Carotid Body: The Primary Peripheral Arterial Chemoreceptor.

The carotid body (CB) is a polymodal chemosensory organ that plays an essential role in initiating respiratory and cardiovascular adjustments to maintain blood gas homeostasis. Much of the available evidence suggests that chronic hypoxia induces marked morphological and neurochemical changes within the CB, but the detailed molecular mechanisms by which these affect the hypoxic chemosensitivity still remain to be elucidated. Dysregulation of the CB function and altered oxygen saturation are implicated in various physiological and pathophysiological conditions. Knowledge of the morphological and functional aspects of the CB would improve our current understanding of respiratory and cardiovascular homeostasis in health and disease.

History and Recent Progress in Carotid Body Studies.

This chapter describes the history of the carotid body (CB) and the subsequent research on its structure and function. The chronological development of ideas about its anatomical structure as a ganglion, the first descriptions of its glandular nature as a ball of highly vascular tissue (glomus), the discovery of its neural crest origin and relevant embryological views as a true paraganglion toward a more conclusive understanding of its sensory nature as a chemoreceptor for chemical changes in blood have been consistently demonstrated. The knowledge of the CB neurochemistry, physiology and pathophysiology has progressed immensely in the past century and a large and compelling body of evidence for the presence of a neurogenic niche in the CB has accumulated over the last two decades, thus underlying its function and possibility for the development of cell replacement therapies.

General Morphology of the Mammalian Carotid Body.

The carotid body (CB) is the main peripheral arterial chemoreceptor that registers the levels of pO2, pCO2 and pH in the blood and responds to their changes by regulating breathing. It is strategically located in the bifurcation of each common carotid artery. The organ consists of "glomera" composed of two cell types, glomus and sustentacular cells, interspersed by blood vessels and nerve bundles and separated by connective tissue. The neuron-like glomus or type I cells are considered as the chemosensory cells of the CB. They contain numerous cytoplasmic organelles and dense-cored vesicles that store and release neurotransmitters. They also form both conventional chemical and electrical synapses between each other and are contacted by peripheral nerve endings of petrosal ganglion neurons. The glomus cells are dually innervated by both sensory nerve fibers through the carotid sinus nerve and autonomic fibers of sympathetic origin via the ganglioglomerular nerve. The parasympathetic efferent innervation is relayed by vasomotor fibers of ganglion cells located around or inside the CB. The glial-like sustentacular or type II cells are regarded to be supporting cells although they sustain physiologic neurogenesis in the adult CB and are thus supposed to be progenitor cells as well. The CB is a highly vascularized organ and its intraorgan hemodynamics possibly plays a role in the process of chemoreception.

Structural Plasticity of the Carotid Body.

The mammalian carotid body (CB) exhibits considerable plasticity of its structure during development and aging and as a consequence of environmental, metabolic and inflammatory stimuli. The structural changes during maturation include an enlargement of the total and vascular volume of the CB. Conversely, aging results in a reduction in the number and volume of glomus cells with progressive cellular degeneration and an apparent increase in the surrounding connective tissue. Age-related structural alterations are similar to those during chronic hypoxia. Long-term hypoxic exposure and sodium nitrate treatment enlarge several-fold the size of the rat CB causing glomus cell hypertrophy and hyperplasia, and evoke changes in its vascular structure, inducing marked vasodilation and neovascularization. In humans, such structural CB adaptation responses to prolonged hypoxia occur during acclimatization to high altitudes. On the other hand, the hyperoxic CB is significantly smaller than those of age-matched normoxic controls. Morphological alterations in the CB in both hypertensive animals and humans are characterized by a slightly enlarged parenchyma without apparent vascular expansion and/or dilation. The CB structural plasticity depends on the existence of a population of multipotent neural crest-derived stem cells, which are activated during hypoxia to proliferate and differentiate into new both neuronal (glomus) and vascular cell types.

Mechanisms of Chemosensory Transduction in the Carotid Body.

