Linagliptin in Combination With Metformin Ameliorates Diabetic Osteoporosis Through Modulating BMP-2 and Sclerostin in the High-Fat Diet Fed C57BL/6 Mice.

Background: Diabetic osteoporosis is a poorly managed serious skeletal complication, characterized by high fracture risk, increased bone resorption, reduced bone formation, and disrupted bone architecture. There is a need to investigate drugs that can improve bone health along with managing glycemic control. DPP-4 inhibitors and metformin have proven benefits in improving bone health. Here, we investigated the effects of linagliptin, a DPP inhibitor, and metformin alone and in combination to treat diabetic osteoporosis in high-fat-fed mice. Methods: C57BL/6 mice were kept on the high-fat diet (HFD) for 22 weeks to induce diabetic osteoporosis. Linagliptin (10mg/Kg), metformin (150mg/Kg), and their combination were orally administered to the diabetic mice from the 18th-22nd week. Femur and tibial bone microarchitecture together with bone mineral density (BMD) were evaluated using µCT and histopathological changes were assessed. Further, bone turnover biomarkers namely bone morphogenetic protein-2 (BMP-2), sclerostin, tartrate-resistant acid phosphatase (TRAP), osteocalcin, alkaline phosphatase (ALP), calcium, and pro-inflammatory cytokines were assessed. Additionally, metabolic parameters including body weight, fasting blood glucose (FBG), glucose & insulin tolerance, lipids profile, and leptin were measured. Results: HFD feeding resulted in impaired bone microarchitecture, reduced BMD, distorted bone histology, and altered bone turnover biomarkers as indicated by the significant reduction in bone ALP, BMP-2, osteocalcin, and an increase in sclerostin, TRAP, and serum calcium. Interestingly, treatment with linagliptin and its combination with metformin significantly reverted the impaired bone architecture, BMD, and positively modulated bone turnover biomarkers, while metformin alone did not exhibit any significant improvement. Further, HFD induced diabetes and metabolic abnormalities (including an increase in body weight, FBG, impaired glucose and insulin tolerance, leptin, triglycerides, cholesterol), and pro-inflammatory cytokines (TNF-alpha and IL-1ß) were successfully reversed by treatment with linagliptin, metformin, and their combination. Conclusion: Linagliptin and its combination with metformin successfully ameliorated diabetic osteoporosis in HFD-fed mice possibly through modulation of BMP-2 and sclerostin. The study provides the first evidence for the possible use of linagliptin and metformin combination for managing diabetic osteoporosis.

Effect of lacosamide on neuroinflammation-mediated seizures comorbid with depression in C57BL/6 mice- Role of kynurenine pathway.

Comorbid conditions in persons with epilepsy (PWE) are very common with depression being highly prevalent. Lacosamide (LCM) is used to treat patients with seizures, but the underlying pathways associating the seizures and comorbid depression are still unknown. Kynurenine pathway (KP) has a major role in seizures, inflammation as well as depression, considering which we evaluated the effect of LCM on kynurenine levels in murine model of neuroinflammation-mediated seizures. We then evaluated the effects on the depressive symptoms associated with seizures. Lipopolysaccharide (LPS) primed pilocarpine (PILO) is an established model for neuro-inflammation-mediated seizures. The anti-seizure and anti-depressive effects of 21 days of LCM administration were studied in this model. After 24 h of seizure termination, behavioral parameters viz. forced swimming test and sucrose preference test were performed to study its antidepressant effect. Biochemical estimations of levels of kynurenine, inflammatory cytokines, and oxidative markers were also evaluated. Lacosamide significantly reduced hippocampal kynurenine levels in LPS and LPS + PILO groups but did not show significant reduction in the PILO alone group. Levels of inflammatory cytokines and oxidative stress markers were also reduced significantly. Lacosamide has shown positive effects against neuroinflammation-mediated model of seizures comorbid with depression by reducing hippocampal kynurenine levels. No reduction in the PILO group is suggestive of the principal contribution of its anti-inflammatory and antioxidant activity in its anti-seizure potential in this model via KP.

