Search

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 proven antioxidant and anti-inflammatory potential, previously found to cross blood-brain barrier (BBB) and to modulate the bioelectric activity of hippocampal neurons. On this basis, we aimed at detecting the specific brain areas where indicaxanthin localizes after oral administration at dietary-achievable amounts and highlighting eventual local effects on the excitability of single neuronal units. HPLC analysis of brain tissue 1 h after ingestion of 2 mmol/kg indicaxanthin indicated that the phytochemical accumulates in cortex, hippocampus, diencephalon, brainstem and cerebellum, but not in the striato-pallidal complex. Then, electrophysiological recordings, applying the microiontophoretic technique, were carried out with different amounts of indicaxanthin (0.34, 0.17, 0.085 ng/neuron) to assess whether indicaxanthin influenced the neuronal firing rate. The data showed that the bioelectric activity of neurons belonging to different brain areas was modulated after local injection of indicaxanthin, mainly with dose-related responses. A predominating inhibitory effect was observed, suggesting a possible novel beneficial effect of indicaxanthin in reducing cell excitability. These findings can constitute a new rationale for exploring biological mechanisms through which PhC could modulate neuronal function with a relapse on complex cognitive brain process and related neurodegenerative conditions. [ABSTRACT FROM AUTHOR]

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 receptors is achieved by administering capsaicin (CAP), the main TRPV1 agonist exerting a widely reported proepileptic effects. In order to focus on nNOS activity, we used 7-nitroindazole (7NI), nNOS inhibitor, or L-Arginine (ARG), NO precursor, before CAP. Then, the effects of each of these co-administration protocols were tested in presence of WIN 55,212, a CB agonist. The study was conducted in rats using an electrically-induced acute model of temporal lobe hyperexcitability, the Maximal Dentate Activation (MDA), considering different indicators of paroxysmal activity such as: percentage of responses to electrical stimulation, MDA discharge parameters and threshold current intensity for MDA. Data showed that the excitatory effects of CAP were reduced by 7NI and enhanced by ARG pretreatments, respectively. In addition, the co-treatment with WIN counteracted CAP effect, substantially resulting in an inhibitory effect. Finally, the CAP-WIN functional interaction appeared to be modulated by interfering with NO signalling since 7NI increased the inhibitory effect induced by the co-treatment with CAP and WIN, whereas ARG reduced it. These findings suggest that nNOS function could be involved in the CB/TRPV1 signalling and shed light on a new putative cannabinoid-related control of neuronal hyperexcitability in the hippocampus [ABSTRACT FROM AUTHOR]

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 results showed that the TRPV1 agonist, capsaicin, increased epileptic outcomes; whilst antagonizing TRPV1 with capsazepine exerts a protective role on paroxysmal discharge. When capsaicin is co-administered with WIN effective dose of 10 mg/kg is able to reduce its antiepileptic strength, especially on the triggering of MDA response. Accordingly, capsazepine at the protective dose of 2 mg/kg managed to potentiate WIN antiepileptic effects, when co-treated. Moreover, WIN subeffective dose of 5 mg/kg was turned into effective when capsazepine comes into play. This evidence suggests that systemic administration of TRPV1-active drugs influences electrically induced epilepsy, with a noticeable protective activity for capsazepine. Furthermore, results from the pharmacological interaction with WIN support an interplay between cannabinoid and TRPV1 signaling that could represent a promising approach for a future pharmacological strategy to challenge hyperexcitability-based diseases. [ABSTRACT FROM AUTHOR]

The article discusses research concerning the modulation of hippocampal hyperexcitability by microtubule-active agent. It highlights the use of in vivo maximal dentate activation (MDA) and in vitro hippocampal epileptiform bursting activity (HEBA) paradigms in assessment the impact of nocodazole (NOC) and paclitaxel (PAC) in the rat. Also emphasized is the effect of cytoskeleton function in the synaptic process and biolectric aspects of epileptic activity.