The mammalian carotid body (CB) is a polymodal chemoreceptor, which is activated by blood-borne stimuli, most notably hypoxia, hypercapnia and acidosis, thus ensuring an appropriate cellular response to changes in physical and chemical parameters of the blood. The glomus cells are considered the CB chemosensory cells and the initial site of chemoreceptor transduction. However, the molecular mechanisms by which they detect changes in blood chemical levels and how these changes lead to transmitter release are not yet well understood. Chemotransduction mechanisms are by far best described for oxygen and acid/carbon dioxide sensing. A few testable hypotheses have been postulated including a direct interaction of oxygen with ion channels in the glomus cells (membrane hypothesis), an indirect interface by a reversible ligand like a heme (metabolic hypothesis), or even a functional interaction between putative oxygen sensors (chemosome hypothesis) or the interaction of lactate with a highly expressed in the CB atypical olfactory receptor, Olfr78, (endocrine model). It is also suggested that sensory transduction in the CB is uniquely dependent on the actions and interactions of gaseous transmitters. Apparently, oxygen sensing does not utilize a single mechanism, and later observations have given strong support to a unified membrane model of chemotransduction.

Neurochemical Plasticity of the Carotid Body.

A striking feature of the carotid body (CB) is its remarkable degree of plasticity in a variety of neurotransmitter/modulator systems in response to environmental stimuli, particularly following hypoxic exposure of animals and during ascent to high altitude. Current evidence suggests that acetylcholine and adenosine triphosphate are two major excitatory neurotransmitter candidates in the hypoxic CB, and they may also be involved as co-transmitters in hypoxic signaling. Conversely, dopamine, histamine and nitric oxide have recently been considered inhibitory transmitters/modulators of hypoxic chemosensitivity. It has also been revealed that interactions between excitatory and inhibitory messenger molecules occur during hypoxia. On the other hand, alterations in purinergic neurotransmitter mechanisms have been implicated in ventilatory acclimatization to hypoxia. Chronic hypoxia also induces profound changes in other neurochemical systems within the CB such as the catecholaminergic, peptidergic and nitrergic, which in turn may contribute to increased ventilatory and chemoreceptor responsiveness to hypoxia at high altitude. Taken together, current data suggest that complex interactions among transmitters markedly influence hypoxia-induced transmitter release from the CB. In addition, the expression of a wide variety of growth factors, proinflammatory cytokines and their receptors have been identified in CB parenchymal cells in response to hypoxia and their upregulated expression could mediate the local inflammation and functional alteration of the CB under hypoxic conditions.

Carotid Body Dysfunction and Mechanisms of Disease.

Emerging evidence shows that the carotid body (CB) dysfunction is implicated in various physiological and pathophysiological conditions. It has been revealed that the CB structure and neurochemical profile alter in certain human sympathetic-related and cardiometabolic diseases. Specifically, a tiny CB with a decrease of glomus cells and their dense-cored vesicles has been seen in subjects with sleep disordered breathing such as sudden infant death syndrome and obstructive sleep apnea patients and people with congenital central hypoventilation syndrome. Moreover, the CB degranulation is accompanied by significantly elevated levels of catecholamines and proinflammatory cytokines in such patients. The intermittent hypoxia stimulates the CB, eliciting augmented chemoreflex drive and enhanced cardiorespiratory and sympathetic responses. High CB excitability due to blood flow restrictions, oxidative stress, alterations in neurotransmitter gases and disruptions of local mediators is also observed in congestive heart failure conditions. On the other hand, the morpho-chemical changes in hypertension include an increase in the CB volume due to vasodilation, altered transmitter phenotype of chemoreceptor cells and elevated production of neurotrophic factors. Accordingly, in both humans and animal models CB denervation prevents the breathing instability and lowers blood pressure. Knowledge of the morphofunctional aspects of the CB, a better understanding of its role in disease and recent advances in human CB translational research would contribute to the development of new therapeutic strategies.

Stem Cell Niche in the Mammalian Carotid Body.

