Satellite glial cells in sensory ganglia play a wider role in chronic pain via multiple mechanisms

Satellite glial cells are unique glial cells that surround the cell body of primary sensory neurons.An increasing body of evidence suggests that in the presence of inflammation and nerve damage,a significant number of satellite glial cells become activated,thus triggering a series of functional changes.This suggests that satellite glial cells are closely related to the occurrence of chronic pain.In this review,we first summarize the morphological structure,molecular markers,and physiological functions of satellite glial cells.Then,we clarify the multiple key roles of satellite glial cells in chronic pain,including gap junction hemichannel Cx43,membrane channel Pannexin1,K channel subunit 4.1,ATP,purinergic P2 receptors,and a series of additional factors and their receptors,including tumor necrosis factor,glutamate,endothelin,and bradykinin.Finally,we propose that future research should focus on the specific sorting of satellite glial cells,and identify genomic differences between physiological and pathological conditions.This review provides an important perspective for clarifying mechanisms underlying the peripheral regulation of chronic pain and will facilitate the formulation of new treatment plans for chronic pain.

Low-frequency Stimulation at the Subiculum Prevents Extensive Secondary Epileptogenesis in Temporal Lobe Epilepsy

Secondary epileptogenesis is characterized by increased epileptic susceptibility and a tendency to generate epileptiform activities outside the primary focus.It is one of the major resultants of pharmacoresistance and failure of surgical outcomes in epilepsy,but still lacks effective treatments.Here,we aimed to test the effects of low-frequency stimulation(LFS)at the subiculum for secondary epileptogenesis in a mouse model.Here,secondary epileptogenesis was simulated at regions both contralateral and ipsilateral to the primary focus by applying successive kindling stimuli.Mice kindled at the right CA3 showed higher seizure susceptibilities at both the contralateral CA3 and the ipsilateral entorhinal cortex and had accelerated kindling processes compared with naive mice.LFS at the ipsilateral subiculum during the primary kindling progress at the right CA3 effectively prevented secondary epileptogenesis at both the contralateral CA3 and the ipsilateral entorhinal cortex,characterized by decreased seizure susceptibilities and a retarded kindling process at those secondary foci.Only application along with the primary epileptogenesis was effective.Notably,the effects of LFS on secondary epileptogenesis were associated with its inhibitory effect at the secondary focus through interfering with the enhancement of synaptic connections between the primary and secondary foci.These results imply that LFS at the subiculum is an effective preventive strategy for extensive secondary epileptogenesis in temporal lobe epilepsy and present the subiculum as a target with potential translational importance.

mTORC2:The“Ace in the Hole”for a Broader Control of Epileptic Seizures?

Over 70 million people worldwide suffer from epilepsy-one of the most prevalent chronic neurological disorders[1].Despite the availability of over thirty anti-seizure drugs(ASDs)that mainly act on voltage-gated ion channels or inhibitory GABAergic receptors,the effectiveness of these drugs in achieving seizure freedom remains unsatisfactory due to pharmacoresistance and the inevitable occurrence of side-effects.

Raising New Hope for Controlling Seizures in Focal Cortical Dysplasia with Gene Therapy

Focal cortical dysplasia(FCD)is characterized by abnormal cortical development and pharmacoresistant epilepsy,often accompanied by cognitive and behavioral malfunctions[1].According to the International League against Epilepsy(ILAE)classification proposed by Najm,Imad et al.in 2022,FCD can be further divided into isolated forms(FCD type Ⅰ and Ⅱ)and another type associated with a principal lesion(FCD type Ⅲ)[2].

Novel Mechanism,Drug Target and Therapy in Epilepsy

Epilepsy,which is characterized by unprovoked seizures and has a prevalence of nearly 1%,is becoming one of the leading causes of disability and death globally[1].The exact mechanisms behind epilepsy are still unknown,which contributes to the inadequate efficacy of anti-seizure medications(ASMs)that mainly target membrane ion channels and neurotransmission[2].

Revealing the complex role of CDKL5 in developmental epilepsy through a calcium channel related vision

Developmental and epileptic encephalopathies are severe neurological conditions in clinical practice,among which loss-of-function mutations in brain-enriched serine-threonine kinase cyclin dependent kinase like-5(CDKL5)exists as one of the most common types.It is unknown,therefore,how precisely CDKL5 mutations lead to neuronal hyper-excitation.A recent study that looked at the connection between voltage-gated calcium channel Cav2.3 and CDKL5 in an experimental context was published in Nature Communications.This study has revealed that Cav2.3,a physi-ological phosphorylation target of CDKL5,would show delayed inactivation and increased cholinergic stimulation in CDKL5 knock out conditions.This would in turn cause neuronal hyperexcitability and related enhanced seizure susceptibility.This work,in our opinion,provided fresh insight into the epileptic encephalopathies linked to CDKL5 and highlighted Cav2.3 as a possible target for it.

