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.
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-
B, IL-1β, IL-6, TNF-α, and TGF-β1 and TGF-β2 signaling both
and
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.
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)aminocarbonylphenyl-benzobthiophene-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.
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•A model of SE co-morbid with inflammation was established in C57BL/6 mice.•LPS-priming in pilocarpine-induced SE enhanced seizure severity and neuronal loss.•Valproate and ...carbamazepine showed loss of efficacy in above model.•Loss of efficacy was associated with NF-κB, IL-1β, IL-6, TNF-α, TGF-β signaling.•Levetiracetam showed only partial efficacy due to involvement of other pathways.
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-1β, IL-6, TNF-α and TGF-β 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.
•eCB modify inflammatory, degenerative, cognitive aspects of Alzheimer’s pathology.•MAGL FAAH inhibitors modulate eCB and inhibit Alzheimer’s progression.•Effects of MAGL FAAH inhibitors on ...experimental behavioural paradigm is presented.•Also included are potencies of different classes of MAGL and FAAH inhibitors.
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-β, reducing phosphorylation of tau, reducing amyloid-β 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.
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.
•Kynurenine pathway links seizures, depression, and inflammation.•Lipopolysaccharide prior to pilocarpine produces neuroinflammation-mediated seizures.•Lacosamide protects against behavioral seizures ...induced in this model.•Lacosamide lowers hippocampal levels of kynurenine and inflammatory cytokines.•Lacosamide protects against behavioral despair, anhedonia, and oxidative stress.
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.
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.
Recent research on human touch supports an emerging view in cognitive neuroscience wherein peripheral sensory information can be emotionally valenced. Here we review recent research on affiliative touch, its regulatory effects, and the factors that modulate it. We further link this research to related work on the design of haptic technologies, devices that stimulate the affiliative touch system, such as wearable technologies that apply affiliative touch to promote physiological regulation.
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•Oxidative stress has been implicated in the pathogenesis of PD.•Nanoemulsion loaded with BRM and GSH showed enhanced permeation capability.•The antioxidant potential of BRM and GSH ...was revealed using nanoemulsion.•The antioxidant activity of nanoemulsion was increased after intranasal delivery.
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.
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