Accumulating evidence suggests that the mammalian carotid body (CB) constitutes a neurogenic center that contains a functionally active germinal niche. A variety of transcription factors is required for the generation of a precursor cell pool in the developing CB. Most of them are later silenced in their progeny, thus allowing for the maturation of the differentiated neurons. In the adult CB, neurotransmitters and vascular cytokines released by glomus cells upon exposure to chronic hypoxia act as paracrine signals that induce proliferation and differentiation of pluripotent stem cells, neuronal and vascular progenitors. Key proliferation markers such as Ki-67 and BrdU are widely used to evaluate the proliferative status of the CB parenchymal cells in the initial phase of this neurogenesis. During hypoxia sustentacular cells which are dormant cells in normoxic conditions can proliferate and differentiate into new glomus cells. However, more recent data have revealed that the majority of the newly formed glomus cells is derived from the glomus cell lineage itself. The mature glomus cells express numerous trophic and growth factors, and their corresponding receptors, which act on CB cell populations in autocrine or paracrine ways. Some of them initially serve as target-derived survival factors and then as signaling molecules in developing vascular targets. Morphofunctional insights into the cellular interactions in the CB stem cell microenvironment can be helpful in further understanding the therapeutic potential of the CB cell niche.

Neurochemical Anatomy of the Mammalian Carotid Body.

Carotid body (CB) glomus cells in most mammals, including humans, contain a broad diversity of classical neurotransmitters, neuropeptides and gaseous signaling molecules as well as their cognate receptors. Among them, acetylcholine, adenosine triphosphate and dopamine have been proposed to be the main excitatory transmitters in the mammalian CB, although subsequently dopamine has been considered an inhibitory neuromodulator in almost all mammalian species except the rabbit. In addition, co-existence of biogenic amines and neuropeptides has been reported in the glomus cells, thus suggesting that they store and release more than one transmitter in response to natural stimuli. Furthermore, certain metabolic and transmitter-degrading enzymes are involved in the chemotransduction and chemotransmission in various mammals. However, the presence of the corresponding biosynthetic enzyme for some transmitter candidates has not been confirmed, and neuroactive substances like serotonin, gamma-aminobutyric acid and adenosine, neuropeptides including opioids, substance P and endothelin, and gaseous molecules such as nitric oxide have been shown to modulate the chemosensory process through direct actions on glomus cells and/or by producing tonic effects on CB blood vessels. It is likely that the fine balance between excitatory and inhibitory transmitters and their complex interactions might play a more important than suggested role in CB plasticity.

Carotid Body and Cell Therapy.

During the past decade, the carotid body (CB) has been considered an innovative therapeutic target for the treatment of certain cardiorespiratory and metabolic diseases most of which are sympathetically mediated. It has recently been revealed that CB stem cells provide new target sites for the development of promising cell-based therapies. Specifically, generation of CB progenitors in vitro which can differentiate into functionally active glomus cells may be a useful procedure to produce the cell mass required for replacement cell therapy. Due to their dopaminergic nature, adult glomus cells can be used for an intrastriatal grafting in neurodegenerative brain disorders including Parkinson's disease. The beneficial effect of throphic factors such as glial cell-derived neurotrophic factor synergistically released by the transplanted cells then enables the transplant to survive. Likewise, intracerebral administration of CB cell aggregates or dispersed cells has been tested for the treatment of an experimental model of stroke. The systematic clinical applicability of CB autotransplants following glomectomy in humans is under investigation. In such autotransplantation studies, cell aggregates from unilaterally resected CB might be used as autografts. In addition, stem cells could offer an opportunity for tissue expansion and might settle the issue of small number of glomus cells available for transplantation.

The Carotid Body: A Tiny Structure with Many Roles.

