10 mg/kg) and 'bupropion + minocycline' (5 mg/kg + 25 mg/kg each) were administered to mice via the intraperitoneal route. In the forced swim and tail suspension test, the immobility period was analysed after 30 min of the treatment. Monoamines like dopamine, norepinephrine and serotonin levels were analysed in brain areas such as the whole brain, hippocampus and cerebral cortex using an HPLC-fluorescence detector. Euthanasia of mice was performed 1 h after treatment. Comparison between the control group and combination therapy and other standard drug groups showed a significant decrease in immobility in both antidepressant animal models. The combination of bupropion and minocycline showed greater benefits with respect to a reduction in the immobility time period and enhancement of dopamine, serotonin, and norepinephrine levels in the cerebral cortex, hippocampus and the whole brain when compared to the monotherapy treated groups. Hence, the side effects may be reduced drastically through this combination by a reduction in the bupropion/minocycline dosage.

In vitro evaluation of hepatic and extra-hepatic metabolism of coumarins using rat subcellular fractions: correlation of in vitro clearance with in vivo data.

7-Ethoxycoumarin (7-EC) and 7-hydroxycoumarin (7-HC) were chosen as model compounds to study hepatic and extra-hepatic metabolism in rat tissue subcellular (microsomal and S9) fractions and to scale the observed in vitro clearance to in vivo plasma clearance. 7-EC and 7-HC showed significant metabolic degradation in liver subcellular fractions as compared to subcellular fractions obtained from intestine, kidney, lung and brain. The total in vitro metabolic clearance for 7-EC and 7-HC was determined by adding the individual in vitro organ clearance values obtained in hepatic and extra-hepatic microsomes or S9 fractions. The predicted in vivo clearance for 7-HC was 63.6 and 81.6 ml/min/kg by in vitro scaling from microsomes and S9 fractions, respectively. For 7-EC, the values were 78.5 and 76.8 ml/min/kg, respectively. The predicted clearance was found to be reasonably accurate with slight over- and underprediction. Interestingly, the relative contribution of hepatic and extra-hepatic metabolism to the total clearance of 7-EC and 7-HC was remarkably high, ranging from 62-77% and 22-38%, respectively, of the total metabolic clearance. It is concluded that the model of multi-organ subcellular fractions is a useful in vitro tool for the prediction of in vivo metabolic clearance, as it can provide information about the relative contribution of extra-hepatic and hepatic metabolism to total metabolic clearance.

Catechin attenuates diabetic autonomic neuropathy in streptozotocin induced diabetic rats.

Diabetic autonomic neuropathy (DAN) is one of the least understood and attended complications which affects the quality of life. Increased oxidative stress, advanced glycation end products (AGEs), overactivation of protein kinase C (PKC) and reduced myoinositol content in autonomic nerves are major pathological conditions responsible for DAN. Limited treatment options appeal researchers to search for alternative treatments for DAN. Natural polyphenols are potent antioxidants and have been reported to have beneficial effects in above mentioned pathological conditions. Diabetes was induced in male Sprague Dawley rats weighing between 190-220 g with streptozotocin (55 mg/kg, i.p.). After 6 weeks of diabetes induction, animals were treated with catechin at dose 25 and 50 mg/kg for the next 28 days. Catechin treatment at dose 25 and 50 mg/kg showed significant improvement in body weight. The treatment with catechin at dose 50 mg/kg; significantly reduced heart hypertrophy (p < 0.001) and plasma glucose levels (p < 0.01). At dose 50 mg/kg catechin significantly improved hemodynamic parameters like heart rate, mean atrial pressure and left ventricular systolic pressure. Catechin also improved oxidative stress parameters in the nerves. Circulatory MMP-9 levels were significantly decreased (p < 0.001) in catechin treated animals at a dose of 50 mg/kg. The histopathology results showed a significant reduction in neuronal damage due to catechin treatment for 28 days. The results of the study showed that catechin has a beneficial effect in the management of diabetic autonomic neuropathy in rats.

Preventive measures in oral cancer: An overview.

Worldwide oral cancer is creating an alarming situation and it's a matter of global concern as it is the 11th most common carcinoma around the globe. After cardiovascular ailments, cancer is the next biggest killer. Approximately 90% of the total oral malignancies are squamous cell carcinomas. The etiological base of oral cancer is tobacco intake, smoking, smokeless tobacco (snuff or chewing tobacco), alcohol and areca nut intake, excessive sunlight exposure, reverse end smoking and Human Papilloma Virus (HPV). The treatment measures for oral cancer are very costly and affordability is low. So, taking preventive measures at the first place itself is of immense importance. Preventive measure is a multidisciplinary approach involving co-ordinated efforts from all the sectors of the society. The preventive measures are categorised into primary, secondary and tertiary measures. Along with the various screening tests employed to detect oral cancer the review focuses on biomarkers, melatonin, tea constituents, polyphenols, chemoprevention, Chios mastic gum extract, Poly (ADP-ribose) Polymerase 1 (PARP1) targeted optical imaging agent, and their role in oral cancer prevention and control. The review gives a brief outline on the preventive measures to be adopted to help prevent oral cancer and improve the quality of life.

