Editorial: Neuromodulatory ascending systems: Their influence at the microscopic and macroscopic levels

Brain activity and behavior are constantly changing (Puig et al., 2014; Disney, 2021). Recent studies in both animal models and humans have revealed that such variations are not random in nature but controlled through slow-acting neuromodulatory systems...

Role of CB2 receptors and cGMP pathway on the cannabinoid-dependent antiepileptic effects in an in vivo model of partial epilepsy.

This study aimed at providing an insight on the possible role of cannabi-noid (CB) type 2 receptors (CB2R) and cGMP pathway in the antiepileptic activity ofWIN 55,212-2, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo[1,2,3-de]-1,4-benzoxazin-6-Yl]-1-naphthalenylmethanone, a non-selective CB agonist, in the maximal dentate activation (MDA) model of partial epilepsy in adult male rats. We evaluated the activity of a CB2 antagonist/inverse agonist AM630, [6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)methanone or 6-iodopravadoline, alone or in co-administration with WIN 55,212-2. Also, in the MDA model it was investigated the co-treatment of WIN55,212…

Correlation of Metabolic Syndrome with Redox Homeostasis Biomarkers: Evidence from High-Fat Diet Model in Wistar Rats

Metabolic Syndrome (MetS) is an extremely complex disease. A non-balanced diet such as high-fat diet (HFD) induces metabolic dysfunction that could modify redox homeostasis. We here aimed at exploring redox homeostasis in male Wistar rats, following 8 weeks of HFD, correlating the eventual modification of selected biomarkers that could be associated with the clinical manifestations of MetS. Therefore, we selected parameters relative to both the glucose tolerance and lipid altered metabolism, but also oxidative pattern. We assessed some biomarkers of oxidative stress i.e., thiols balance, lipid peroxidation and antioxidant barriers, via the use of specific biochemical assays, individuating e…

Cannabinoid-‐mediated modulation of hippocampal hyperexcitability: focus on the interplay with nitrergic system in different rat models of temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is the most common type of partial complex seizure in adulthood [1]. Within the framework of hyperexcitability, growing interest has risen on the impact of cannabinoids on the control of paroxysmal phenomena [2], despite their reputation as psychotropic substances with addictive properties [3; 4]. In this regard, it was reported that the on-demand production of endocannabinoids from over-activated postsynaptic cells inhibits neurotransmitter release, hence protecting against excitotoxicity in the hippocampus [5; 6]. Nonetheless, the potential anticonvulsant action of cannabinoids has not been fully addressed. Indeed, CB-mediated effects in animal models are attr…

Being in the Past and Perform the Future in a Virtual World: VR Applications to Assess and Enhance Episodic and Prospective Memory in Normal and Pathological Aging

The process of aging commonly features a gradual deterioration in cognitive performance and, in particular, the decline of memory. Despite the increased longevity of the world's population, the prevalence of neurodegenerative conditions, such as dementia, continues to be a major burden on public health, and consequently, the latest research has been focused on memory and aging. Currently, the failure of episodic and Prospective memory (PM) is one of the main complaints in the elderly, considered among the early symptoms of dementia. It is therefore increasingly important to define more clearly the boundaries between normal and pathological aging. Recently, researchers have begun to build an…

Neuronal nitric oxide synthase is involved in CB/TRPV1 signalling: Focus on control of hippocampal hyperexcitability

Cannabinoids (CB), transient receptors potential vanilloid type 1 (TRPV1) and nitric oxide (NO) were found to be interlinked in regulating some neuronal functions such as membrane excitability and synaptic transmission. TRPV1 play a fundamental role since it represents a synaptic target for CB that triggers several downstream cellular pathways. In this regard, recent evidence report that TRPV1 could influence NO production by modulating neuronal NO synthase (nNOS) activity. In the present research, we pointed to manipulate nNOS function to assess its role on TRPV1 signalling in hyperexcitability conditions elicited in the dentate gyrus of hippocampal formation. The activation of TRPV1 recep…

Cannabinoids, TRPV and nitric oxide: the three ring circus of neuronal excitability

