Downregulation of the Astroglial Connexin Expression and Neurodegeneration after Pilocarpine-Induced Status Epilepticus.

Astrocytic networks and gap junctional communication mediated by connexins (Cxs) have been repeatedly implicated in seizures, epileptogenesis, and epilepsy. However, the effect of seizures on Cx expression is controversial. The present study focused on the response of Cxs to status epilepticus (SE), which is in turn an epileptogenic insult. The expression of neuronal Cx36 and astrocytic Cx30 and Cx43 mRNAs was investigated in the brain of rats in the first day after pilocarpine-induced SE. In situ hybridization revealed a progressive decrease in Cx43 and Cx30 mRNA levels, significantly marked 24 h after SE onset in neocortical areas and the hippocampus, and in most thalamic domains, whereas Cx36 mRNA did not exhibit obvious changes. Regional evaluation with quantitative real-time-RT-PCR confirmed Cx43 and Cx30 mRNA downregulation 24 h after SE, when ongoing neuronal cell death was found in the same brain regions. Immunolabeling showed at the same time point marked a decrease in Cx43, microglia activation, and interleukin-1ß induction in some microglial cells. The data showed a transient downregulation of astroglial Cxs in the cortical and thalamic areas in which SE triggers neurodegenerative events in concomitance with microglia activation and cytokine expression. This could potentially represent a protective response of neuroglial networks to SE-induced acute damage.

Gut microbiota modulates seizure susceptibility.

A bulk of data suggest that the gut microbiota plays a role in a broad range of diseases, including those affecting the central nervous system. Recently, significant differences in the intestinal microbiota of patients with epilepsy, compared to healthy volunteers, have been reported in an observational study. However, an active role of the intestinal microbiota in the pathogenesis of epilepsy, through the so-called "gut-brain axis," has yet to be demonstrated. In this study, we evaluated the direct impact of microbiota transplanted from epileptic animals to healthy recipient animals, to clarify whether the microbiota from animals with epilepsy can affect the excitability of the recipients' brain by lowering seizure thresholds. Our results provide the first evidence that mice who received microbiota from epileptic animals are more prone to develop status epilepticus, compared to recipients of "healthy" microbiota, after a subclinical dose of pilocarpine, indicating a higher susceptibility to seizures. The lower thresholds for seizure activity found in this study support the hypothesis that the microbiota, through the gut-brain axis, is able to affect neuronal excitability in the brain.

The Anti-Inflammatory Properties of Mesenchymal Stem Cells in Epilepsy: Possible Treatments and Future Perspectives.

Mesenchymal stem cells (MSCs) are multipotent adult cells with self-renewing capacities. MSCs display specific properties, such as the ability to repair damaged tissues, resulting in optimal candidates for cell therapy against degenerative diseases. In addition to the reparative functions of MSCs, growing evidence shows that these cells have potent immunomodulatory and anti-inflammatory properties. Therefore, MSCs are potential tools for treating inflammation-related neurological diseases, including epilepsy. In this regard, over the last decades, epilepsy has no longer been considered a purely neuronal pathology, since inflammatory events underlying the genesis of epilepsy have been demonstrated. This review assessed current knowledge on the use of MSCs in the treatment of epilepsy. Mostly, attention will be focused on the anti-inflammatory and immunological skills of MSCs. Understanding the mechanisms by which MSCs might modulate the severity of the disease will contribute to the development of new potential alternatives for both prophylaxis and treatment against epilepsy.

Glial Response and Neuronal Modulation Induced by Epidural Electrode Implant in the Pilocarpine Mouse Model of Epilepsy.

