The administration of Cerebrolysin elicits neuroprotective and neurorepair effects in an animal model of type 1 diabetes mellitus.

Diabetes mellitus (DM) is a metabolic disorder impacting cerebral function. The administration of Streptozotocin (STZ) is a well-known animal model of insulinopenic type 1 DM in rats. STZ-induced DM results in a myriad of alteration in the periphery and central nervous system (CNS). Cerebrolysin (CBL) is a neuropeptide preparation that promotes synaptic and neuronal plasticity in various animal models. In all cases, CBL was administered when the model was established. This research aims to investigate the neuroprotective and neurorepair effect of CBL on the cytoarchitecture of neurons and spine density in pyramidal neurons of the prefrontal (PFC) and the CA1 region of the dorsal hippocampus, as well as spheroidal neurons of the dentate gyrus (DG), in STZ-induced DM. In the first experimental condition, STZ and CBL are administered at the same time to evaluate the potential preventive effect of CBL. In the second experimental condition, CBL was administered two months after establishing the DM model to measure the potential neurorepair effect of CBL. STZ-induced hyperglycemia remained unaltered by the administration of CBL in both experimental conditions. In the first experimental condition, CBL treatment preserved the neuronal morphology in PFC layer 3, PFC layer 5 and the DG of the hippocampus, while also maintaining spine density in the PFC-3, DG and CA1 hippocampus. Furthermore, CBL induced neurorepair in neurons within the PFC-3, PFC-5 and CA1 regions of the hippocampus, along with an increase in spine density in the PFC-3, DG and CA1 hippocampus. These findings suggest that CBL´s effects on neuroplasticity could be observed before or after the damage was evident.

Structural and biochemical alterations in dendritic spines as key mechanisms for severe mental illnesses.

Severe mental illnesses (SMI) collectively affect approximately 20% of the global population, as estimated by the World Health Organization (WHO). Despite having diverse etiologies, clinical symptoms, and pharmacotherapies, these diseases share a common pathophysiological characteristic: the misconnection of brain areas involved in reality perception, executive control, and cognition, including the corticolimbic system. Dendritic spines play a crucial role in excitatory neurotransmission within the central nervous system. These small structures exhibit remarkable plasticity, regulated by factors such as neurotransmitter tone, neurotrophic factors, and innate immunity-related molecules, and other mechanisms - all of which are associated with the pathophysiology of SMI. However, studying dendritic spine mechanisms in both healthy and pathological conditions in patients is fraught with technical limitations. This is where animal models related to these diseases become indispensable. They have played a pivotal role in elucidating the significance of dendritic spines in SMI. In this review, the information regarding the potential role of dendritic spines in SMI was summarized, drawing from clinical and animal model reports. Also, the implications of targeting dendritic spine-related molecules for SMI treatment were explored. Specifically, our focus is on major depressive disorder and the neurodevelopmental disorders schizophrenia and autism spectrum disorder. Abundant clinical and basic research has studied the functional and structural plasticity of dendritic spines in these diseases, along with potential pharmacological targets that modulate the dynamics of these structures. These targets may be associated with the clinical efficacy of the pharmacotherapy.

The antipsychotic olanzapine reduces memory deficits and neuronal abnormalities in a male rat model of Autism.