Endocannabinoid system is considered a relevant player in the regulation of neuronal excitability, since it contributes to maintaining the balance of the synaptic ionic milieu. Perturbations to bioelectric conductances have been implicated in the pathophysiological processes leading to hyperexcitability and epileptic seizures. Cannabinoid influence on neurosignalling is exerted on classic receptor-mediated mechanisms or on further molecular targets. Among these, transient receptor potential vanilloid (TRPV) are ionic channels modulated by cannabinoids that are involved in the transduction of a plethora of stimuli and trigger fundamental downstream pathways in the post-synaptic site. In this…

Multimodal determinants of phase-locked dynamics across deep-superficial hippocampal sublayers during theta oscillations

Theta oscillations play a major role in temporarily defining the hippocampal rate code by translating behavioral sequences into neuronal representations. However, mechanisms constraining phase timing and cell-type-specific phase preference are unknown. Here, we employ computational models tuned with evolutionary algorithms to evaluate phase preference of individual CA1 pyramidal cells recorded in mice and rats not engaged in any particular memory task. We applied unbiased and hypothesis-free approaches to identify effects of intrinsic and synaptic factors, as well as cell morphology, in determining phase preference. We found that perisomatic inhibition delivered by complementary populations…

Haptic Perception in Extreme Obesity: qEEG Study Focused on Predictive Coding and Body Schema

Haptic perception (HP) is a perceptual modality requiring manual exploration to elaborate the physical characteristics of external stimuli through multisensory integrative cortical pathways. Cortical areas exploit processes of predictive coding that collect sensorial inputs to build and update internal perceptual models. Modifications to the internal representation of the body have been associated with eating disorders. In the light of this, obese subjects were selected as a valid experimental model to explore predictive coding in haptic perception. To this purpose, we performed electroencephalographic (EEG) continuous recordings during a haptic task in normally weighted versus obese subjec…

TRPV1 channels in nitric oxide-mediated signalling: insight on excitatory transmission in rat CA1 pyramidal neurons

Nitric oxide (NO) is a fascinating signalling molecule implicated in a plethora of biological functions, especially at the synaptic level. Exploring neurotransmission in the hippocampus could be instrumental in the individuation of putative targets for nitric-oxide mediated neuromodulation, especially in terms of the potential repercussions on fundamental processes i.e. synaptic plasticity and excitability-related phenomena. Among these targets, endovanilloid signalling constitutes an object of study since Transient Receptors Vanilloid type 1 (TRPV1) channels possess a NO-sensitive gate modulating its activation. Also, NO has been referred to as a mediator for numerous endocannabinoid effec…

Microtubule Dynamics and Neuronal Excitability: Advances on Cytoskeletal Components Implicated in Epileptic Phenomena

AbstractExtensive researches have deepened knowledge on the role of synaptic components in epileptogenesis, but limited attention has been devoted to the potential implication of the cytoskeleton. The study of the development of epilepsy and hyperexcitability states involves molecular, synaptic, and structural alterations of neuronal bioelectric activity. In this paper we aim to explore the neurobiological targets involved in microtubule functioning and cytoskeletal transport, i.e. how dynamic scaffolding of microtubules can influence neuronal morphology and excitability, in order to suggest a potential role for microtubule dynamics in the processes turning a normal neuronal network in a hy…

Involvement of TRPV1 channels in the activity of the cannabinoid WIN 55,212-2 in an acute rat model of temporal lobe epilepsy

The exogenous cannabinoid agonist WIN 55,212-2, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo[1,2,3-de]-1,4-benzoxazin-6-Yl]-1-naphthalenylmethanone (WIN), has revealed to play a role on modulating the hyperexcitability phenomena in the hippocampus. Cannabinoid-mediated mechanisms of neuroprotection have recently been found to imply the modulation of transient receptor potential vanilloid 1 (TRPV1), a cationic channel subfamily that regulate synaptic excitation. In our study, we assessed the influence of pharmacological manipulation of TRPV1 function, alone and on WIN antiepileptic activity, in the Maximal Dentate Activation (MDA) acute model of temporal lobe epilepsy. Our r…

“Golden” Tomato Consumption Ameliorates Metabolic Syndrome: A Focus on the Redox Balance in the High-Fat-Diet-Fed Rat