In animal models of epilepsy, cranial surgery is often required to implant electrodes for electroencephalography (EEG) recording. However, electrode implants can lead to the activation of glial cells and interfere with physiological neuronal activity. In this study, we evaluated the impact of epidural electrode implants in the pilocarpine mouse model of temporal lobe epilepsy. Brain neuroinflammation was assessed 1 and 3 weeks after surgery by cytokines quantification, immunohistochemistry, and western blotting. Moreover, we investigated the effect of pilocarpine, administered two weeks after surgery, on mice mortality rate. The reported results indicate that implanted mice suffer from neuroinflammation, characterized by an early release of pro-inflammatory cytokines, microglia activation, and subsequent astrogliosis, which persists after three weeks. Notably, mice subjected to electrode implants displayed a higher mortality rate following pilocarpine injection 2 weeks after the surgery. Moreover, the analysis of EEGs recorded from implanted mice revealed a high number of single spikes, indicating a possible increased susceptibility to seizures. In conclusion, epidural electrode implant in mice promotes neuroinflammation that could lower the seizure thresholds to pilocarpine and increase the death rate. An improved protocol considering the persistent neuroinflammation induced by electrode implants will address refinement and reduction, two of the 3Rs principles for the ethical use of animals in scientific research.

Late-onset Parkinsonism in NFκB/c-Rel-deficient mice.

Activation of the nuclear factor κB/c-Rel can increase neuronal resilience to pathological noxae by regulating the expression of pro-survival manganese superoxide dismutase (MnSOD, now known as SOD2) and Bcl-xL genes. We show here that c-Rel-deficient (c-rel(-/-)) mice developed a Parkinson's disease-like neuropathology with ageing. At 18 months of age, c-rel(-/-) mice exhibited a significant loss of dopaminergic neurons in the substantia nigra pars compacta, as assessed by tyrosine hydroxylase-immunoreactivity and Nissl staining. Nigral degeneration was accompanied by a significant loss of dopaminergic terminals and a significant reduction of dopamine and homovanillic acid levels in the striatum. Mice deficient of the c-Rel factor exhibited a marked immunoreactivity for fibrillary α-synuclein in the substantia nigra pars compacta as well as increased expression of divalent metal transporter 1 (DMT1) and iron staining in both the substantia nigra pars compacta and striatum. Aged c-rel(-/-) mouse brain were characterized by increased microglial reactivity in the basal ganglia, but no astrocytic reaction. In addition, c-rel(-/-) mice showed age-dependent deficits in locomotor and total activity and various gait-related deficits during a catwalk analysis that were reminiscent of bradykinesia and muscle rigidity. Both locomotor and gait-related deficits recovered in c-rel(-/-) mice treated with l-3,4-dihydroxyphenylalanine. These data suggest that c-Rel may act as a regulator of the substantia nigra pars compacta resilience to ageing and that aged c-rel(-/-) mice may be a suitable model of Parkinson's disease.

Neurovascular unit in chronic pain.

Chronic pain is a debilitating condition with major socioeconomic impact, whose neurobiological basis is still not clear. An involvement of the neurovascular unit (NVU) has been recently proposed. In particular, the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB), two NVU key players, may be affected during the development of chronic pain; in particular, transient permeabilization of the barrier is suggested by several inflammatory- and nerve-injury-based pain models, and we argue that the clarification of molecular BBB/BSCB permeabilization events will shed new light in understanding chronic pain mechanisms. Possible biases in experiments supporting this theory and its translational potentials are discussed. Moving beyond an exclusive focus on the role of the endothelium, we propose that our understanding of the mechanisms subserving chronic pain will benefit from the extension of research efforts to the NVU as a whole. In this view, the available evidence on the interaction between analgesic drugs and the NVU is here reviewed. Chronic pain comorbidities, such as neuroinflammatory and neurodegenerative diseases, are also discussed in view of NVU changes, together with innovative pharmacological solutions targeting NVU components in chronic pain treatment.

Age-Dependent Neuropsychiatric Symptoms in the NF-κB/c-Rel Knockout Mouse Model of Parkinson's Disease.

