High Doses of ANA12 Improve Phenobarbital Efficacy in a Model of Neonatal Post-Ischemic Seizures.

Phenobarbital (PB) remains the first-line medication for neonatal seizures. Yet, seizures in many newborns, particularly those associated with perinatal ischemia, are resistant to PB. Previous animal studies have shown that in postnatal day P7 mice pups with ischemic stroke induced by unilateral carotid ligation, the tyrosine receptor kinase B (TrkB) antagonist ANA12 (N-[2-[[(hexahydro-2-oxo-1H-azepin-3-yl)amino]carbonyl]phenyl]-benzo[b]thiophene-2-carboxamide, 5 mg/kg) improved the efficacy of PB in reducing seizure occurrence. To meet optimal standards of effectiveness, a wider range of ANA12 doses must be tested. Here, using the unilateral carotid ligation model, we tested the effectiveness of higher doses of ANA12 (10 and 20 mg/kg) on the ability of PB to reduce seizure burden, ameliorate cell death (assessed by Fluoro-Jade staining), and affect neurodevelopment (righting reflex, negative geotaxis test, open field test). We found that a single dose of ANA12 (10 or 20 mg/kg) given 1 h after unilateral carotid ligation in P7 pups reduced seizure burden and neocortical and striatal neuron death without impairing developmental reflexes. In conclusion, ANA12 at a range of doses (10-20 mg/kg) enhanced PB effectiveness for the treatment of perinatal ischemia-related seizures, suggesting that this agent might be a clinically safe and effective adjunctive agent for the treatment of pharmacoresistant neonatal seizures.

Characterizing affiliative touch in humans and its role in advancing haptic design.

An emerging view in cognitive neuroscience holds that the extraction of emotional relevance from sensory experience extends beyond the centralized appraisal of sensation in associative brain regions, including frontal and medial-temporal cortices. This view holds that sensory information can be emotionally valenced from the point of contact with the world. This view is supported by recent research characterizing the human affiliative touch system, which carries signals of soft, stroking touch to the central nervous system and is mediated by dedicated C-tactile afferent receptors. This basic scientific research on the human affiliative touch system is informed by, and informs, technology design for communicating and regulating emotion through touch. Here, we review recent research on the basic biology and cognitive neuroscience of affiliative touch, its regulatory effects across the lifespan, and the factors that modulate it. We further review recent work on the design of haptic technologies, devices that stimulate the affiliative touch system, such as wearable technologies that apply the sensation of soft stroking or other skin-to-skin contact, to promote physiological regulation. We then point to future directions in interdisciplinary research aimed at both furthering scientific understanding and application of haptic technology for health and wellbeing.

Amelioration of oxidative stress utilizing nanoemulsion loaded with bromocriptine and glutathione for the management of Parkinson's disease.

Parkinson's disease (PD) is triggered by the formation of free radicals in dopaminergic neurons, which results in oxidative stress-induced neurodegeneration. The objective of the work was to relieve oxidative stress by employing intranasal delivery of Bromocriptine Mesylate (BRM) and Glutathione (GSH) loaded nanoemulsion for the better management of PD. The depth of permeation of the nanoemulsion was assessed through confocal laser scanning microscopy (CLSM) which revealed higher nanoemulsion permeation in contrast to suspension. Biocompatibility of nanoemulsion was confirmed by nasal cilio toxicity study. The DPPH study showed that the nanoemulsion had significant antioxidant activity. Biochemical estimation studies in Wistar rats were carried out in order to determine the effect of nanoemulsion on oxidative stress. The levels of GSH, superoxide dismutase (SOD), and catalase (CAT) were significantly enhanced; and the level of thiobarbituric acid reactive substances (TBARS) was significantly reduced after the intranasal administration of nanoemulsion in the haloperidol-induced model of PD. Furthermore, the levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were also determined which reduced significantly after the administration of nanoemulsion. The oxidative stress levels were lowered with nanoemulsion, showing the combined antioxidant capability of BRM and GSH. The neuroprotective effect of the prepared nanoemulsion was confirmed by histopathological studies. Pharmacokinetic study revealed a higher concentration of BRM and GSH in the brain of Wistar rats after intranasal administration of nanoemulsion with a higher Brain/Plasma ratio. A higher value of AUC(0-8) of nanoemulsion in the brain after intranasal administration revealed that BRM and GSH remained in the brain for a longer period due to sustained release from nanoemulsion. According to the findings, BRM and GSH loaded nanoemulsion has the potential to provide a combined and synergistic anti-oxidant effect for efficient management of PD.

Approaches for Ear-targeted Delivery Systems in Neurosensory Disorders to avoid Chronic Hearing Loss Mediated Neurological Diseases.