From Acupoints to Mylohyoid: Revealing the Neural Circuitry Basis of Electroacupuncture for Dysphagia

Acupuncturea representative and historical treatment in traditional Chinese medicine(TCM),has been used to cure diseases for Chinese people in the past centuries.Since the late 1990s,acupuncture has been further accepted worldwide.The World Health Organization(WHO)proposed Clinical Research Specification for acupuncture in 1995 and the US Food and Drug Administration(FDA)approved acupuncture as a complementary and alternative therapy for various kinds of diseases in 1996,with clinical advantages such as convenience and effectiveness[1].Cumulative evidence has proved that acupuncture could produce different degrees of efficacy for treating various kinds of diseases(such as neuropathic pain,migraine,Parkinson's disease et al.)and alleviate symptoms[2-4].However,unlike its evidence-based efficacies.

Excitatory somatostatin interneurons in the dentate gyrus drive a widespread seizure network in cortical dysplasia

Seizures due to cortical dysplasia are notorious for their poor prognosis even with medications and surgery,likely due to the widespread seizure network.Previous studies have primarily focused on the disruption of dysplastic lesions,rather than remote regions such as the hippocampus.Here,we first quantified the epileptogenicity of the hippocampus in patients with late-stage cortical dysplasia.We further investigated the cellular substrates leading to the epileptic hippocampus,using multiscale tools including calcium imaging,optogenetics,immunohistochemistry and electrophysiology.For the first time,we revealed the role of hippocampal somatostatin-positive interneurons in cortical dysplasia-related seizures.Somatostatin-positive were recruited during cortical dysplasia-related seizures.Interestingly,optogenetic studies suggested that somatostatin-positive interneurons paradoxically facilitated seizure generalization.By contrast,parvalbumin-positive interneurons retained an inhibitory role as in controls.Electrophysiological recordings and immunohistochemical studies revealed glutamate-mediated excitatory transmission from somatostatin-positive interneurons in the dentate gyrus.Taken together,our study reveals a novel role of excitatory somatostatin-positive neurons in the seizure network and brings new insights into the cellular basis of cortical dysplasia.

Adult-born neurons in critical period maintain hippocampal seizures via local aberrant excitatory circuits

Temporal lobe epilepsy(TLE),one common type of medically refractory epilepsy,is accompanied with altered adult-born dentate granule cells(abDGCs).However,the causal role of abDGCs in recurrent seizures of TLE is not fully understood.Here,taking advantage of optogenetic and chemogenetic tools to selectively manipulate abDGCs in a reversible manner.

Anticonvulsant Effect of Xingnaojing Injection on Acute Seizure Models in Mice

Background:Epilepsy is characterized by acute recurrent seizures.The control of seizures is largely hampered by the tolerance to current anti-seizure drugs.Complementary anti-convulsant pharmacotherapies are urgently needed.Objective:Here,we aimed to investigate the anti-convulsant effects of Xingnaojing Injection(XNJ)which is an approved Traditional Chinese Medicine injection on different acute seizure models in mice.Methods:The effects of XNJ were tested on the maximal electroshock(MES),pentylenetetrazol(PTZ)and kainic acid(KA)acute seizure models.Also,whether XNJ can directly inhibit hippocampal neuronal firings were exam-ined by in vitro electrophysiology.Results:XNJ could shorten the durations of generalized tonic-clonic seizures in the MES model.It also significantly prolonged the latencies to generalized myo-clonic seizures in the PTZ model.In the KA model,XNJ showed various efficacies including inhibiting the seizure stages,prolonging the latency to the occurrence of the first seizures or generalized seizures,shortening the seizure durations,decreasing the numbers of generalized seizures.In vitro electrophysiological recordings further verified XNJ directly inhibited both the spontaneous and evoked action potentials of hippocampal pyramidal neurons,but did not influence the excitatory or inhibitory synaptic transmissions.Conclusion:These findings proposed XNJ as an alternative anti-convulsant pharmacotherapy for controlling acute epileptic seizures.