Non-motor symptoms are frequently observed in Parkinson's disease (PD) and precede the onset of motor deficits by years. Among them, neuropsychiatric symptoms, including anxiety, depression, and apathy, are increasingly considered as a major challenge for patients with PD and their caregivers. We recently reported that mice lacking the nuclear factor-κB (NF-κB)/c-Rel protein (c-rel-/- mice) develop an age-dependent PD-like pathology and phenotype characterized by the onset of non-motor symptoms, including constipation and hyposmia, starting at 2 months of age, and motor deficits at 18 months. To assess whether c-rel-/- mice also suffer from neuropsychiatric symptoms, in this study we tested different cohorts of wild-type (wt) and c-rel-/- mice at 3, 6, 12, and 18-20 months with different behavioral tests. Mice lacking c-Rel displayed anxiety and depressive-like behavior starting in the premotor phase at 12 months, as indicated by the analysis with the open field (OF) test and the forced swim test with water wheel (FST), respectively. A deficit in the goal-oriented nesting building test was detected at 18-20 months, suggesting apathetic behavior. Taken together, these results indicate that c-rel-/- mice recapitulate the onset and the progression of PD-related neuropsychiatric symptoms. Therefore, this animal model may represent a valuable tool to study the prodromal stage of PD and for testing new therapeutic strategies to alleviate neuropsychiatric symptoms.

Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis.

Chorea-Acanthocytosis (ChAc) is a devastating, little understood, and currently untreatable neurodegenerative disease caused by VPS13A mutations. Based on our recent demonstration that accumulation of activated Lyn tyrosine kinase is a key pathophysiological event in human ChAc cells, we took advantage of Vps13a-/- mice, which phenocopied human ChAc. Using proteomic approach, we found accumulation of active Lyn, γ-synuclein and phospho-tau proteins in Vps13a-/- basal ganglia secondary to impaired autophagy leading to neuroinflammation. Mice double knockout Vps13a-/- Lyn-/- showed normalization of red cell morphology and improvement of autophagy in basal ganglia. We then in vivo tested pharmacologic inhibitors of Lyn: dasatinib and nilotinib. Dasatinib failed to cross the mouse brain blood barrier (BBB), but the more specific Lyn kinase inhibitor nilotinib, crosses the BBB. Nilotinib ameliorates both Vps13a-/- hematological and neurological phenotypes, improving autophagy and preventing neuroinflammation. Our data support the proposal to repurpose nilotinib as new therapeutic option for ChAc patients.

Electrographic seizures induced by activation of ETA and ETB receptors following intrahippocampal infusion of endothelin-1 in immature rats occur by different mechanisms.

We have demonstrated previously that activation of either the ETA or ETB receptor can induce acute electrographic seizures following the intrahippocampal infusion of endothelin-1 (ET-1) in immature (P12) rats. We also demonstrated that activation of the ETA receptor is associated with marked focal ischemia, while activation of the ETB receptor is not. Exploring the mechanisms underlying seizures induced by these two ET-1 receptor interactions can potentially provide insight into how focal ischemia in immature animals produces seizures and whether ischemiarelated seizures differ from seizures not associated with ischemia. To explore these seizure mechanisms we used microdialysis to determine biomarkers associated with seizures in P12 rats following the intrahippocampal infusion of two different agents: (1) ET-1, which activates both the ETA and ETB receptors and causes focal ischemia and (2) Ala-ET-1, which selectively activates only the ETB receptor and does not cause ischemia. Our results show that seizures associated with combined ETA and ETB receptor activation (and ischemia) have a different temporal distribution and microdialysis profile from seizures associated with ETB activation alone (and without ischemia). Seizures with combined activation peak within the first hour after infusion and the microdialysis profile is characterized by a significant increase in the ratio of glutamic acid to GABA. By contrast, seizures with activation of only the ETB receptor peak in the second hour after infusion and microdialysis shows a significant increase in the ratio of leukotriene B4 to prostaglandin E2. These findings suggest that ischemia-related seizures in immature animals involve an imbalance of excitation and inhibition, while non-ischemiarelated seizures involve an inflammatory process resulting from an excess of leukotrienes.

Ongoing Electroencephalographic Rhythms Related to Exploratory Movements in Transgenic TASTPM Mice.