Investigation into the Role of PI3K and JAK3 Kinase Inhibitors in Murine Models of Asthma.

Asthma is a clinical disorder commonly characterized by chronic eosinophilic inflammation, remodeling and hyper responsiveness of the airways. However, the kinases like Phosphoinositide 3 kinase (PI3K) and Janus kinase 3 (JAK3) are involved in mast cell proliferation, activation, recruitment, migration, and prolonged survival of inflammatory cells. The present study was designed to evaluate the in-vivo comparative effects of two kinase inhibitors on airway inflammation and airway remodeling in acute and chronic models of asthma. Mice were sensitized twice intra-peritoneally and then challenged by inhalation with ovalbumin (OVA). They developed an extensive inflammatory response, goblet cell hyperplasia, collagen deposition, airway smooth muscle thickening similar to pathologies observed in human asthma. The effects of PI3K inhibitor (30 mg/kg, p.o), JAK3 inhibitor (30 mg/kg, p.o) and Dexamethasone (0.3 mg/kg) on airway inflammation and remodeling in OVA sensitized/challenged BALB/c mice were evaluated. Twenty-four hours after the final antigen challenge, bronchoalveolar lavage (BAL) and histological examinations were carried out. It was observed that kinase inhibitors significantly reduced airway inflammation as evidenced by the decrease in pro inflammatory cytokines in BALF and lung homogenate and inflammatory cell count in sensitized mice after allergen challenge. Lung histological analysis showed increased infiltration of inflammatory cells, hyperplasia of goblet cells and the collagen deposition, which were significantly reduced with kinase inhibitor. In conclusion, our data suggest that PI3K and JAK3 inhibitors showed promising alternative therapeutic activity in asthma, which might significantly counteract the airway inflammation in patients with allergic asthma.

Enhancement of nootropic effect of duloxetine and bupropion by caffeine in mice.

OBJECTIVE: The existing evidence suggests an association between depression and memory impairment. The objective of present study was to assess the effect of low dose caffeine with duloxetine and bupropion on memory. MATERIALS AND METHODS: Mice were divided randomly into seven groups. Intra-peritoneal treatment of normal saline (10 ml/kg), caffeine (10 mg/kg), duloxetine (10 mg/kg), bupropion alone (10 mg/kg), caffeine + duloxetine (5 mg/kg, each), caffeine + bupropion (5 mg/kg, each), and bupropion + duloxetine (5 mg/kg, each) were given to groups I-VII, respectively. Elevated plus maze was used to evaluate transfer latency (TL) and Morris water maze was used to estimate the time spent in target quadrant. RESULTS: Caffeine with duloxetine treated group was better than other combination treated groups in terms of a significant decrease in TL and increase in the time spent in target quadrant recorded. CONCLUSION: Combining lower dose of caffeine with duloxetine may enhance cognitive benefits than respective monotherapies.

Effect of a combination of duloxetine with hydroxyzine on experimental models of anxiety in mice.

OBJECTIVE: There is a strong association between depression and anxiety. Duloxetine, an antidepressant agent, is also used in the treatment of anxiety. Hydroxyzine is preferred over benzodiazepines in the treatment of anxiety. Present study was designed to study the impact of a combination of duloxetine with hydroxyzine in treatment of anxiety. MATERIALS AND METHODS: Mice received intraperitoneal injection of normal saline (10 ml/kg), duloxetine alone (10 mg/kg), hydroxyzine alone (10 mg/kg), and hydroxyzine plus duloxetine (5 mg/kg, each). RESULTS: The in vivo results (elevated plus maze and light/dark transition tests) showed significant anxiolytic activity with the hydroxyzine treatment than the control group. The brain monoamines were significantly increased in hippocampi, cerebral cortices, and whole brain in drug-treated groups than in the control group. The group receiving the combination showed similar results in the in vivo models and in vitro tests (brain monoamine estimations) than respective monotherapies, with the exception of a greater increase of norepinephrine levels in cerebral cortices in duloxetine-treated group. CONCLUSION: Combination of duloxetine with hydroxyzine is not beneficial in anxiolytic treatment than the respective monotherapies. There is a need to study the pharmacokinetic drug-drug interactions to understand the present study outcomes.

