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The prevalence of depression has dramatically increased, and it has been estimated that over 300 million people suffer from depression all over the world. Depression is highly comorbid with many central and peripheral disorders. In this regard, depressive states have been associated with the development of neurological disorders such as Alzheimer's disease (AD). Accordingly, depression is a risk factor for AD and depressive symptomatology is common in pre-clinical AD, representing an early manifestation of this disease. Neuropsychiatric symptoms may represent prodromal symptoms of dementia deriving from neurobiological changes in specific cerebral regions; thus, the search for common biological substrates is becoming an imperative and intriguing field of research. Soluble forms of beta amyloid peptide (Aβ) have been implicated both in the development of early memory deficits and neuropsychiatric symptoms. Indeed, soluble Aβ species have been shown to induce a depressive-like phenotype in AD animal models. Alterations in monoamine content are a common feature of these neuropathologies. Interestingly, serotonergic system modulation has been implicated in alteration of Aβ production. In addition, noradrenaline is considered crucially involved in compensatory mechanisms, leading to increased Aβ degradation several mechanisms, including microglia modulation. In further agreement, antidepressant drugs have also been shown to potentially modulate cognitive symptoms in AD and depression. Thus, the present review summarizes the main knowledge about biological and pathological substrates, such as monoamine and related molecules, commonly involved in AD and depression pathology, thus shading light on new therapeutic approaches.

Pharmacological interventions for traumatic brain injury (TBI) are limited. Together with parvalbumin (PV) loss, increased production of reactive oxygen species (ROS) by the NADPH oxidase NOX enzymes represents a key step in TBI. Here, we investigated the contribution of NOX2-derived oxidative stress to the loss of PV immunoreactivity associated to TBI, performing immunohistochemistry for NOX2, 8-hydroxy-2′-deoxyguanosine (8OHdG) and PV on post mortem brain samples of subjects died following TBI, subjects died from spontaneous intracerebral hemorrhage (SICH) and controls (CTRL). We detected an increased NOX2 expression and 8OHdG immunoreactivity in subjects died from TBI with respect to CTRL and SICH. NOX2 increase was mainly observed in GABAergic PV-positive interneurons, with a minor presence in microglia. No significant differences in other NADPH oxidase isoforms (NOX1 and NOX4) were detected among experimental groups. NOX2-derived oxidative stress elevation appeared a specific TBI-induced phenomenon, as no alterations in the nitrosative pathway were detected. Our results suggest that NOX2-derived oxidative stress might play a crucial role in the TBI-induced loss of PV-positive interneurons.

Celastrol, the most abundant compound derived from the root of Tripterygium wilfordii, largely used in traditional Chinese medicine, has shown preclinical and clinical efficacy for a broad range of disorders, acting via numerous mechanisms, including the induction of the expression of several neuroprotective factors, the inhibition of cellular apoptosis, and the decrease of reactive oxygen species (ROS). Given the crucial implication of these pathways in the pathogenesis of Central Nervous System disorders, both in vitro and in vivo studies have focused their attention on the possible use of this compound in these diseases. However, although most of the available studies have reported significant neuroprotective effects of celastrol in cellular and animal models of these pathological conditions, some of these data could not be replicated. This review aims to discuss current in vitro and in vivo lines of evidence on the therapeutic potential of celastrol in neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases, amyotrophic lateral sclerosis, Huntington’s disease, multiple sclerosis, and cadmium-induced neurodegeneration, as well as in psychiatric disorders, such as psychosis and depression. In vitro and in vivo studies focused on celastrol effects in cerebral ischemia, ischemic stroke, traumatic brain injury, and epilepsy are also described.

In recent years, an increasing number of studies have been published, focusing on the potential therapeutic use of small catalytic agents with strong biological properties. So far, most of these works have only regarded specific clinical fields, such as oncology, infectivology and general pathology, in particular with respect to the treatment of significant inflammatory processes. However, interesting data on possible therapeutic applications of small molecules for the treatment of neuropsychiatric and neurodegenerative illnesses are emerging, especially with respect to the possibility to modulate the cellular redox state. Indeed, a crucial role of redox dysregulation in the pathogenesis of these disorders has been widely demonstrated by both pre-clinical and clinical studies, being the reduction of the total amount of free radicals a promising novel therapeutic approach for these diseases. In this review, we focused our interest on studies published during the last ten years reporting therapeutic potential of small molecules for the treatment of neuropsychiatric and neurodegenerative disorders, also based on the biological efficiency of these compounds in detecting intracellular disturbances induced by increased production of reactive oxygen species.

Previous studies have provided extensive evidence that administration of cannabinoid drugs after training modulates the consolidation of memory for an aversive experience. The present experiments investigated whether the memory consolidation is regulated by endogenously released cannabinoids. The experiments first examined whether the endocannabinoids anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) are released by aversive training. Inhibitory avoidance training with higher footshock intensity produced increased levels of AEA in the amygdala, hippocampus, and medial prefrontal cortex (mPFC) shortly after training in comparison with levels assessed in rats trained with lower footshock intensity or unshocked controls exposed only to the training apparatus. In contrast, 2-AG levels were not significantly elevated. The additional finding that posttraining infusions of the fatty acid amide hydrolase (FAAH) inhibitor URB597, which selectively increases AEA levels at active synapses, administered into the basolateral complex of the amygdala (BLA), hippocampus, or mPFC enhanced memory strongly suggests that the endogenously released AEA modulates memory consolidation. Moreover, in support of the view that this emotional training-associated increase in endocannabinoid neurotransmission, and its effects on memory enhancement, depends on the integrity of functional interactions between these different brain regions, we found that disruption of BLA activity blocked the training-induced increases in AEA levels as well as the memory enhancement produced by URB597 administered into the hippocampus or mPFC. Thus, the findings provide evidence that emotionally arousing training increases AEA levels within prefrontal-limbic circuits and strongly suggest that this cannabinoid activation regulates emotional arousal effects on memory consolidation. Significance An involvement of exogenous cannabinoids in the regulation of memory for emotional events has emerged over the past decade. The present findings demonstrate that after an aversive training experience the endogenous cannabinoid anandamide is released into the amygdala, hippocampus, and medial prefrontal cortex (mPFC) and normally plays a role in the formation of a strong memory trace. Furthermore, an intact basolateral amygdala is required to coordinate both hippocampal and mPFC endocannabinoid activity during aversive memory consolidation. Thus, our findings provide the first evidence, to our knowledge, that a dynamic network involving anandamide signaling within this prefrontal-limbic circuit modulates the consolidation of memory for emotionally arousing training.