Over the last century, the structure of the mammalian carotid body (CB) has repeatedly been studied, and our present understanding of its normal morphology is comprehensive. It has been demonstrated that the CB has an intricate internal structure and a remarkable ability to release a wide variety of neurotransmitters and neuromodulators in response to different chemical stimuli. The advances in modern cellular/molecular biological methods and newly developed single-cell electrophysiological techniques have provided an additional insight into the precise working mechanisms and roles of the CB in health and disease. Emerging experimental evidence has also shown that the CB exhibits an extraordinary structural and functional plasticity as a consequence of various environmental stimuli. Lately, the CB has attracted much clinical interest because its dysfunction relates to a number of cardiovascular and respiratory disorders. Expanding knowledge about the pathophysiological mechanisms that alter the CB cell function would certainly help to facilitate the translational research. Recent progress in cell fate experiments has further revealed that the CB is a neurogenic center with a functionally active germinal niche. This may lead to the development of promising new candidate therapies to combat these diseases and improve the quality of human life. Thus, the CB has entered the twenty-first century with its actual designation.

Neurochemical plasticity of the carotid body in hypertension.

The carotid body (CB), a main peripheral arterial chemoreceptor, has lately been implicated in the pathophysiology of various cardiovascular disorders. Emerging experimental evidence supports a causal relationship between CB dysfunction and augmented sympathetic outflow which is the common hallmark of human sympathetic-related diseases, including essential hypertension. To gain insight into the neurotransmitter profile of chemosensory cells in the hypertensive CB, we examined the expression and cellular localization of some classical neurotransmitters, neuropeptides, and gaseous signaling molecules as well as neurotrophic factors and their receptors in the CB of spontaneously hypertensive rats, a common animal model of hypertension. Our immunohistochemical experiments revealed an elevated catecholamine and serotonin content in the hypertensive CB compared to normotensive controls. GABA immunostaining was seen in some peripherally located glomus cells in the CB of SHR and it was significantly lower than in control animals. The density of substance P and vasoactive intestinal peptide-immunoreactive fibers was diminished whereas that of neuropeptide Y-immunostained nerve fibers was increased and that of calcitonin gene-related peptide-containing fibers remained almost unchanged in the hypertensive CB. We have further demonstrated that in the hypertensive state the production of nitric oxide is impaired and that the components of the neurotrophin signaling system display an abnormal enhanced expression. Our results provide immunohistochemical evidence that the altered transmitter phenotype of CB chemoreceptor cells and the elevated production of neurotrophic factors modulate the chemosensory processing in hypertensive animals which contributes to autonomic dysfunction and elicits sympathetic hyperactivity, consequently leading to elevated blood pressure.

Effect of Chitosan-Diosgenin Combination on Wound Healing.

The difficult-to-heal wounds continue to be a problem for modern medicine. Chitosan and diosgenin possess anti-inflammatory and antioxidant effects making them relevant substances for wound treatment. That is why this work aimed to study the effect of the combined application of chitosan and diosgenin on a mouse skin wound model. For the purpose, wounds (6 mm diameter) were made on mice's backs and were treated for 9 days with one of the following: 50% ethanol (control), polyethylene glycol (PEG) in 50% ethanol, chitosan and PEG in 50% ethanol (Chs), diosgenin and PEG in 50% ethanol (Dg) and chitosan, diosgenin and PEG in 50% ethanol (ChsDg). Before the first treatment and on the 3rd, 6th and 9th days, the wounds were photographed and their area was determined. On the 9th day, animals were euthanized and wounds' tissues were excised for histological analysis. In addition, the lipid peroxidation (LPO), protein oxidation (POx) and total glutathione (tGSH) levels were measured. The results showed that ChsDg had the most pronounced overall effect on wound area reduction, followed by Chs and PEG. Moreover, the application of ChsDg maintained high levels of tGSH in wound tissues, compared to other substances. It was shown that all tested substances, except ethanol, reduced POx comparable to intact skin levels. Therefore, the combined application of chitosan and diosgenin is a very promising and effective medication for wound healing.

Neurochemical profile of the myenteric plexus in the rat colorectal region.

