Neuroprotective role of chloroquine via modulation of autophagy and neuroinflammation in MPTP-induced Parkinson's disease.

Parkinson's disease (PD) is a neuro-motor ailment that strikes adults in their older life and results in both motor and non-motor impairments. In neuronal and glial cells, PD has recently been linked to a dysregulated autophagic system and cerebral inflammation. Chloroquine (CQ), an anti-malarial drug, has been demonstrated to suppress autophagy in a variety of diseases, including cerebral ischemia, Alzheimer's disease (AD), and Traumatic brain injury (TBI), while its involvement in PD is still unclear. BALB/c mice were randomly allocated to one of four groups: 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), CQ treatment with or without MPTP, or control. The CQ treatment group received CQ (intraperitoneally, 8 mg/kg body weight) after 1 h of MPTP induction on day 1, and it lasted for 7 days. CQ therapy preserves dopamine levels stable, inhibits tyrosine hydroxylase (TH) positive dopaminergic cell death, and lowers oxidative stress. CQ reduces the behavioural, motor, and cognitive deficits caused by MPTP after injury. Furthermore, CQ therapy slowed aberrant neuronal autophagy (microtubule-associated protein-1 light chain 3B; LC3B & Beclin1) and lowered expression levels of the inflammatory cytokines interleukin 1 (IL-1ß) and tumour necrosis factor (TNF-α) in the mice brain. In addition, CQ's antioxidant and anti-inflammatory effects were also tested in MPTP-mediated cell death in PC12 cells, demonstrating that CQ has a neurorestorative impact by successfully rescuing MPTP-induced ROS generation and cell loss. Our findings show that CQ's can help to prevent dopaminergic degeneration and improve neurological function after MPTP intoxication by lowering the harmful effects of neuronal autophagy and cerebral inflammation.

SNPs of FOXO1 and Their Interactions Contributes to the Enhanced Risk of Diabetes Among Elderly Individuals.

We have assessed the impact of three single nucleotide polymorphisms (SNPs) of Forkhead Box O1 (FOXO1) and their interaction on susceptibility of type 2 diabetes mellitus in geriatric population from northern India. We genotyped three SNPs (rs2721068, rs17446614, and rs4581585) of FOXO1 gene in 190 elderly individuals with diabetes and 182 unrelated healthy controls of similar ethnicity by using TaqMan SNP assays. SNP-SNP and SNP-environment interactions among polymorphic loci were studied by the multifactor dimensionality reduction (MDR) method. The AA genotype carriers of rs17446614 was associated with the increased susceptibility of diabetes in both adjusted and unadjusted model, whereas rs4581585 was associated with the risk in unadjusted model only. Genotype and minor allele interaction with quantitative parameters revealed that AA genotype of rs17446614 had significantly higher fasting plasma glucose (FPG) in diabetic subjects, also minor allele (A) in patients was positively associated with FPG and glycated hemoglobin. Haplotype Trs2721068Grs17446614Trs4581585 increases the risk of diabetes, whereas carrier of haplotypes Crs2721068Grs17446614Crs4581585 and Crs2721068 Grs17446614Trs4581585 were protective. The MDR analysis revealed that interaction of rs17446614 with body mass index (BMI) increased the susceptibility of diabetes. Therefore presence of rs17446614 variant and its interaction with BMI and haplotype Trs2721068Grs17446614Trs4581585 modulates the risk of diabetes and can be used as a promising tool for identifying high-risk individuals.

Pharmacological, Biochemical and Immunological Studies on Protective Effect of Mangiferin in 6-Hydroxydopamine (6-OHDA)-Induced Parkinson's Disease in Rats.

Background: Parkinson's disease is a neurodegenerative disorder and is marked by inflammation and death of neurons in the striatum region of the midbrain. It has been reported that expression of NF-κB increases during Parkinson's disease, which promotes oxidative stress, stimulates release of proinflammatory cytokines, and induces expression of nitric oxide. Therefore, in this study, we have used mangiferin a specific NF-κB inhibitor. Mangiferin is a polyphenolic compound traditionally used for its antioxidant and anti-inflammatory properties. Methods: The study utilized male Wistar rats weighing 200-250 g (56 rats; n = 8/group). On day "0," stereotaxic surgery of rats was done to induce 6-hydroxydopamine lesioning in rats. Coordinates for substantia nigra were anteroposterior-2 mm, mediolateral-5 mm and dorsoventral-8.2 mm. After 14 days, those rats which show at least 210 contralateral rotations after administration of apomorphine (0.5 mg/kg S.C.) were selected for the study and were given treatment for 28 days. On day 28 of treatment, rats were subjected to behavioral studies to evaluate the effect of mangiferin and their brains were taken out after euthanasia to perform biochemical, molecular and immunological studies. Results: Treatment with mangiferin significantly improves the key parameters of locomotor activity and oxidative stress and reduces the parameters of inflammatory stress. Also, the activity of caspases was reduced. Significant decrease in activity of both cyclooxygenase 1 and 2 was also observed. Maximum improvement in all parameters was observed in rats treated with grouping of mangiferin 45 µg/kg and levodopa 10 mg/kg. Treatment with levodopa alone has no significant effect on biochemical and molecular parameters though it significantly improves behavioral parameters. Conclusion: Current treatment of Parkinson's disease does not target progression of Parkinson's disease. Results of this study suggest that mangiferin has protective effect in hemi-Parkinsonian rats. Therefore, the combination therapy of mangiferin and levodopa can be helpful in management of Parkinson's disease.