BACKGROUND AND OBJECTIVE: Hearing loss is a common audio-vestibular-related neurosensory disability of inner ears, in which patients exhibit clinical symptoms of dizziness, gait unsteadiness, and oscillopsia, at an initial stage. While, if such disorders are untreated for a prolonged duration then the progression of disease into a chronic state significantly decreases GABA level as well as an alteration in the neurotransmission of CNS systems. Hence, to control the progression of disease into a chronic approaches for timely and targeted delivery of the drugs at the site of action in the ear is now attracting the interest of neurologists for effective and safe treatment of such disorders. Among delivery systems, owing to small dimension, better penetration, rate-controlled release, higher bioavailability; nanocarriers are preferred to overcome delivery barriers, improvement in residence time, and enhanced the performance of loaded drugs. Subsequently, these carriers also stabilize encapsulated drugs while also provide an opportunity to modify the surface of carriers to favor guided direction for site-specific targeting. Contrary to this; conventional routes of drug delivery such as oral, intravenous, and intramuscular are poorer in performance because of inadequate blood supply to the inner ear and limited penetration of blood-inner ear barrier. CONCLUSION: This review summarized novel aspects of non-invasive and biocompatible nanoparticles- based approaches for targeted delivery of drugs into the cochlea of the ear to reduce the rate, and extent of the emergence of any hearing loss mediated neurological disorders.

Dual Targeting by Inhibition of Phosphoinositide-3-Kinase and Mammalian Target of Rapamycin Attenuates the Neuroinflammatory Responses in Murine Hippocampal Cells and Seizures in C57BL/6 Mice.

Emerging evidence suggests the association of seizures and inflammation; however, underlying cell signaling mechanisms are still not fully understood. Overactivation of phosphoinositide-3-kinases is associated with both neuroinflammation and seizures. Herein, we speculate the PI3K/Akt/mTOR pathway as a promising therapeutic target for neuroinflammation-mediated seizures and associated neurodegeneration. Firstly, we cultured HT22 cells for detection of the downstream cell signaling events activated in a lipopolysaccharide (LPS)-primed pilocarpine (PILO) model. We then evaluated the effects of 7-day treatment of buparlisib (PI3K inhibitor, 25 mg/kg p.o.), dactolisib (PI3K/mTOR inhibitor, 25 mg/kg p.o.), and rapamycin (mTORC1 inhibitor, 10 mg/kg p.o.) in an LPS-primed PILO model of seizures in C57BL/6 mice. LPS priming resulted in enhanced seizure severity and reduced latency. Buparlisib and dactolisib, but not rapamycin, prolonged latency to seizures and reduced neuronal loss, while all drugs attenuated seizure severity. Buparlisib and dactolisib further reduced cellular redox, mitochondrial membrane potential, cleaved caspase-3 and p53, nuclear integrity, and attenuated NF-κB, IL-1ß, IL-6, TNF-α, and TGF-ß1 and TGF-ß2 signaling both in vitro and in vivo post-PILO and LPS+PILO inductions; however, rapamycin mitigated the same only in the PILO model. Both drugs protected against neuronal cell death demonstrating the contribution of this pathway in the seizure-induced neuronal pyknosis; however, rapamycin showed resistance in a combination model. Furthermore, LPS and PILO exposure enhanced pAkt/Akt and phospho-p70S6/total-p70S6 kinase activity, while buparlisib and dactolisib, but not rapamycin, could reduce it in a combination model. Partial rapamycin resistance was observed possibly due to the reactivation of the pathway by a functionally different complex of mTOR, i.e., mTORC2. Our study substantiated the plausible involvement of PI3K-mediated apoptotic and inflammatory pathways in LPS-primed PILO-induced seizures and provides evidence that its modulation constitutes an anti-inflammatory mechanism by which seizure inhibitory effects are observed. We showed dual inhibition by dactolisib as a promising approach. Targeting this pathway at two nodes at a time may provide new avenues for antiseizure therapies.

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.

The role of endocannabinoid pathway in the neuropathology of Alzheimer's disease: Can the inhibitors of MAGL and FAAH prove to be potential therapeutic targets against the cognitive impairment associated with Alzheimer's disease?