The enteric nervous system, a major subdivision of the autonomic nervous system, is known for its neurochemical heterogeneity and complexity. The myenteric plexus, one of its two principal components, primarily controls peristalsis and its dysfunction may lead to a number of gastrointestinal motility disorders. The myenteric neurons have been described to use a wide variety of neurotransmitters although no evidence has been reported for the existence of adrenergic neurons in the hindgut. This study aims at elucidating the chemical coding of neurons in the myenteric plexus of the rat colon and anorectal region with particular emphasis on cholinergic and the so-called nonadrenergic, noncholinergic (NANC) transmitter systems. The immunostaining for choline acetyltransferase revealed an intense staining of the myenteric ganglia with clear delineation of their neuronal cell bodies and without local distributional differences in the colonic region. The myenteric ATPergic structures were mostly limited to fiber bundles surrounding unstained myenteric neurons and penetrating the two muscle layers. We also observed an abundance of intensely stained varicose substance P-immunopositive fibers, ensheathing the immunonegative myenteric neuronal cell bodies in a basket-like manner. Applying NADPH-diaphorase histochemistry and nitric oxide synthase immunohistochemistry, we were able to demonstrate numerous nitrergic somata of myenteric neurons with Dogiel Type I morphology. Apart from the observed nitrergic distributional patterns, no distinct variations were found in the staining intensity or distribution of myenteric structures in the colon and anorectal area. Our results suggest that myenteric neurons in the distal intestinal portion utilize a broad spectrum of enteric transmitters, including classical and NANC transmitters.

Use of an Online Forum for Relatives of People With Psychosis and Bipolar Disorder: Mixed Methods Study.

BACKGROUND: Relatives of people with psychosis or bipolar disorder experience high levels of distress but are typically not offered the support they need. Online peer forums may offer a solution, but knowledge about who uses them, how, and why is limited. This study reported on online forum use during the Relatives Education and Coping Toolkit (REACT) trial. OBJECTIVE: We aimed to report who used the forum and why; how sociodemographic factors are associated with participation; the relationship among frequency, type of use, and outcomes; and how the forum was used. METHODS: The relationships between key sociodemographic characteristics, levels of forum use, and distress were statistically analyzed. We used thematic and semantic analyses to understand the reasons for relatives joining the forum and the key topics initiated by them. We also used the University Centre for Computer Corpus Research on Language Semantic Analysis System to compare how relatives and REACT supporters (moderators) used the forum. RESULTS: A total of 348 participants with full forum use data from REACT were included in this study. The forum was accessed by 59.4% (207/348) of the relatives across the entire age range, with no significant associations between sociodemographic factors and forum participation, or between level or type of use and relatives' distress levels. Relatives joined the forum primarily to find people in similar circumstances, express concerns, and talk about stressful events. Relatives were most concerned about recent events, negative emotions linked to caring, experiences of conflict or threat, and concerns about suicide. These posts underscored both the challenges the relatives were facing and the fact that they felt safe sharing them in this context. CONCLUSIONS: Although only a proportion of REACT participants engaged actively with its forum, they were widely distributed across age and other sociodemographic groupings. Relatives used the forum for information, support, and guidance and to offer detailed information about their experiences. The topics raised highlighted the burden carried by relatives and the potential value of easy-access, moderated, peer-supported forums in helping relatives to manage the challenges they faced.

Siponimod ameliorates metabolic oligodendrocyte injury via the sphingosine-1 phosphate receptor 5.