Administration of subanesthetic doses of ketamine during brain maturation represents a tool to mimic an early insult to the central nervous system (CNS). The cerebellum is a key player in psychosis pathogenesis, to which oxidative stress also contributes. Here, we investigated the impact of early celastrol administration on behavioral dysfunctions in adult mice that had received ketamine (30 mg/kg i.p.) at postnatal days (PNDs) 7, 9, and 11. Cerebellar levels of 8-hydroxydeoxyguanosine (8-OHdG), NADPH oxidase (NOX) 1 and NOX2, as well as of the calcium-binding protein parvalbumin (PV), were also assessed. Furthermore, celastrol effects on ketamine-induced alterations of proinflammatory (TNF-α, IL-6 and IL-1β) and anti-inflammatory (IL-10) cytokines in this brain region were evaluated. Early celastrol administration prevented ketamine-induced discrimination index decrease at adulthood. The same was found for locomotor activity elevations and increased close following and allogrooming, whereas no beneficial effects on sniffing impairment were detected. Ketamine increased 8-OHdG in the cerebellum of adult mice, which was also prevented by early celastrol injection. Cerebellar NOX1 levels were enhanced at adulthood following postnatal ketamine exposure. Celastrol per se induced NOX1 decrease in the cerebellum. This effect was more significant in animals that were early administered with ketamine. NOX2 levels did not change. Ketamine administration did not affect PV amount in the cerebellum. TNF-α levels were enhanced in ketamine-treated animals; however, this was not prevented by early celastrol administration. While no changes were observed for IL-6 and IL-1β levels, ketamine determined a reduction of cerebellar IL-10 expression, which was prevented by early celastrol treatment. Our results suggest that NOX inhibition during brain maturation prevents the development of psychotic-like behavioral dysfunctions, as well as the increased cerebellar oxidative stress and the reduction of IL-10 in the same brain region following ketamine exposure in postnatal life. This opens novel neuroprotective opportunities against early detrimental insults occurring during brain development.

Oregano and thyme essential oils are used for therapeutic, aromatic and gastronomic purposes due to their richness in active substances, like carvacrol; however, the effects of the latter on the central nervous system have been poorly investigated. The aim of our study was to define the effects of carvacrol on brain neurochemistry and behavioural outcome in rats. Biogenic amine content in the prefrontal cortex and hippocampus after chronic or acute oral carvacrol administration was measured. Animals were assessed by a forced swimming test. Carvacrol, administered for seven consecutive days (12.5 mg/kg p.o.), was able to increase dopamine and serotonin levels in the prefrontal cortex and hippocampus. When single doses were used (150 and 450 mg/kg p.o.), dopamine content was increased in the prefrontal cortex at both dose levels. On the contrary, a significant dopamine reduction in hippocampus of animals treated with 450 mg/kg of carvacrol was found. Acute carvacrol administration only significantly reduced serotonin content in either the prefrontal cortex or in the hippocampus at the highest dose. Moreover, acute carvacrol was ineffective in producing changes in the forced swimming test. Our data suggest that carvacrol is a brain-active molecule that clearly influences neuronal activity through modulation of neurotransmitters. If regularly ingested in low concentrations, it might determine feelings of well-being and could possibly have positive reinforcer effects.

Autism Spectrum Disorders (ASD) are principally diagnosed by three core behavioural symptoms, such as stereotyped repertoire, communication impairments and social dysfunctions. This complex pathology has been linked to abnormalities of corticostriatal and limbic circuits. Despite experimental efforts in elucidating the molecular mechanisms behind these abnormalities, a clear etiopathogenic hypothesis is still lacking. To this aim, preclinical studies can be really helpful to longitudinally study behavioural alterations resembling human symptoms and to investigate the underlying neurobiological correlates. In this regard, the BTBR T + Itpr3 tf /J (BTBR) mice are an inbred mouse strain that exhibits a pattern of behaviours well resembling human ASD-like behavioural features. In this study, the BTBR mice model was used to investigate neurochemical and biomolecular alterations, regarding Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF), together with GABAergic, glutamatergic, cholinergic, dopaminergic and noradrenergic neurotransmissions and their metabolites in four different brain areas, i.e. prefrontal cortex, hippocampus, amygdala and hypothalamus. In our results, BTBR strain reported decreased noradrenaline, acetylcholine and GABA levels in prefrontal cortex, while hippocampal measurements showed reduced NGF and BDNF expression levels, together with GABA levels. Concerning hypothalamus, no differences were retrieved. As regarding amygdala, we found reduced dopamine levels, accompanied by increased dopamine metabolites in BTBR mice, together with decreased acetylcholine, NGF and GABA levels and enhanced glutamate content. Taken together, our data showed that the BTBR ASD model, beyond its face validity, is a useful tool to untangle neurotransmission alterations that could be underpinned to the heterogeneous ASD-like behaviours, highlighting the crucial role played by amygdala.