Alzheimer's disease is a neurodegenerative disease characterized by progressive decline of cognitive function in combination with neuronal death. Current approved treatment target single dysregulated pathway instead of multiple mechanism, resulting in lack of efficacy in slowing down disease progression. The proclivity of endocannabinoid system to exert neuroprotective action and mitigate symptoms of neurodegeneration condition has received substantial interest. Growing evidence suggest the endocannabinoids (eCB) system, viz. anadamide (AEA) and arachidonoyl glycerol (2-AG), as potential therapeutic targets with the ability to modify Alzheimer's pathology by targeting the inflammatory, neurodegenerative and cognitive aspects of the disease. In order to modulate endocannabinoid system, number of agents have been reported amongst which are inhibitors of the monoacylglycerol (MAGL) and fatty acid amide hydrolase (FAAH), the enzymes that hydrolyses 2-AG and AEA respectively. However, little is known regarding the exact mechanistic signalling and their effects on pathophysiology and cognitive decline associated with Alzheimer's disease. Both MAGL and FAAH inhibitors possess fascinating properties that may offer a multi-faceted approach for the treatment of Alzheimer's disease such as potential to protect neurons from deleterious effect of amyloid-ß, reducing phosphorylation of tau, reducing amyloid-ß induced oxidative stress, stimulating neurotrophin to support brain intrinsic repair mechanism etc. Based on empirical evidence, MAGL and FAAH inhibitors might have potential for therapeutic efficacy against cognitive impairment associated with Alzheimer's disease. The aim of this review is to summarize the experimental studies demonstrating the polyvalent properties of MAGL or FAAH inhibitor compounds for the treatment of Alzheimer's disease, and also effect of these on learning and types of memories, which together encourage to study these compounds over other therapeutics targets. Further research in this direction would enhance the molecular mechanisms and development of applicable interventions for the treatment of Alzheimer's disease, which nevertheless stay as the primary unmet need.

The role of melatonin and its analogues in epilepsy.

Extensive research has gone into proposing a promising link between melatonin administration and attenuation of epileptic activity, the majority of which suggest its propensity as an antiseizure with antioxidant and neuroprotective properties. In the past few years, a number of studies highlighting the association of the melatonergic ligands with epilepsy have also emerged. In this context, our review is based on discussing the recent studies and various mechanisms of action that the said category of drugs exhibit in the context of being therapeutically viable antiseizure drugs. Our search revealed several articles on the four major drugs i.e. melatonin, agomelatine, ramelteon and piromelatine along with other melatonergic agonists like tasimelteon and TIK-301. Our review is suggestive of antiseizure effects of both melatonin and its analogues; however, extensive research work is still required to study their implications in the treatment of persons with epilepsy. Further evaluation of melatonergic signaling pathways and mechanisms may prove to be helpful in the near future and might prove to be a significant advance in the field of epileptology.

Loss of Protection by Antiepileptic Drugs in Lipopolysaccharide-primed Pilocarpine-induced Status Epilepticus is Mediated via Inflammatory Signalling.

The evidences from various studies show the association of peripheral and neuronal inflammation with complex pathophysiology of status epilepticus (SE). In this view, the present work attempted to develop a model of neuronal inflammation mediated SE by combining both epileptic and inflammatory components of the disease and also to mimic SE co-morbid with systemic inflammation by peripheral administration of the lipopolysaccharide (LPS) 2 h prior to the pilocarpine (PILO) induction in C57BL/6 mice. We evaluated the anti-convulsant and neuroprotective effects of 7-day prophylactic treatment with three conventional anti-epileptic drugs (Sodium valproate, SVP 300 mg/kg p.o.; Carbamazepine CBZ 100 mg/kg p.o.; Levetiracetam; LEV 200 mg/kg p.o.) of widespread clinical use. Morris water maze and Rota rod tests were carried out 24-h post-exposure to evaluate the neurobehavioral co-morbidities associated with neuroinflammation-mediated status epilepticus. Upon priming with LPS, the loss of protection against PILO-induced seizures was observed by SVP and CBZ, however, LEV showed protection by delaying the seizures. Dramatic elevation in the seizure severity and neuronal loss demonstrated the possible pro-convulsant effect of LPS in the PILO model. Also, the decreased cytokine levels by the AEDs showed their association with NF-κB, IL-1ß, IL-6, TNF-α and TGF-ß pathways in PILO model. The loss of protective activities of SVP and CBZ in LPS+PILO model was due to increased cytokine levels associated with over-activation of neuroinflammatory pathways, however, partial efficacy of LEV is possibly due to association of other neuroinflammatory mechanisms. The current work provides direct evidence of the contribution of increased peripheral and neuronal inflammation in seizures via regulation of inflammatory pathways in the brain.

Ten Little Fingers, Ten Little Toes: Can Toes Match Fingers for Haptic Discrimination?

In comparison with fingers, toes are relatively unexplored candidates for multi-site haptic rendering. This is likely due to their reported susceptibility to erroneous perception of haptic stimuli, owing to their anatomical structure. We hypothesize that this shortcoming can be mitigated by careful design of the tactile encoding to account for the idiosyncrasies of toe perception. Our efforts to design such an encoding achieved an improved perceptual accuracy of 18% for poking and 16% for vibrotactile stimuli. As we demonstrate, in this article, the resulting perceptual accuracy achieved by the proposed tactile encoding approaches that of the fingers, allowing for consideration of the toes as a practical location to render multi-site haptic stimuli.