Multiple sclerosis (MS), an autoimmune-driven, inflammatory demyelinating disease of the central nervous system (CNS), causes irreversible accumulation of neurological deficits to a variable extent. Although there are potent disease-modifying agents for its initial relapsing-remitting phase, immunosuppressive therapies show limited efficacy in secondary progressive MS (SPMS). Although modulation of sphingosine-1 phosphate receptors has proven beneficial during SPMS, the underlying mechanisms are poorly understood. In this project, we followed the hypothesis that siponimod, a sphingosine-1 phosphate receptor modulator, exerts protective effects by direct modulation of glia cell function (i.e., either astrocytes, microglia, or oligodendrocytes). To this end, we used the toxin-mediated, nonautoimmune MS animal model of cuprizone (Cup) intoxication. On the histological level, siponimod ameliorated cuprizone-induced oligodendrocyte degeneration, demyelination, and axonal injury. Protective effects were evident as well using GE180 translocator protein 18-kDa (TSPO) imaging with positron emission tomography (PET)/computed tomography (CT) imaging or next generation sequencing (NGS). Siponimod also ameliorated the cuprizone-induced pathologies in Rag1-deficient mice, demonstrating that the protection is independent of T and B cell modulation. Proinflammatory responses in primary mixed astrocytes/microglia cell cultures were not modulated by siponimod, suggesting that other cell types than microglia and astrocytes are targeted. Of note, siponimod completely lost its protective effects in S1pr5-deficient mice, suggesting direct protection of degenerating oligodendrocytes. Our study demonstrates that siponimod exerts protective effects in the brain in a S1PR5-dependent manner. This finding is not just relevant in the context of MS but in other neuropathologies as well, characterized by a degeneration of the axon-myelin unit.

The anticonvulsant effect of chronic treatment with topiramate after pilocarpine-induced status epilepticus is accompanied by a suppression of comorbid behavioral impairments and robust neuroprotection in limbic regions in rats.

Epilepsy is a widespread neurological disorder frequently associated with a lot of comorbidities. The present study aimed to evaluate the effects of the antiseizure medication topiramate (TPM) on spontaneous motor seizures, the pathogenesis of comorbid mood and cognitive impairments, hippocampal neuronal loss, and oxidative stress and inflammation in a rat model of temporal lobe epilepsy (TLE). Vehicle/TPM treatment (80 mg/kg, p.o.) was administered 3 h after the pilocarpine (pilo)-induced status epilepticus (SE) and continued for up to 12 weeks in Wistar rats. The chronic TPM treatment caused side effects in naïve rats, including memory disturbance, anxiety, and depressive-like responses. However, the anticonvulsant effect of this drug, administered during epileptogenesis, was accompanied by beneficial activity against comorbid behavioral impairments. The drug treatment suppressed the SE-induced neuronal damage in limbic structures, including the dorsal (CA1 and CA2 subfield), the ventral (CA1, CA2 and CA3) hippocampus, the basolateral amygdala, and the piriform cortex, while was ineffective against the surge in the oxidative stress and inflammation. Our results suggest that neuroprotection is an essential mechanism of TPM against spontaneous generalized seizures and concomitant emotional and cognitive impairments.

Chronic agomelatine treatment alleviates icvAß-induced anxiety and depressive-like behavior through affecting Aß metabolism in the hippocampus in a rat model of Alzheimer's disease.

Recently, we reported that the atypical antidepressant agomelatine (Ago) exerted a beneficial impact on behavioral changes and concomitant neuropathological events in icvSTZ rat model of sporadic Alzheimer diseases (AD). In the present study, we aimed to explore the effect of Ago (40 mg/kg, i.p. for 30 days) on beta-amyloid (Aß) metabolism in icvAß1-42 rat model of AD. The melatonin analogue was administered either simultaneously with Aß1-42 (AßAgo1) or 30 days later during the late stage of the progression of AD (AßAgo2). Treatment with Ago in the early stage of AD attenuated anxiety and depressive-like responses but was inefficient against Aß-induced impairment of hippocampus-dependent spatial memory. The melatonin analogue, administered both during the early and the late stage of AD, corrected to control level the elevated Aß1-42 in the frontal cortex (FC) and the hippocampus. The concentration of α-secretase was enhanced by AßAgo1 compared to the sham- and Aß-veh groups in the hippocampus. No changes in the concentration of ß-secretase in the FC and the hippocampus as well as of γ-secretase in the FC were observed among groups. Both the AßAgo1 and AßAgo2 attenuated to control level the Aß-induced increased concentration of γ-secretase in the hippocampus. AßAgo1 exerted also structure-specific neuroprotection observed mainly in the CA1, septal CA3b subfield of the dorsal hippocampus and septo-temporal piriform cortex (Pir) and partially in the temporal CA3c, septal and temporal Pir. These findings suggest that Ago treatment in the early stage of AD can exert beneficial effects on concomitant behavioral impairments and neuroprotection in associated brain structures. The antidepressant administration both in the early stage and after the progression of AD affected Aß metabolism via decreasing of γ-secretase concentration in the hippocampus.