Amelioration of diabetic nephropathy by orange peel extract in rats.

This study was aimed to evaluate the effect of alcoholic orange peel extract (OPE) on streptozotocin-induced diabetic nephropathy. Four weeks after the induction of diabetes, treatment with OPE (100 and 200 mg/kg) was further given for 4 weeks. Treatment with OPE 200 improved renal functions and significantly prevented the increase in creatinine, urea and blood urea nitrogen levels. Histological analysis of the kidneys revealed that tubulointerstitial fibrosis index was significantly decreased in OPE 200-treated group. The results indicated the prevention of diabetic nephropathy in rats by OPE treatment and suggest OPE as a potential treatment option.

Augmentation of antidepressant effects of duloxetine and bupropion by caffeine in mice.

There is an unmet need in the treatment of depression suggesting requirement of new therapeutic approaches having better efficacy and safety profile. Patients receiving antidepressant therapy generally consume caffeine in the form of tea or coffee. The objective of the present study was to evaluate the augmentation of antidepressant effects of duloxetine and/or bupropion with caffeine. Male Swiss Albino mice received treatment of normal saline (10 ml/kg), 'caffeine alone' (10mg/kg), 'duloxetine alone' (10mg/kg), 'bupropion alone' (10mg/kg), caffeine+duloxetine (5mg/kg, each), bupropion+caffeine (5mg/kg, each), and bupropion+duloxetine (5mg/kg, each) through the intra-peritoneal route. The immobility period was analyzed 30 min after the treatment in forced swim and tail suspension tests. Norepinephrine, dopamine, and serotonin levels were analyzed in hippocampus, cerebral cortex and whole brain using HPLC with fluorescence detector. Euthanasia was performed 1h after treatment. Comparison between vehicle treated group and other groups showed significant decrease in immobility in all drug treated groups in both antidepressant models. Caffeine plus duloxetine treated group was better among the combination treated groups in terms of decrease in immobility and increase in norepinephrine, dopamine, and serotonin levels in hippocampi, cerebral cortices, and whole brain when compared to their respective monotherapy treated groups. These combination approaches may help in reducing the dose of duloxetine/bupropion, and consequently lower the associated side/adverse effects.

The Combination of Antidepressant Duloxetine with Piracetam in Mice does not Produce Enhancement of Nootropic Activity.

There is a strong association between depression and memory impairment. The present study aims to assess the nootropic activity of duloxetine and piracetam combination. Male Swiss Albino mice were divided randomly into 4 groups. Treatment of normal saline (10 ml/kg), duloxetine (10 mg/kg), piracetam (100 mg/kg), and duloxetine (5 mg/kg) plus piracetam (50 mg/kg) were given through intra-peritoneal route to group I-IV, respectively. Transfer latency in elevated plus maze (EPM) and time spent in target quadrant in Morris water maze (MWM) were recorded. Estimation of brain monoamines in hippocampus, cerebral cortex, and whole brain were done using HPLC with fluorescence detector. Piracetam treated group showed significant decrease in transfer latency in EPM and increase in time spent in target quadrant recorded in MWM. Combination treated group failed to produce statistically significant nootropic effect in both EPM and MWM. Combination treated group failed to increase brain monoamine levels when compared against duloxetine and piracetam treated groups, separately. But there was exception of significant increase in norepinephrine levels in hippocampi when compared against duloxetine treated group. Results indicate no cognitive benefits with piracetam plus duloxetine combination. These findings can be further probed with the aim of understanding the interaction between duloxetine and piracetam as a future endeavor.

Renoprotective activity of aliskiren, a renin inhibitor in cyclosporine A induced hypertensive nephropathy in dTG mice.

BACKGROUND: Hypertensive nephropathy is moving up the charts to number 2 after diabetic nephropathy in terms of diagnostic frequency cited as causing end stage renal disease (ESRD). METHOD: Hypertensive nephropathy was produced in mildly hypertensive C57BL/6-(hREN)/(hAGT) double transgenic (dTG) mice with 20 mg/kg of cyclosporine A (CsA) administered subcutaneously (sc) daily for 28 days. CsA dose 20 mg/kg was selected for the study as this dose offered significant alteration in blood pressure, biochemical parameters and moderate nephropathy in kidney. Effect of aliskiren oral treatment twice daily consequently for 28 days at 10 mg/kg body weight was evaluated against CsA induced hypertensive nephropathy. Systolic blood pressure (SBP) was measured by non invasive tail cuff method. Kidney function test (blood urea nitrogen, serum creatinine, urea and uric acid) and kidney injury biomarker (tumor necrosis factor-alpha (TNF-α) and interlekin-6) level was assessed in serum, TNF-α, IL-6, transforming growth factor-beta1 (TGF-ß1) and kidney injury molecule-1 (KIM-1) was assayed in kidney homogenate. Urinary KIM-1 levels were assessed as an early biomarker of nephropathy. RESULT: Significant hypertensive nephropathy and increase in serum levels of biomarkers was observed in CsA treated animals when compared with Control group. Aliskiren treatment elicited significant renoprotection by preventing the increase in blood pressure and levels of serum biomarkers and also reduced the nephropathic alterations in the kidney histoarchitecture. CONCLUSION: A correlation between pharmacological, biochemical and histological findings has been established in mouse model. The present findings have indicated the renoprotective activity of aliskiren in CsA induced hypertensive nephropathy, which may be due to its antihypertensive, anti-inflammatory as well as anti-apoptopic action.