Pharmacological and biochemical studies on protective effects of mangiferin and its interaction with nitric oxide (NO) modulators in adjuvant-induced changes in arthritic parameters, inflammatory, and oxidative biomarkers in rats.

Current study was designed to evaluate protective effect of mangiferin and its interaction with low dose of nitric oxide (NO) modulators in complete Freund's adjuvant (CFA) inoculated rats. Male wistar rats (200-300 g, n = 8 per group) were used in the study. On day ''0'' of study arthritis was induced in rats by injecting 0.2 ml CFA in sub-planter region of right hind paw of animals. Treatment with methotrexate (5 mg/kg), mangiferin (10-30 mg/kg) alone and in combination with NO modulators was given (i.p.) from days 14 to 28. After 28 days, blood and joint synovial fluid was collected for biochemical analysis and rat paws were excised to estimate MDA and SOD in tissue (paw) homogenates. CFA inoculation significantly increases (1) arthritic index, (2) ankle diameter, (3) paw volume, and (4) serum TNF-α, IL-6, IL-1ß, and synovial TNF-α levels (p < 0.001). The serum Th1 (IFN-γ) and Th2 (IL-4) cytokine levels, MDA levels in rat paw tissue homogenates and serum NF-κB levels were also found significantly increased. Significant decrease in serum IL-10 levels and SOD activity was found after CFA inoculation. These CFA-induced arthritic changes, cytokine profile, and oxidative stress markers were significantly reversed by mangiferin (10-30 mg/kg) treatment alone and in combination with L-arginine and L-NAME nitric oxide modulators (p < 0.05). Treatment with methotrexate (5 mg/kg) also significantly reversed these adjuvant changes (p < 0.05). However, effect of methotrexate was less marked as compared to mangiferin (30 mg/kg) alone and in combination with L-NAME (10 mg/kg), but was comparable or slightly better than mangiferin (10 and 20 mg/kg). Thus, on the basis of our findings, we can suggest that interaction of mangiferin with nitric oxide modulators may have therapeutic value for chronic inflammatory disease such as RA.

Pharmacological studies on the anti-inflammatory and immunomodulatory role of pentoxifylline and its interaction with nitric oxide (NO) in experimental arthritis in rats.

AIM: Present study was designed to evaluate protective effects of pentoxifylline and its potentiation with low dose of nitric oxide (NO) modulators in adjuvant-induced experimental arthritis in rats. METHOD: Wistar rats (200-300 g, n = 8 per group) of both sexes were used in the study. On day "0" experimental arthritis was induced by injecting 0.2 ml of Complete Freund's adjuvant (CFA) in sub-planter region of right hind paw of animals. Pentoxifylline treatment alone and in combination with NO modulators was given (i.p.) from day 14 to 28. Various arthritic parameters were recorded and blood and joint synovial fluid was collected for biochemical analysis. RESULTS: CFA inoculation significantly increases (1) arthritic index (2) ankle diameter (3) paw volume (4) histopathology score (5) serum TNF-α, IL-6, IL-1ß and synovial TNF-α levels (p < 0.001) (6) serum Th1 and Th2 cytokine levels g) MDA levels in rat paw tissue homogenates (7) serum NF-κB levels. Significant decrease in serum IL-10 levels and SOD activity was observed in rats after CFA inoculation. Decrease in body weight and suppressed general quality of life of CFA inoculated rats was also observed. These CFA-induced arthritic changes were significantly reversed by pentoxifylline alone and in combination with low dose of NO modulators (p < 0.05). CONCLUSION: These results are suggestive of protective effects of pentoxifylline and its potentiation in combination with low dose of NO modulators. These results may provide new pharmacological therapy for management of rheumatoid arthritis (RA).

Functional outcome of surgical management of degenerative lumbar canal stenosis.