Tomato fruits defined as “golden” refer to a food product harvested at an incomplete ripening stage with respect to red tomatoes at full maturation. The aim of this study is to explore the putative influence of “golden tomato” (GT) on Metabolic Syndrome (MetS), especially focusing on the effects on redox homeostasis. Firstly, the differential chemical properties of the GT food matrix were characterized in terms of phytonutrient composition and antioxidant capacities with respect to red tomato (RT). Later, we assessed the biochemical, nutraceutical and eventually disease-modifying potential of GT in vivo in the high-fat-diet rat model of MetS. Our data revealed that G…

Modulating Long Term Memory at Late-Encoding Phase: An rTMS Study

Despite a huge effort of the scientific community, the functioning of Long-Term Memory (LTM) processes is still debated and far from being elucidated. Functional and neurophysiological data point to an involvement of Dorsolateral Prefrontal Cortex (DLPFC) in both encoding and retrieval phases. However, the recently proposed Explicit/Implicit Memory Encoding and Retrieval (EIMER) model proposes that LTM at the encoding phase consists of anatomically and chronologically different sub-phases. On this basis, we aimed to investigate the role of right DLPFC during a late-encoding phase by means of low-frequency rTMS. Thirty right-handed healthy subjects were divided into three experimental groups…

Brain Distribution and Modulation of Neuronal Excitability by Indicaxanthin From Opuntia Ficus Indica Administered at Nutritionally-Relevant Amounts

Several studies have recently investigated the role of nutraceuticals in complex pathophysiological processes such as oxidative damages, inflammatory conditions and excitotoxicity. In this regard, the effects of nutraceuticals on basic functions of neuronal cells, such as excitability, are still poorly investigated. For this reason, the possible modulation of neuronal excitability by phytochemicals (PhC) could represent an interesting field of research given that excitotoxicity phenomena are involved in neurodegenerative alterations leading, for example, to Alzheimer's disease. The present study was focused on indicaxanthin from Opuntia ficus indica, a bioactive betalain pigment, with a pro…

TRPV1 channels as putative targets in the cannabinoid-mediated synaptic activity of hippocampal neurons

Endocannabinoids (eCBs) play a critical part in pathophysiological conditions rooted on neuronal excitability such as epilepsy. eCBs seem to be involved in neuroprotection, putatively acting on the cannabinoid receptor type 1 (CB1r), but also on Transient Receptor Potential Vanilloid type 1 channels (TRPV1). Indeed, CB1r and TRPV1 are involved in the transduction of stimuli at synaptic level, though exact molecular mechanisms are far from being unveiled. Thus, we aimed to investigate the role of CB1r/TRPV1 interplay in the rat hippocampal neurotransmission by whole-cell patch clamp technique to evaluate excitatory bioelectric activity in the CA1. We pharmacologically manipulated this pathwa…

Ketogenic and Modified Mediterranean Diet as a Tool to Counteract Neuroinflammation in Multiple Sclerosis: Nutritional Suggestions.

Ketogenic Diet is a nutritional pattern often used as dietotherapy in inflammatory diseases, including neurological disorders. Applied on epileptic children since 1920, in recent years it has been taken into account again as a tool to both reduce inflammatory burdens and ameliorate the nutritional status of patients affected by different pathologies. Multiple sclerosis (MS) is considered an immune-mediated neuro-inflammatory disease and diet is a possible factor in its pathogenesis. The aim of this work is to investigate the main potential targets of MS-related impairments, in particular the cognitive deficits, focusing on the alteration of biomarkers such as the Brain Derived-Neurotrophic …

Comparative Study of the Effects Exerted by N-Valproyl-L-Phenylalanine and N-valproyl-L-tryptophan on CA1 Hippocampal Epileptiform Activity in Rat

Background: The research on the improvement of epilepsy therapy is constantly growing. Valproyl-LPhenylalanine (VPA-Phen) and N-valproyl-L-tryptophan (VPA-Tryp) were synthesized to increase the antiepileptic efficacy of valproic acid. Methods: VPA-Phen and VPA-Tryp were comparatively tested on CA1 hippocampal epileptiform bursting activity obtained by increasing potassium and lowering calcium and magnesium concentrations in the fluid perfusing rat brain slices. Each slice was treated with a single concentration (0.2, 0.5, 1 mM) of VPA-Phen or VPA-Tryp. Both burst duration and interburst frequency, during and after treatment, were off-line compared with baseline values. For both parameters,…