Potentiation of aspirin-induced cerebroprotection by minocycline: a therapeutic approach to attenuate exacerbation of transient focal cerebral ischaemia.

Cerebrovascular disease is a major cause of mortality and disability in adults. Diabetes mellitus increases the risk of cerebral ischaemia and is associated with worse clinical outcome following an event. Upregulation of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in diabetes appears to play a role in vascular complications of diabetes. We hypothesised that inhibition of MMP-2 and MMP-9 by minocycline can be potentiated by aspirin through inhibition of cyclooxygenase-2 and tissue plasminogen activator, resulting in amelioration of clinical cerebral ischaemia in diabetes. In the present study, cerebral ischaemia/reperfusion injury was induced in streptozotocin diabetic rats by 1 h middle cerebral artery occlusion and 24 h reperfusion. Infarct volume, cerebral oedema, neurological severity score and blood-brain barrier disruption were significantly increased in diabetic animals compared with the normoglycemic control group. The combination of aspirin and minocycline treatment significantly improved these parameters in diabetic animals. Moreover, this therapy was associated with significantly lower mortality and reduction in MMP-2 and MMP-9 levels. Our data indicate that combination of aspirin and minocycline therapy protects from the consequences of cerebral ischaemia in animal models of diabetes and is associated with inhibition of MMP-2 and MMP-9. Therefore, this combination therapy may represent a novel strategy to reduce the neurological complications of cerebral ischaemia in diabetes.

The potentials of selected therapeutic targets for inflammation: a snapshot.

Inflammation is a complex integrated host response to infection and injury. Inflammatory cells respond to foreign substances and inflammatory stimulus by producing various chemical bioactive mediators such as prostanoids, cytokines and chemokines. These mediators have complex, pleiotropic effects and interact with many cell types and cellular pathways to amplify the inflammatory response. Dysregulation of these processes can lead to acute and chronic inflammatory diseases necessitating pharmacological intervention to attenuate cellular inflammation pathways. This review focuses on new targets and alternative approaches to the development of novel therapeutics based on the endogenous chemicals mediators and the regulation of the associated cellular pathways that modulate inflammation leading its resolution and patents relevant to these targets.

Attenuation of diabetic retinopathy by enhanced inhibition of MMP-2 and MMP-9 using aspirin and minocycline in streptozotocin-diabetic rats.

Interruptions of Matrix Metalloproteinase-2 (MMP-2) and Matrix Metalloproteinase-9 (MMP-9) have been shown to reduce the ensuing threatening risk factors of vascular complications of diabetes by alteration in Extracellular Matrix (ECM). We hypothesized that minocycline induced MMP-2 and MMP-9 inhibition can be enhanced by aspirin, a non-selective COX and tPA inhibitor and this combination can reduce progression of diabetic retinopathy. Diabetes was induced in male Wistar rats by streptozotocin (55 mg/kg i.p.). Four weeks after diabetes induction rats were treated with minocycline (50 mg/kg, p.o.) per se, aspirin (50 mg/kg, p.o.) per se, or minocycline in combination with aspirin for a period of four weeks. At the end of eighth week rats were anesthetized and electroretinograms were recorded. B-wave latency, B-wave amplitude and retinal permeability were measured. Histology was done and retinal thickness was measured. Zymography was carried out for MMP-2 and MMP-9 level determinations. B-wave amplitude was significantly decreased while B- wave latency was significantly increased in diabetic group when compared with normo-glycemic rats. Treatment with combination of minocycline and aspirin significantly reversed B-wave amplitude and latency compared with vehicle-treated diabetic controls. Blood retinal permeability and retinal thickness were also significantly attenuated by the treatment of minocycline in combination with aspirin. Results of the present study suggest that MMP-2 and MMP-9 inhibition in presence of COX inhibitor prevents the development of experimental diabetic retinopathy in rats and can be a potential approach for the treatment.