Liposomes as multifaceted delivery system in the treatment of osteoporosis.

Introduction: Treatment of osteoporosis with the available drug formulations is still challenging due to multiple associated limitations such as chronic treatment, off-target side effects, poor bone targeting, and low bioavailability. Adopting advanced bone-targeted drug delivery strategies like liposomes is one of the safe and effective approaches for osteoporosis treatment.Areas covered: This review summarizes the applications of liposomes in gene delivery, bone regeneration, bone-targeted delivery, and as a carrier for drug encapsulation in the treatment of osteoporosis. Details of all the supportive studies are discussed here and the bone-specific roles of the strategies like new generation liposomes in osteoporosis are elaborated. The future scope of performing in-depth research on the bone-targeted liposomes is discussed.Expert opinion: Liposomes-based bone-targeted delivery of therapeutics seems to be a promising approach for the effective treatment of osteoporosis. But till date, the tremendous in vitro and in vivo research on liposomes has failed to attain significant progress in their clinical translation. From bench to bedside success of the research an interdisciplinary collaboration between the preclinical and clinical experts engaged at different stages of liposomes development is required.

Inverted-U response of lacosamide on pilocarpine-induced status epilepticus and oxidative stress in C57BL/6 mice is independent of hippocampal collapsin response mediator protein-2.

OBJECTIVE: Currently, lacosamide (LCM) is not approved for use in status epilepticus (SE) but several shreds of evidence are available to support its use. The present study was, therefore, undertaken to evaluate the effect of LCM on pilocarpine (PILO) induced SE and neurodegeneration in C57BL/6 mice and to ascertain the involvement of CRMP-2 in mediating above effect. METHODS: Pilocarpine-induced SE model was developed to explore the effect of LCM 20, 40 and 80 mg/kg in mice. We assessed the seizure severity, seizure latency, spontaneous alternation behavior (SAB) and motor coordination by behavioral observation. Histopathological evaluation and measurement of the levels of CRMP-2, reduced glutathione (GSH) and malondialdehyde (MDA) were carried out in mice hippocampus. RESULTS: LCM exhibited a biphasic effect i.e., protection against SE at 20 mg/kg and 40 mg/kg dose whilst aggravated seizure-like behavior and mortality at 80 mg/kg. Further, it increased percentage alternation (i.e., restored spatial memory) in SAB and elevated motor impairment with increasing dose. Histologically, LCM 20 mg/kg and 40 mg/kg (but not 80 mg/kg) reduced neurodegeneration. LCM 20 mg/kg and 40 mg/kg reversed the elevated MDA and GSH levels while 80 mg/kg showed a tendency to increase oxidative stress. In contrast, LCM (at all doses) reversed the pilocarpine-induced elevation of collapsin response mediator protein-2 (CRMP-2). CONCLUSION: LCM protected against pilocarpine-induced SE, associated neurodegeneration and improved pilocarpine-associated impairment of spatial memory. The study reveals that CRMP-2 may not be mediating the inverted-U-response of LCM at least in pilocarpine model. Therefore, the anti-oxidant effect of LCM (and not its ability to modulate CRMP-2) was anticipated as the mechanism underlying neuroprotection.

Animal models of status epilepticus and temporal lobe epilepsy: a narrative review.

Temporal lobe epilepsy (TLE) is the chronic and pharmacoresistant form of epilepsy observed in humans. The current literature is insufficient in explicating the comprehensive mechanisms underlying its pathogenesis and advancement. Consequently, the development of a suitable animal model mimicking the clinical characteristics is required. Further, the relevance of status epilepticus (SE) to animal models is dubious. SE occurs rarely in people; most epilepsy patients never experience it. The present review summarizes the established animal models of SE and TLE, along with a brief discussion of the animal models that have the distinctiveness and carries the possibility to be developed as effective models for TLE. The review not only covers the basic requirements, mechanisms, and methods of induction of each model but also focuses upon their major limitations and possible modifications for their future use. A detailed discussion on chemical, electrical, and hypoxic/ischemic models as well as a brief explanation on the genetic models, most of which are characterized by development of SE followed by neurodegeneration, is presented.