Indicaxanthin from Opuntia ficus-indica Crosses the Blood–Brain Barrier and Modulates Neuronal Bioelectric Activity in Rat Hippocampus at Dietary-Consistent Amounts

Indicaxanthin is a bioactive and bioavailable betalain pigment from the Opuntia ficus-indica fruits. In this in vivo study, kinetic measurements showed that indicaxanthin is revealed in the rat brain within 1 h from oral administration of 2 μmol/ kg, an amount compatible with a dietary consumption of cactus pear fruits in humans. A peak (20 ± 2.4 ng of indicaxanthin per whole brain) was measured after 2.5 h; thereafter the molecule disappeared with first order kinetics within 4 h. The potential of indicaxanthin to affect neural activities was in vivo investigated by a microiontophoretic approach. Indicaxanthin, administered in a range between 0.085 ng and 0.34 ng per neuron, dose-dependentl…

Through Predictive Personalized Medicine.

Neuroblastoma (NBM) is a deadly form of solid tumor mostly observed in the pediatric age. Although survival rates largely differ depending on host factors and tumor-related features, treatment for clinically aggressive forms of NBM remains challenging. Scientific advances are paving the way to improved and safer therapeutic protocols, and immunotherapy is quickly rising as a promising treatment that is potentially safer and complementary to traditionally adopted surgical procedures, chemotherapy and radiotherapy. Improving therapeutic outcomes requires new approaches to be explored and validated. In-silico predictive models based on analysis of a plethora of data have been proposed by Lomba…

Guanosine modulates K+ membrane currents in SH-SY5Y cells: involvement of adenosine receptors

AbstractGuanosine (GUO), widely considered a key signaling mediator, is implicated in the regulation of several cellular processes. While its interaction with neural membranes has been described, GUO still is an orphan neuromodulator. It has been postulated that GUO may eventually interact with potassium channels and adenosine (ADO) receptors (ARs), both particularly important for the control of cellular excitability. Accordingly, here, we investigated the effects of GUO on the bioelectric activity of human neuroblastoma SH-SY5Y cells by whole-cell patch-clamp recordings. We first explored the contribution of voltage-dependent K+ channels and, besides this, the role of ARs in the regulation…

Modulation of Human Motor Cortical Excitability and Plasticity by Opuntia Ficus Indica Fruit Consumption: Evidence from a Preliminary Study through Non-Invasive Brain Stimulation

Indicaxanthin (IX) from Opuntia Ficus Indica (OFI) has been shown to exert numerous biological effects both in vitro and in vivo, such as antioxidant, anti-inflammatory, neuro-modulatory activity in rodent models. Our goal was to investigate the eventual neuro-active role of orally assumed fruits containing high levels of IX at nutritionally-relevant amounts in healthy subjects, exploring cortical excitability and plasticity in the human motor cortex (M1). To this purpose, we applied paired-pulse transcranial magnetic stimulation and anodal transcranial direct current stimulation (a-tDCS) in basal conditions and followed the consumption of yellow cactus pear fruits containing IX or white ca…

Vulnerability to alcohol operant-drinking behaviour: implications of environmental stim

Environmental stimuli, occurring early in life, shape the drinking trajectories and the psychopathological outcome of alcohol consumption in adult life. In particular, early perinatal procedures can permanently alter various patterns of drug use and behaviour in rat adulthood (Pryce CR, 2001). Early handling (EH) apparently is responsible for neurochemical and behavioural changes in adulthood, due to boosts in maternal care after daily reunion. It has been suggested that fostered maternal care, in the form of licking and grooming, is a key feature in determining neural changes and offspring fear responses and alter the reward/reinforcement pathway through epigenetic mechanisms that likely u…