Reduced neuroinflammation and enhanced neurogenesis following chronic agomelatine treatment in rats undergoing chronic constant light.

Experimental studies have revealed the involvement of neuroinflammation mediated by activated microglia in the pathophysiology of depression, suggesting a novel target for treatment. The atypical antidepressant Agomelatine (Ago) has an advantage compared to the classical antidepressants due to its chronobiotic activity and unique pharmacological profile as a selective agonist at the melatonin receptors and an antagonist at the 5HT2C receptors. We have recently revealed that Ago can exert a potent antidepressant effect in rats exposed to a chronic constant light (CCL). In the present study, we hypothesized that the anti-inflammatory activity of this melatonin analog on activated neuroglia in specific brain structures might contribute to its antidepressant effect in this model. Chronic Ago treatment (40 mg/kg, i.p. for 21 days) was executed during the last 3 weeks of a 6-week period of CCL exposure in rats. The CCL-vehicle-treated rats showed a profound neuroinflammation characterized by microgliosis and astrogliosis in the hippocampus, basolateral amygdala (BL) and partly in the piriform cortex (Pir) confirmed by immunohistochemistry. With the exception of the Pir, the CCL regime was accompanied by neuronal damage, identified by Nissl staining, in the hippocampus and basolateral amygdala and impaired neurogenesis with reduced dendritic complexity of hippocampal neuroprogenitor cells detected by doublecortin-positive cells in the dentate gyrus (DG) subgranular zone compared to the control group. Ago reversed the gliosis in a region-specific manner and partially restored the suppressed DG neurogenesis. Ago failed to produce neuroprotection in CCL exposed rats. The present results suggest that the beneficial effects of Ago represent an important mechanism underlying its antidepressant effect in models characterized by impaired circadian rhythms.

Effects of Lacosamide Treatment on Epileptogenesis, Neuronal Damage and Behavioral Comorbidities in a Rat Model of Temporal Lobe Epilepsy.

Clinically, temporal lobe epilepsy (TLE) is the most prevalent type of partial epilepsy and often accompanied by various comorbidities. The present study aimed to evaluate the effects of chronic treatment with the antiepileptic drug (AED) lacosamide (LCM) on spontaneous motor seizures (SMS), behavioral comorbidities, oxidative stress, neuroinflammation, and neuronal damage in a model of TLE. Vehicle/LCM treatment (30 mg/kg, p.o.) was administered 3 h after the pilocarpine-induced status epilepticus (SE) and continued for up to 12 weeks in Wistar rats. Our study showed that LCM attenuated the number of SMS and corrected comorbid to epilepsy impaired motor activity, anxiety, memory, and alleviated depressive-like responses measured in the elevated plus maze, object recognition test, radial arm maze test, and sucrose preference test, respectively. This AED suppressed oxidative stress through increased superoxide dismutase activity and glutathione levels, and alleviated catalase activity and lipid peroxidation in the hippocampus. Lacosamide treatment after SE mitigated the increased levels of IL-1ß and TNF-α in the hippocampus and exerted strong neuroprotection both in the dorsal and ventral hippocampus, basolateral amygdala, and partially in the piriform cortex. Our results suggest that the antioxidant, anti-inflammatory, and neuroprotective activity of LCM is an important prerequisite for its anticonvulsant and beneficial effects on SE-induced behavioral comorbidities.