BACKGROUND: The European PharmaCog study (http://www.pharmacog.org) has reported a reduction in delta (1-6 Hz) electroencephalographic (EEG) power (density) during cage exploration (active condition) compared with quiet wakefulness (passive condition) in PDAPP mice (hAPP Indiana V717F mutation) modeling Alzheimer's disease (AD) amyloidosis and cognitive deficits. OBJECTIVE: Here, we tested the reproducibility of that evidence in TASTPM mice (double mutation in APP KM670/671NL and PSEN1 M146V), which develop brain amyloidosis and cognitive deficits over aging. The reliability of that evidence was examined in four research centers of the PharmaCog study. METHODS: Ongoing EEG rhythms were recorded from a frontoparietal bipolar channel in 29 TASTPM and 58 matched "wild type" C57 mice (range of age: 12-24 months). Normalized EEG power was calculated. Frequency and amplitude of individual delta and theta frequency (IDF and ITF) peaks were considered during the passive and active conditions. RESULTS: Compared with the "wild type" group, the TASTPM group showed a significantly lower reduction in IDF power during the active over the passive condition (p < 0.05). This effect was observed in 3 out of 4 EEG recording units. CONCLUSION: TASTPM mice were characterized by "poor reactivity" of delta EEG rhythms during the cage exploration in line with previous evidence in PDAPP mice. The reliability of that result across the centers was moderate, thus unveiling pros and cons of multicenter preclinical EEG trials in TASTPM mice useful for planning future studies.

Rehabilitation and Biomarkers of Stroke Recovery: Study Protocol for a Randomized Controlled Trial.

Background: Stroke is a leading cause of disability. Nonetheless, the care pathway for stroke rehabilitation takes partially into account the needs of chronic patients. This is due in part to the lack of evidence about the mechanisms of recovery after stroke, together with the poor knowledge of related and influencing factors. Here we report on the study protocol "Rehabilitation and Biomarkers of Stroke Recovery," which consists of 7 work-packages and mainly aim to investigate the effects of long-term neurorehabilitation on stroke patients and to define a related profile of (clinical-biological, imaging, neurophysiological, and genetic-molecular) biomarkers of long-term recovery after stroke. The work-package 1 will represent the main part of this protocol and aims to compare the long-term effects of intensive self-rehabilitation vs. usual (rehabilitation) care for stroke. Methods: We planned to include a total of 134 adult subacute stroke patients (no more than 3 months since onset) suffering from multidomain disability as a consequence of first-ever unilateral ischemic stroke. Eligible participants will be randomly assigned to one of the following groups: intensive self-rehabilitation (based on the principles of "Guided Self-Rehabilitation Contract") vs. usual care (routine practice). Treatment will last 1 year, and patients will be evaluated every 3 months according to their clinical presentation. The following outcomes will be considered in the main work-package: Fugl-Meyer assessment, Cognitive Oxford Screen Barthel Index, structural and functional neuroimaging, cortical excitability, and motor and somatosensory evoked potentials. Discussion: This trial will deal with the effects of an intensive self-management rehabilitation protocol and a related set of biomarkers. It will also investigate the role of training intensity on long-term recovery after stroke. In addition, it will define a set of biomarkers related to post-stroke recovery and neurorehabilitation outcome in order to detect patients with greater potential and define long-term individualized rehabilitation programs. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT04323501.

Nonsteroidal anti-inflammatory drugs in clinical and experimental epilepsy.