The prevalence of autism spectrum disorder (ASD), a neurodevelopmental condition that impacts social interaction and sensory processing, is rising. Valproic acid (VPA) exposure during pregnancy causes autistic-like traits in offspring. Olanzapine (OLZ), an atypical antipsychotic, is used to treat ASD. We assessed the impact of OLZ on behavior, neuromorphology, and nitric oxide (NO) levels in the hippocampus using prenatal VPA treatment in rats. It is commonly known that ASD patients exhibit sensory abnormalities. As such, we utilized the tail flick test to validate the ASD model. In the novel object recognition test (NORT), VPA exposure reduces the discrimination index (DI) in the first introduction to the novel object. Moreover, OLZ and vehicle-treated rats perform differently in the second exposition to the DI of the novel object, suggesting that OLZ reverses VPA-induced deficits in recognition memory. The latency to find the hidden platform in the Morris water maze test of memory and learning improves in VPA-exposed rats after OLZ administration, indicating that OLZ improves spatial memory in these rats. Administration of prenatal VPA induces neuronal hypotrophy and reduces spine density in pyramidal neurons of the CA1 region of the hippocampus. Treatment with OLZ corrects the neuromorphological changes brought on by VPA. In the CA1 region of the hippocampus, VPA treatment increases the number of neurons, which normalizes with OLZ treatment. OLZ increases the NO levels in the dorsal hippocampus in control rats. In rats exposed to VPA, the second-generation antipsychotic OLZ reduces memory-related and neuroplastic alterations. The current findings support the use of OLZ in this illness and further validate the use of prenatal VPA as a model of ASD.

Olfactory bulbectomy induces nociceptive alterations associated with gliosis in male rats.

Major depressive disorder (MDD) is a major health concern worldwide with a wide array of symptoms. Emerging evidence suggests a high comorbidity between MDD and chronic pain, however, the relationship between these two diseases is not completely understood. Growing evidence suggests that glial cells play a key role in both disorders. Hence, we examined the effect of olfactory bulbectomy (OBX), a well-known model of depression-related behavior, on nociceptive behaviors and the number and morphology of astrocytes and glial cells in brain regions involved in the control of nociceptive processes in male rats. The brain regions analyzed included the basolateral amygdala (BLA), central amygdala (CeA), prefrontal cortex (PFC), and CA1 subregion of the hippocampus. A battery of behavioral tests, mechanical allodynia, thermal cold allodynia and mechanical hyperalgesia, was evaluated before and four weeks after OBX. Quantitative morphological analysis, as well as assessment of the number of glial fibrillary acidic protein (GFAP) and ionizing calcium-binding adaptor molecule 1 (Iba1) positive astrocytes and microglia were carried out to characterize glial remodeling and density, respectively. OBX caused mechanical and cold allodynia in an asynchronous pattern. The cold allodynia was noticeable one week following surgery, while mechanical allodynia became apparent two weeks after surgery. In the BLA, CeA and CA1, OBX caused significant changes in glial cells, such as hypertrophy and hypotrophy in GFAP-positive astrocytes and Iba1-positive microglia, respectively. Iba1-positive microglia in the PFC underwent selective hypotrophy due to OBX and OBX enhanced both GFAP-positive astrocytes and Iba1-positive microglia in the BLA. In addition, OBX increased the number of GFAP-positive astrocytes in the CeA and CA1. The amount of Iba1-positive microglia in the PFC also increased as a result of OBX. Furthermore, we found that there was a strong link between the observed behaviors and glial activation in OBX rats. Overall, our work supports the neuroinflammatory hypothesis of MDD and the comorbidity between pain and depression by demonstrating nociceptive impairment and significant microglial and astrocytic activation in the brain.

Neonatal olfactory bulbectomy induces anxiety-related behavior and modifies dopaminergic receptor expression in post-pubertal rats.

Olfaction is a complex physiological process producing effects in the central nervous system (CNS) and implicated in emotional processes. Indeed, the olfactory bulbs (OB) send projections to various CNS regions including the nucleus accumbens (NAcc) and caudate-putamen (CPu). Both the NAcc and CPu receive important dopaminergic input. Emerging evidence suggests that dopamine (DA) is related to anxiety-related behaviors. Therefore, we aimed to investigate the consequences of neonatal olfactory bulbectomy (nOBX) to anxiety-related behavior as assayed in the elevated plus maze (EPM) as well as the expression of dopaminergic receptors (D1-like, D2-like, and D3) in the NAcc and CPu at pre- and post-pubertal ages in the rat. The results show that nOBX increased the number of entries in the open arm of the EPM post-pubertally, suggesting an anxiolytic-related effect. nOBX increased the D2-like binding in the NAcc shell and D3 binding in the NAcc core pre-pubertally. At post-pubertal ages, the D3 binding was reduced at the olfactory tubercle and islands of Calleja in nOBX rats. Alterations in the DA receptor expression may be one mechanism responsible for the observed behavioral modifications in nOBX rats.