BACKGROUND: The long term outcomes of decompressive surgery on relief of pain and disability in degenerative lumbar canal stenosis are unclear. The aim of our study was to evaluate the outcome of surgical management of secondary degenerative lumbar canal stenosis and to analyze the effect on outcome variables using Japanese Orthopaedic Association (JOA) score. MATERIALS AND METHODS: Thirty-two patients of degenerative lumbar canal stenosis managed surgically were included in this study. Laminectomy (n=2), laminectomy with disectomy (n=23), laminectomy and disectomy with instrumental stabilization (n=5), and laminectomy, disectomy with posterior interbody fusion (n=2) were performed. JOA scoring system for low backache was used to assess the patients. The recovery rate was calculated as described by Hirabayashi et al. (1981). Surgical outcome was assessed based on the recovery rate and was classified using a four-grade scale: Excellent, improvement of >90%; good, 75-89% improvement; fair, 50-74% improvement; and poor, below 49% improvement. The patients were evaluated at 3 months, one year and at last followup. RESULTS: At 3-month followup, 18.75% patients showed excellent outcome, 62.50% patients showed good outcome, and 18.75% showed fair outcome. At 1-year followup, 64% patients showed excellent outcome and 36% patients showed good outcome. At >1 year followup (average 34.2 months, range: 2-110 months), 64% patients showed excellent outcome, 28% showed good outcome, and 8% showed fair outcome. No patient had poor outcome. Outcome of the patients improved as the time after surgery increased till 1 year and was sustained thereafter till the last followup. CONCLUSION: Operative treatment in patients of degenerative lumbar canal stenosis yields excellent results as observed on the basis of JOA scoring system. No patient got recurrence of symptoms of nerve compression.

Primary cemented total hip arthroplasty: 10 years follow-up.

BACKGROUND: Primary cemented total hip arthroplasty is a procedure for non-traumatic and traumatic affections of the hip. Long term follow-up is required to assess the longevity of the implant and establish the procedure. Indo-Asian literature on long term result of total hip arthroplasty is sparse. We present a 10-year follow-up of our patients of primary cemented total hip arthroplasty. MATERIALS AND METHODS: We operated 31 hips in 30 patients with primary cemented total hip arthroplasty. We followed the cases for a minimum period of 10 years with a mean follow-up period of 12.7 years. The mean age of the patients was 60.7 years (range 37-82 yrs) male to female ratio was 2:1. The clinical diagnoses included - avascular necrosis of femoral head (n=15), sero positive rheumatoid arthritis (n=5), seronegative spondylo-arthropathy (n=4), neglected femoral neck fractures (n=3), healed tubercular arthritis (n=2) and post traumatic osteoarthritis of hip (n=2). The prostheses used were cemented Charnley's total hip (n=12) and cemented modular prosthesis (n=19). The results were assessed according to Harris hip score and radiographs taken at yearly intervals. RESULTS: The mean follow-up is 12.7 yrs (range 11-16 yrs) Results in all operated patients showed marked improvement in Harris hip score from preoperative mean 29.2 to 79.9 at 10 years or more followup. However, the non-inflammatory group showed more sustained long term improvement as compared to the inflammatory group, as revealed by the Harris hip score. Mean blood loss was 450ml (+/-3.7 ml), mean transfusion rate was 1.2 units (+/-.3). The complications were hypotension (n=7), shortening >1.5 cm (n=9), superficial infection (n=2) and malposition of prosthesis (n=1). CONCLUSION: The needs of Indian Asian patients, vary from what is discussed in literature. The pain tolerance is greater than western population and financial constraints are high. Thus revision surgery among Indian-Asian patients is less compared to western yard sticks.

PARFLEX--a very useful drug for management of surgical pain.

The aim was to assess and document the efficacy and tolerability of parflex (FDC of aceclofenac with paracetamol and serratiopeptidase) in management of pain and inflammation in adult patients undergoing surgical procedures (or operations). The design was open, prospective, non-comparative and multi-dose study of patients undergoing surgical procedures at a leading, tertiary-care, teaching hospital (setting) in Lucknow, the name being, King George's Medical College, Lucknow 226003. The patients were 50 adult patients of either sex undergoing surgery. They were given 1 tablet twice daily, taken after meals. Treatment duration was for a total of up to 7 days (intervention). Primary efficacy variables were relief from postoperative pain. Secondary efficacy variables were global assessment of efficacy and toleration by patients and treating physicians. Record was made of spontaneously reported adverse events with their nature, intensity and outcome (tolerability). Out of 50 patients, 31% were (ENT), 36% were (Orthopaedic) and 33% were (Gynaecology). They were enroled in this study. The observations made were mean pain score showed significant improvement with study drug - decreasing from 2.66 at baseline to 1.36 after 48 hours, and to 0.8 at the end of study. Composite score for pain, fever and swelling also showed substantial gains visit-on- visit-decreasing from 3.62 at baseline to 2.04 after 48 hours, and to 0.98 at final visit. None of the patients reported any adverse event. Global efficacy assessment was rated as 'excellent or good' by 54% of patients and in 59% of patients by their treating physicians. To conclude, parflex is an effective analgesic, anti-inflammatory drug that has a valuable therapeutic option for controlling pain and inflammation after surgical procedures.