Current antiepileptic drugs have limited efficacy and provide little or no benefits in 30% of the patients. Given that a role for brain inflammation in epilepsy has been repeatedly reported in recent years, the potential of anti-inflammatory drugs should be explored in depth, as they may provide new therapeutical approaches in preventing or reducing epileptogenesis. Here, we review preclinical (both in vivo and in vitro) and clinical epilepsy studies in which nonsteroidal antiinflammatory drugs (NSAIDs), i.e. cyclooxygenase-2 (COX-2) selective inhibitors (COXIBs) and nonselective NSAIDs, were used for seizure control. The effects of NSAIDs are reviewed in animal models of both chemical (pilocarpine, kainic acid, pentylenetetrazol, or carbachol administration) and electrical (tetanic hippocampal stimulation, electroshock) seizure induction. In the pilocarpine model, NSAIDs are neuroprotective, reduce mossy fiber sprouting or diminish P-glycoprotein upregulation, but only rarely protect against seizures. While neuroprotective effects have also been observed in the kainic acid model, NSAIDs tend in general to worsen seizure activity. Effects of COXIB administration in the pentylenetetrazol-induced seizures model are variable, alternating from protection against seizures to null effects or even increased incidence of convulsions. Moreover, NSAIDs tested in the tetanic hippocampal stimulation model diminished the seizure-associated P-glycoprotein upregulation, but were not very effective in seizure control. NSAIDs efficacy in experimental in vivo epilepsy studies may be influenced by multiple factors, including the timing of administration (before or after status epilepticus induction), the animal model of epilepsy or some of the signaling pathways involved in cyclooxygenase induction (e.g. prostaglandins and their receptors). On the other hand, the few clinical studies on the use of NSAIDs in neurological pathologies accompanied/characterized by seizures indicate that nonselective NSAIDs (e.g. aspirin) in prolonged, low-dose treatments may offer protection against seizures and stroke-like events. No clinical trials in epileptic patients using COXIBs have been conducted so far, as several international drug-control authorities have withdrawn these drugs from the market; future studies should focus on improved COXIB formulations. We argue that, while the available evidence is still inconclusive, the potential therapeutic benefits of controlling and diminishing brain inflammation in the treatment of epilepsy should be actively explored.

All muscarinic acetylcholine receptors (M1-M5) are expressed in murine brain microvascular endothelium.

Clinical and experimental studies indicate that muscarinic acetylcholine receptors are potential pharmacological targets for the treatment of neurological diseases. Although these receptors have been described in human, bovine and rat cerebral microvascular tissue, a subtype functional characterization in mouse brain endothelium is lacking. Here, we show that all muscarinic acetylcholine receptors (M1-M5) are expressed in mouse brain microvascular endothelial cells. The mRNA expression of M2, M3, and M5 correlates with their respective protein abundance, but a mismatch exists for M1 and M4 mRNA versus protein levels. Acetylcholine activates calcium transients in brain endothelium via muscarinic, but not nicotinic, receptors. Moreover, although M1 and M3 are the most abundant receptors, only a small fraction of M1 is present in the plasma membrane and functions in ACh-induced Ca2+ signaling. Bioinformatic analyses performed on eukaryotic muscarinic receptors demonstrate a high degree of conservation of the orthosteric binding site and a great variability of the allosteric site. In line with previous studies, this result indicates muscarinic acetylcholine receptors as potential pharmacological targets in future translational studies. We argue that research on drug development should especially focus on the allosteric binding sites of the M1 and M3 receptors.

On-going electroencephalographic rhythms related to cortical arousal in wild-type mice: the effect of aging.

Resting state electroencephalographic (EEG) rhythms reflect the fluctuation of cortical arousal and vigilance in a typical clinical setting, namely the EEG recording for few minutes with eyes closed (i.e., passive condition) and eyes open (i.e., active condition). Can this procedure be back-translated to C57 (wild type) mice for aging studies? On-going EEG rhythms were recorded from a frontoparietal bipolar channel in 85 (19 females) C57 mice. Male mice were subdivided into 3 groups: 25 young (4.5-6 months), 18 middle-aged (12-15 months), and 23 old (20-24 months) mice to test the effect of aging. EEG power density was compared between short periods (about 5 minutes) of awake quiet behavior (passive) and dynamic exploration of the cage (active). Compared with the passive condition, the active condition induced decreased EEG power at 1-2 Hz and increased EEG power at 6-10 Hz in the group of 85 mice. Concerning the aging effects, the passive condition showed higher EEG power at 1-2 Hz in the old group than that in the others. Furthermore, the active condition exhibited a maximum EEG power at 6-8 Hz in the former group and 8-10 Hz in the latter. In the present conditions, delta and theta EEG rhythms reflected changes in cortical arousal and vigilance in freely behaving C57 mice across aging. These changes resemble the so-called slowing of resting state EEG rhythms observed in humans across physiological and pathological aging. The present EEG procedures may be used to enhance preclinical phases of drug discovery in mice for understanding the neurophysiological effects of new compounds against brain aging.