Assessment of different pretreatment technologies for efficient bioconversion of lignocellulose to ethanol.

The future supply of energy to meet growing energy demand of rapidly exapanding populations is based on wide energy resources, particularly the renewable ones. Among all resources, lignocellulosic biomasses such as agriculture, forest, and agro-industrial residues are the most abundant and easily available bioresource for biorefineries to provide fuels, chemicals, and materials. However, pretreatment of biomass is required to overcome the physical and chemical barriers that exist in the lignin-carbohydrate composite and pretreatment facilitate the entry of biocatalysts for the conversion of biomass into fermentable sugars and other by-products. Therefore, pretreatment of the biomass is necessary prerequisite for efficient hydrolysis of lignocelluloses into different type of fermentable sugars. The physiochemical, biochemical and biological pretreatment methods are considered as most promising technologies for the biomass hydrolysis and are discussed in this review article. We also discussed the recent advancements and modern trends in pretreatment methods of lignocelluloses conversion into ethanol with special focus on fermentation methods.

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.

Biomass breakdown: A review on pretreatment, instrumentations and methods.

Enzymatic breakdown of lignocellulosic biomass for liquid fuel production is a viable alternative to fossil fuels, due to its renewable and environmental friendly nature. Naturally, plants protect their cell wall polysaccharides by giving limited access to the cell wall degrading enzymes. Lignocellulose breakdown requires proper pretreatments that disrupt the close inter-component association between the constituents of the plant cell wall. For efficient biomass conversion, the choice of the correct pretreatment is important for removing the barriers to enhance access to microbial enzymes. Among the pretreatment methods available, biological pretreatment is a promising approach for biomass degradation as there are no inhibitors generated. Another significant area that needs attention is the development of methods that can qualitatively and quantitatively determine the degradation of biomass and product generation. More technological advancement would be required in the field of pretreatment technology and fermentation processes to make the whole process economical. Here, we review the recent developments in the field of lignocellulosics, role of various pretreatments, instruments & methods and role of microbial enzymes in biomass degradations.

Phosphoinositide-3-kinases as the Novel Therapeutic Targets for the Inflammatory Diseases: Current and Future Perspectives.

OBJECTIVE: To review the role of PI3K/AKT/mTOR signalling pathway, and the current and future prospects of targeting PI3Ks for various diseases, like malignant, autoimmune, inflammatory, cardiovascular, neurological disorders etc., laying special emphasis on the inflammatory diseases and associated cellular responses. BACKGROUND: Recent findings have publicized phosphoinositide-3-kinases (PI3Ks) as novel therapeutic targets, which are also purported to be involved in the complex pathophysiology of inflammatory and various other diseases. They are recognized to participate in the inflammatory cellular responses by modulating the growth, development and proliferation of various immune cells and hence, affect the release of various cytokines and other inflammatory mediators involved in these manifestations. The recent literature relating this pathway with these diseases is highlighted, with a hope, which remains for the progression of PI3K inhibitors in the market as a treatment option. RESULT: With Idelalisib entering the market for cancer, PI3K/AKT signalling has also gained significance as an investigational target for various diseases, particularly for inflammation. Based on the pharmacological, genetic, and clinical data available, PI3K/AKT signalling can be designated as an outstanding target for their treatment. CONCLUSION: Further exploration of this pathway may also uncover its involvement in these disorders, which may further contribute to developing the new treatments and can turn out to be an innovative brainwave in the field of experimental and clinical pharmacology in future.

Innovative Targets For Asthma And COPD: Exploring The Existing And Screening The New!!

The inadequate benefits of the existing therapies and the new insights into the pathophysiology of inflammatory airway diseases like chronic obstructive pulmonary disease (COPD) and asthma have led to the breakthrough of newer targets and innovative compounds as the treatment alternatives. The enhanced interpretation of immune cell signalling and signal transduction pathways at the molecular level involved in this process allows the selection of new therapeutic targets and designing of new molecules to combat such multifactorial diseases. Pertaining to the marked variability in type of inflammation observed in their disease phenotypes, the blockade of a particular receptor or mediator yielding strong restorative effect in one patient may not be significant to other. Therefore, their management requires the prompt and phenotype specific optimized drug therapies and development of new and improved molecular compounds targeting the immune cell signalling. This whole process including the approval of such compounds as the standard drug therapies is time taking, expensive and complicated task. It ranges from the selection of novel anti-inflammatory drug target to the final approval of biologically active restorative molecules. Grounded on this, the current review gives a comprehensive idea of the basic immunological network involved in these inflammatory airway diseases at the cellular level along with the discussion of their potential therapeutic targets. It also follows brief over viewing of the drug development process generally employed for the exploration of such innovative targets leading to the discovery of novel anti-inflammatory molecules for these inflammatory airway diseases.