Reducing Visuospatial Pseudoneglect in Healthy Subjects by Active Video Gaming

Pseudoneglect phenomenon refers to a condition in which healthy subjects tend to perceive the left side of exactly bisected lines as being slightly longer than the right one. However, behavioural data showed that athletes practising an open-skill sport display less pseudoneglect than the general population. Given the fact that so-called exergames (also known as active video games) are platforms designed to fully mimic sport activity, this work intends to investigate whether and how a one-week training period of exergame open-skill sport can determine a similar decrease in pseudoneglect. Fifteen healthy participants (non-athletes) responded to a visuospatial attention task and a control memo…

Cannabinoid and nitric oxide signaling interplay in the modulation of hippocampal hyperexcitability: study on electrophysiological and behavioral models of temporal lobe epilepsy in the rat

A growing bulk of evidence suggests that cannabinoid system plays a pivotal role in the control of hyperexcitability phenomena. Notwithstanding, the anticonvulsant action of cannabinoids has not been fully addressed, in particular the involvement of potential cellular neuromodulators, for instance nitric oxide. In the current study, we focused on two distinct rat models of temporal lobe epilepsy, the Maximal Dentate Activation and the pilocarpine-induced acute seizures, providing both electrophysiological and behavioral data on cannabinoid and nitrergic system interplay. We evaluated the antiepileptic effects of WIN 55,212-2, (R)-(+)-[2,3-dihydro-5-methyl-3-(4- morpholinylmethyl) pyrrolo[1,…

Early handling effect on female rat spatial and non-spatial learning and memory

This study aims at providing an insight into early handling procedures on learning and memory performance in adult female rats. Early handling procedures were started on post-natal day 2 until 21, and consisted in 15 min, daily separations of the dams from their litters. Assessment of declarative memory was carried out in the novel-object recognition task; spatial learning, reference- and working memory were evaluated in the Morris water maze (MWM). Our results indicate that early handling induced an enhancement in: (1) declarative memory, in the object recognition task, both at 1h and 24h intervals; (2) reference memory in the probe test and working memory and behavioral flexibility in the…

Dopamine involvement in Acetaldehyde drinking behaviour: role of Ropinirole on.

Rats self-administer acetaldehyde(ACD), ethanol's first metabolite, directly into cerebral ventricles (1), and multiple ICV infusions of ACD produce conditioned place preference (2). ACD, such as alcohol and other substances of abuse, interacts with dopaminergic reward system (3) and its reinforcing and addictive properties have been assessed through an operant-conflict conditioning procedure (4). Since dopamine D2receptor over-expression in the Nacc attenuates alcohol intake (5), this study aims at exploring the effects of ropinirole administration during abstinence, on ACD relapse. The protocol has been scheduled into 3 different periods: training ( animals have been trained to self-admin…

EFFECTS OF INDICAXANTHIN ON HUMAN MOTOR CORTICAL EXCITABILITY AND PLASTICITY

The role of nutraceuticals has risen interest in the last decade for complex biological activities exerted on pathophysiological processes such as oxidative stress, inflammatory conditions and excitotoxicity. In this regard, the effects of nutraceuticals on basic functions of neuronal processes, such as cortical excitability and cortical plasticity are still to be unveiled. Translational studies performed on phytochemicals (PhC) with anti-inflammatory and antioxidant properties could trace the path for the possible modulation of neuronal excitability in humans, phenomena involved in neurodegenerative alterations and cell stress. In this context, Opuntia ficus indica is a mediterranean plant…

Hippocampal hyperexcitability is modulated by microtubule-active agent: evidence from in vivo and in vitro epilepsy models in the rat

The involvement of microtubule dynamics on bioelectric activity of neurons and neurotransmission represents a fascinating target of research in the context of neural excitability. It has been reported that alteration of microtubule cytoskeleton can lead to profound modifications of neural functioning, with a putative impact on hyperexcitability phenomena. Altogether, in the present study we pointed at exploring the outcomes of modulating the degree of microtubule polymerization in two electrophysiological epileptiform activity in the rat hippocampus. To this aim, we used in vivo Maximal Dentate Activation (MDA) and in vitro hippocampal epileptiform bursting activity (HEBA) paradigms to asse…

ROLE OF NITRIC OXIDE/cGMP PATHWAY IN CANNABINOID MODULATION OF PAROXYSMAL PHENOMENA