The hydrolipidic ratio in age-related maturation of adipose tissues.

The hydrolipidic ratio (HLR) expresses the amount of water and fat in a tissue. HLR can be studied non-invasively in the living organism and can be mapped in different areas of the body with high spatial and temporal resolution. In the present work we have evaluated the HLR in different adipose tissue depots in young or adult rats using tissue arrays of fat fragments by 1H-spectroscopy. In young animals, the highest percentage of water (33%) was found in the interscapular brown adipose tissue (iBAT). Mesenteric fat (mWAT) also appeared highly hydrated (24%). The deposits composed of epididymal, retroperitoneal and pelvic white adipose tissue (eWAT, rWAT and pWAT, respectively) contained an amount of water ranging from 14% to 17%. In adult animals, a reduction of the water content was found in all the depots. In e/r/pWAT, the age-related maturation was characterized by large changes in adipocyte diameter accompanied by a small change in HLR. In the iBAT, the maturation was accompanied by small change in adipocyte diameter and a greater diminution of HLR. mWAT showed an intermediate pattern between e/r/pWAT and iBAT. In all the studied depots, an age-related increase in leptin expression was found. This increase was relatively low in iBAT (40%) and high in the e/r/pWAT (204-273%). The work expand the knowledge about the physiological significance of the HLR by 1H-spectroscopy.

Are they in or out? The elusive interaction between Qtracker ® 800 vascular labels and brain endothelial cells.

AIM: Qtracker(®)800 Vascular labels (Qtracker(®)800) are promising biomedical tools for high-resolution vasculature imaging; their effects on mouse and human endothelia, however, are still unknown. MATERIALS & METHODS: Qtracker(®)800 were injected in Balb/c mice, and brain endothelium uptake was investigated by transmission electron microscopy 3-h post injection. We then investigated, in vitro, the effects of Qtracker(®)800 exposure on mouse and human endothelial cells by calcium imaging. RESULTS: Transmission electron microscopy images showed nanoparticle accumulation in mouse brain endothelia. A subset of mouse and human endothelial cells generated intracellular calcium transients in response to Qtracker(®)800. CONCLUSION: Qtracker(®)800 nanoparticles elicit endothelial functional responses, which prompts biomedical safety evaluations and may bias the interpretation of experimental studies involving vascular imaging.

Antidepressant activity of fingolimod in mice.

Recent findings indicate that fingolimod, the first oral drug approved for the treatment of multiple sclerosis (MS), acts as a direct inhibitor of histone deacetylases (HDACs) and enhances the production of brain-derived neurotrophic factor (BDNF) in the CNS. Both mechanisms are relevant to the pathophysiology and treatment of major depression. We examined the antidepressant activity of fingolimod in mice subjected to chronic unpredictable stress (CUS), a model of reactive depression endowed with face and pharmacological validity. Chronic treatment with fingolimod (3 mg kg(-1), i.p., once a day for 4 weeks) reduced the immobility time in the forced swim test (FST) in a large proportion of CUS mice. This treatment also caused anxiogenic-like effects in the social interaction test without affecting anxiety-like behavior in the elevated plus maze or spatial learning in the water maze. CUS mice showed reduced BDNF levels and enhanced HDAC2 levels in the hippocampus. These changes were reversed by fingolimod exclusively in mice that showed a behavioral response to the drug in the FST. Fingolimod treatment also enhanced H3 histone K14-acetylation and adult neurogenesis in the hippocampus of CUS mice. Fingolimod did not affect most of the parameters we have tested in unstressed control mice. The antidepressant-like activity of fingolimod was confirmed in mice chronically treated with corticosterone. These findings show for the first time that fingolimod exerts antidepressant-like effect acting in a "disease-dependent" manner, and raise the interesting possibility that the drug could relieve depressive symptoms in MS patients independently of its disease-modifying effect on MS.