Persistent peripheral inflammation and pain induces immediate early gene activation in supraspinal nuclei in rats.

Pain is a public health concern worldwide and can present simultaneously with anxiety and depression. c-Fos is a marker used to identify activated cells in response to various stimuli. Specifically, it can be used as a brain marker of pain. We examined whether peripheral inflammation produces mechanical allodynia, anxiety- and depression-related behaviors in male rats (Rattus norvegicus, Wistar strain) and if these behaviors can have an impact on c-Fos expression in the supraspinal nuclei involved in pain control. We assessed mechanical thresholds by von Frey monofilaments, depression-like behaviors in the forced swimming test (FST) and anxiety-related behaviors in the open field test (OFT) after the administration of the inflamogen Complete Freund´s Adjuvant (CFA) in rats. We found that CFA increased paw diameter is all rats, however, CFA treatment resulted in a subgroup of rats developing allodynia [CFA- mechanical allodynia (CFA-MA)] and a subgroup of rats not developing allodynia [CFA-no mechanical allodynia (CFA-NMA)]. The peak of tactile allodynia and inflammation were coupled with an increase in c-Fos expression in several supraspinal brain nuclei, i.e. basolateral amygdala, periaqueductal gray matter and rostroventromedial medulla in CFA-MA rats. Moreover, we found a correlation between c-Fos levels and mechanical thresholds. No modification in c-Fos expression was observed in CFA-NMA rats. CFA did not modulate behaviors in the OFT or FST. In summary, we show that mechanical allodynia but not peripheral inflammation activates c-Fos in several supraspinal nuclei, which sheds new light on brain regions involved in the control of pain following peripheral injury and decouples this effect from mere peripheral inflammation. This model may be used to study resistance to pain development in future studies.

Evidence for Endogenous Opioid Dependence Related to Latent Sensitization in a Rat Model of Chronic Inflammatory Pain.

Studies performed in a mouse model of chronic inflammatory pain induced by intraplantar injection of complete Freund's adjuvant (CFA) have shown that constitutive activation of the endogenous opioid signaling, besides serving as a mechanism of endogenous analgesia that tonically represses pain sensitization, also generates a state of endogenous opioid dependence. Since species-related differences concerning pain biology and addictive behaviors occur between mice and rats, the present study explored whether the coexistence of endogenous opioid analgesia and endogenous opioid dependence also characterizes a homologous rat model. To this aim, CFA-injured Wistar rats were treated with either 3 mg/kg or 10 mg/kg of the opioid receptor inverse agonist naltrexone (NTX) during the pain remission phase and monitored for 60 min for possible withdrawal behaviors. At 3 mg/kg, NTX, besides inducing the reinstatement of mechanical allodynia, also caused a distinct appearance of ptosis, with slight but nonsignificant changes to the occurrence of teeth chatters and rearing. On the other hand, 10 mg/kg of NTX failed to unmask pain sensitization and induced significantly lower levels of ptosis than 3 mg/kg. Such an NTX-related response pattern observed in the rat CFA model seems to differ substantially from the pattern previously described in the mouse CFA model. This supports the knowledge that mice and rats are not identical in terms of pharmacological response and stresses the importance of choosing the appropriate species for preclinical pain research purposes depending on the scientific question being asked.

A nutraceutical formulation combined with sclerofoam-assisted laser treatment ameliorates chronic venous insufficiency.