Now We Can Tame the Wild West of Controlling Astrocytes for Treating Neocortical Epilepsy

Are activated astrocytes pro-excitatory in epilepsy?The answer tends to be"yes"with cumulative evidence proposing that astrocytic activation leads to hyperexcitability through excitatory transmitter release or neuroinflammatory pathways[1-3].But a very recent study published in Nature Communications by Zhao J et al.has refreshed this viewpoint by showing that optogenetic activation of astrocytes can alleviate neocortical seizures(a type of epileptic symptom that originates in the neocortex which is part of the external surface layer of the brain)through astrocytic Na^(+)-K^(+)-ATPase in animal models[4](Fig.1).

One Small Step for Neurotechnology,One Giant Leap for an In-Depth Understanding of the Brain

Is science mostly driven by ideas or by tools?The answers to the everlasting question remain open.But the advances in techniques undoubtedly push forward scientific research to investigate both more in-breadth and in-depth aspects.

Shed a New Light on Spinal Cord Injury-induced Permanent Paralysis with the Brain-spine Interface

How to deal with severe spinal cord injuries(SCI)?This question remains an everlasting challenge for neurologists.Recent innovative therapies such as neuromodulation,which targets the surviving tissue,have shown the potential to restore cognitive functions in patients with severe SCI after rehabilitation[1,2].These therapies might enable SCI patients to sustain active movements during rehabilitation training to enhance the reorganization of the neuronal pathways,however,the complete recovery of body movement functions was still not reached with these therapies.A characteristic feature of SCI is the impairment of neural information communication between the neurons in the spinal cord and the brain,which are responsible for regulating body movement.Brain-computer interfaces(BCIs)have been successfully applied in dealing with movement dysfunction by establishing a direct connection between brain cortical activity and electrical muscle stimulation,thereby restoring limb function in cases of paralysis[2].

Effect of Ningxin-Yishen Formula on D-galactose-induced Premature Ovarian Insufficiency Mice by Inhibiting p53

Background:The prevalence of premature ovarian insufficiency(POI)is gradually increasing,safer and more effective treatments are urgently needed.Objective:The aim of this study was to evaluate the effects of Ningxin-Yishen formula(NXYSF)on D-galactose-induced POI mice as well as to shed a light on its potential mechanisms.Methods:Six to eight weeks old female C57BL/6 mice were used in this study and randomly divided into six groups:control group;model group;estradiol valerate(EV)treatment group and NXYSF treatment group with graded doses(9.5,19,and 38 g·kg^(−1)/d).Both EV and NXYSF treatments were initiated at the 15th day of modeling and lasted for 28 days.Afterwards,the ovarian function was evaluated in each group by analyzing the proportion of primordial follicles as well as the serum sex hormone levels.Furthermore,network pharmacology approach was performed to elucidate the potential targets of NXYSF,which was verified through western blotting experiments finally.Results:NXYSF could significantly reverse the inefficiency of weight gain caused by POI,and promote the devel-opment of primordial follicles.In addition,it could restore the abnormal serum anti-Müllerian hormone(AMH),estradiol(E 2),luteinizing hormone(LH)and follicle-stimulating hormone(FSH).Moreover,some crucial key gene targets including TP53 were as propose to be relate with the effect of NXYSF through network pharmacology anal-ysis.Last but importantly,western blotting experiments confirmed that NXYSF could inhibit the expression of p53 protein in mouse ovaries.

Low-frequency Stimulation at the Subiculum is Anti-convulsant and Anti-drug-resistant in a Mouse Model of Lamotrigine-resistant Temporal Lobe Epilepsy

Dear Editor,Epilepsy is a common neurological disease.About 30%of epileptic patients develop resistance to antiepileptic drugs(AEDs),and are considered to have refractory or drugresistant epilepsy[1].Based on the time course over which drug-resistance develops,refractory epilepsy can be further divided into an early-onset type(drug-resistance more likely innate and correlated with gene mutations)and a delayed-onset type(drug-resistance emerges after a period of medication)[2].

Thermo-sensitive micelles extend therapeutic potential for febrile seizures

Dear Editor,Febrile seizures(FS)are common convulsive disorder induced by fever,affecting up to 5% of children under the age of 5 years.Although FS are characterized by their benign prognosis,children with complex FS,in the condition with recurrent or prolonged seizures,are at high risks of temporal lobe epilepsy in later life.1 Currently,there is no appropriate pharmacotherapeutic option to control FS,and later epileptogenesis in the perspective of both therapeutic efficacy and safety.