New players in the neurovascular unit: insights from experimental and clinical epilepsy.

The conventional notion that neurons are exclusively responsible for brain signaling is increasingly challenged by the idea that brain function in fact depends on a complex interplay between neurons, glial cells, vascular endothelium, and immune-related blood cells. Recent data demonstrates that neuronal activity is profoundly affected by an entire cellular and extracellular 'orchestra', the so-called neurovascular unit (NVU). Among the 'musical instruments' of this orchestra, there may be molecules long-known in biomedicine as important mediators of inflammatory and immune responses in the organism, as well as non-neuronal cells, e.g., leukocytes. We here review recent evidence on the structure and function of the NVU, both in the healthy brain and in pathological conditions, such as the abnormal NVU activation observed in epilepsy. We will argue that a better understanding of NVU function will require the addition of new players to the 'orchestra'.

Effects of pharmacological agents, sleep deprivation, hypoxia and transcranial magnetic stimulation on electroencephalographic rhythms in rodents: towards translational challenge models for drug discovery in Alzheimer's disease.

Different kinds of challenge can alter spontaneous ongoing electroencephalographic (EEG) rhythms in animal models, thus providing paradigms to evaluate treatment effects in drug discovery. The effects of challenges represented by pharmacological agents, hypoxia, sleep deprivation and transcranial magnetic stimulation (TMS) on EEG rhythms are here reviewed to build a knowledge platform for innovative translational models for drug discovery in Alzheimer's disease (AD). It has been reported that antagonists of cholinergic neurotransmission cause synchronisation of spontaneous ongoing EEG rhythms in terms of enhanced power of EEG low frequencies and decreased power of EEG high frequencies. Acetylcholinesterase inhibitors and serotonergic drugs may restore a normal pattern of EEG desynchronisation. Sleep deprivation and hypoxia challenges have also been reported to elicit abnormal synchronisation of spontaneous ongoing EEG rhythms in rodents. The feasibility and reproducibility of TMS have been demonstrated in rodents but information on a consistent modulation of EEG after TMS manipulation is very limited. Transgenic mice over-expressing human amyloid precursor protein complementary DNAs (cDNAs) harbouring the 'Swedish' mutation and PS-1 cDNAs harbouring the A264E mutation, which recapitulate some of the pathological features of AD, exhibit alterations of spontaneous ongoing EEG rhythms at several low and high frequencies. This does not appear, however, to be a consequence of beta-amyloid deposition in the brain. The present review provides a critical evaluation of changes of spontaneous ongoing EEG rhythms due to the experimental manipulations described above, in order to stimulate the promote more adherent models fitting dynamics in humans.

Does pilocarpine-induced epilepsy in adult rats require status epilepticus?

Pilocarpine-induced seizures in rats provide a widely animal model of temporal lobe epilepsy. Some evidences reported in the literature suggest that at least 1 h of status epilepticus (SE) is required to produce subsequent chronic phase, due to the SE-related acute neuronal damage. However, recent data seems to indicate that neuro-inflammation plays a crucial role in epileptogenesis, modulating secondarily a neuronal insult. For this reason, we decided to test the following hypotheses: a) whether pilocarpine-injected rats that did not develop SE can exhibit long-term chronic spontaneous recurrent seizures (SRS) and b) whether acute neurodegeneration is mandatory to obtain chronic epilepsy. Therefore, we compared animals injected with the same dose of pilocarpine that developed or did not SE, and saline treated rats. We used telemetric acquisition of EEG as long-term monitoring system to evaluate the occurrence of seizures in non-SE pilocarpineinjected animals. Furthermore, histology and MRI analysis were applied in order to detect neuronal injury and neuropathological signs. Our observations indicate that non-SE rats exhibit SRS almost 8 (+/22) months after pilocarpine-injection, independently to the absence of initial acute neuronal injury. This is the first time reported that pilocarpine injected rats without developing SE, can experience SRS after a long latency period resembling human pathology. Thus, we strongly emphasize the important meaning of including these animals to model human epileptogenesis in pilocarpine induced epilepsy.