Chronic venous insufficiency has a high impact on the healthcare system due to its high incidence worldwide. We performed a study in 30 women with thigh and leg varices due to major saphenous vein valve incontinence with saphenous trunk reflux causing phlebo-lymphoedema to assess the efficacy of sclerofoam-assisted laser treatment combined with nutraceutical administration. The patients underwent endovascular combination sealing of the saphenous trunk with sclerofoam-assisted laser treatment technique into the major saphenous veins under low-volume tumescent anesthesia followed by intraoperative phlebectomies. Post-operatively, the patients received capsules containing Aesculus Hippocastanum, chondroitin sulphate, proanthocyanidins from Pinus pinaster Aiton, proanthocyanidins from Vitis vinifera L., hydrolysed marine collagen and carcinine dihydrochloride for 3 weeks. We evaluated the extracellular fluid volume of the lower limbs using bioimpedance spectroscopy pre- (T0) and post-surgery (T2) (impedance is a vector which is composed of two components, resistance [RES] and reactance [REA)]). In addition, we evaluated the following parameters pre- and post-surgery: pain, heaviness, paresthesia, itching, swelling, daily urine volume output and leg volume. Limb volume was significantly decreased at T2 compared to T0 (p < 0.01). RES and REA were significantly increased at T2 compared to T0 (p < 0.0001 and p < 0.01, respectively). A significant improvement in heaviness, paresthesia, pain, swelling and itch was also observed (all p < 0.0001) while no changes in terms of diuresis occurred. No adverse effects were observed. The present study shows a promising approach to the treatment of chronic venous insufficiency that warrants further clinical studies in larger cohorts of patients.

Curcumin induces cortico-hippocampal neuronal reshaping and memory improvements in aged mice.

Aging induces cognitive decline, reduces of synaptic plasticity and increases oxidative reactive species (ROS) in the central nervous system. Traditional medicine has long benefitted from naturally occurring molecules such as curcumin (diferuloymethane). Curcumin is extracted from the plant Curcuma longa and is known for its synaptic and antioxidant-related benefits. In this study, we tested the hypothesis that chronic curcumin treatment reduces cognitive and cellular effects of aging. Curcumin-treated mice showed improved learning and memory using the Morris Water Maze and novel object recognition task. In addition, using the Golgi-Cox stain, curcumin treatment increased spine density in all evaluated regions and increased dendritic arborization in the prefrontal cortex (PFC) layer 3 and CA3 subregion of the hippocampus. Moreover, chronic curcumin exposure increased synaptophysin and actin expression and reduced glial fibrillary acidic protein expression, a marker of astrocytes, in the hippocampus (CA1 and CA3 subregions), while simultaneously reducing the ROS-related molecule, metallothionein 3 expression in the PFC and hippocampus. Collectively, these novel findings suggest that curcumin reduces cognitive, neuronal and astrocytic signs of aging in mice.

Threshold for copulation-induced analgesia varies according to the ejaculatory endophenotypes in rats.

Analgesia may be modulated by multiple internal and external factors. In prior studies, copulatory-induced analgesia was demonstrated using the vocalization threshold to tail shock (VTTS) in male and female rats. Three ejaculatory endophenotypes have been characterized in male Wistar rats based upon their ejaculation latency (EL). Since intromissions and ejaculations produce analgesia, and these copulatory patterns are performed with different frequency depending on the male's ejaculatory endophenotype, we hypothesized that copulation-induced analgesia would vary in relation to these endophenotypes. In the present study, we used three groups according to the EL (medians): rapid ejaculators (236 s; n = 21), intermediate ejaculators (663.2 s; n = 20) and sluggish ejaculators (1582.2 s; n = 8). Our aim was to evaluate whether copulation-induced analgesia is related to the ejaculatory endophenotypes during two consecutive ejaculatory series (EJS). In the first EJS, the VTTS of the rapid ejaculators was significantly higher than that of intermediate and sluggish rats. At the onset of the second EJS, the VTTS of the rapid and intermediate ejaculators was significantly higher than that of the sluggish rats. No differences in VTTS were observed during the first or second post-ejaculatory intervals among the three groups. These findings provide evidence that the more intromissions that occurred per unit time, the higher was the level of analgesia.