Depletion of transit amplifying cells in the adult brain does not affect quiescent neural stem cell pool size.

Neural stem cells (NSCs) are maintained in the adult mammalian brain throughout the animal's lifespan. NSCs in the subependymal zone infrequently divide and generate transit amplifying cells, which are destined to become olfactory bulb neurons. When transit amplifying cells are depleted, they are replenished by the quiescent NSC pool. However, the cellular basis for this recovery process remains largely unknown. In this study, we traced NSCs and their progeny after transit amplifying cells were eliminated by intraventricular infusion of cytosine ß-D-arabinofuranoside. We found that although the number of neurosphere-forming NSCs decreased shortly after the treatment, they were restored to normal levels 3 weeks after the cessation of treatment. More importantly, the depletion of transit amplifying cells did not induce a significant expansion of the NSC pool by symmetric divisions. Our data suggest that the size of the NSC pool is hardly affected by brain damage due to antimitotic drug treatment.

Low-dose peripheral leptin infusion produces selective activation of ventromedial hypothalamic and hindbrain STAT3.

Previous studies have shown that very low dose, acute, single peripheral leptin injections fully activate arcuate nucleus signal transducer and activator of transcription 3 (STAT3), but ventromedial hypothalamus (VMH) pSTAT3 continues to increase with higher doses of leptin that inhibit food intake. The lowest dose that inhibited intake increased circulating leptin 300-fold whereas food intake is inhibited by chronic peripheral leptin infusions that only double circulating leptin. This study examined whether the pattern of hypothalamic pSTAT3 was the same in leptin-infused rats as in leptin-injected rats. Male Sprague-Dawley rats received intraperitoneal infusions of 0, 5, 10, 20, or 40 µg leptin/day for 9 days. The highest dose of leptin increased serum leptin by 50-100%, inhibited food intake for 5 days, but inhibited weight gain and retroperitoneal fat mass for 9 days. Energy expenditure, respiratory exchange ratio, and brown fat temperature did not change. pSTAT3 was quantified in hypothalamic nuclei and the nucleus of the solitary tract (NTS) when food intake was inhibited and when it had returned to control levels. There was no effect of leptin on pSTAT3 in the medial or lateral arcuate nucleus or in the dorsomedial nucleus of the hypothalamus. VMH pSTAT3 was increased only at day 4 when food intake was inhibited, but NTS pSTAT3 was increased at both 4 and 9 days of infusion. These results suggest that activation of leptin VMH receptors contributes to the suppression of food intake, but that hindbrain receptors contribute to a sustained change in metabolism that maintains a reduced weight and fat mass.NEW & NOTEWORTHY Low-dose, chronic peripheral infusions of leptin produced an initial, transient inhibition of food intake that correlated with signal transducer and activator of transcription 3 (STAT3) activation in the ventromedial hypothalamus (VMH) and nucleus of the solitary tract (NTS). When intake normalized, but weight remained suppressed, the NTS was the only area that remained activated. These data suggest that leptin's primary function is to reduce body fat, that hypophagia is a means of achieving this and that different areas of the brain are responsible for the progressive response.

A protocol for collection and infusion of cerebrospinal fluid in mice.

Here, we provide a step-by-step protocol for the collection and intracerebroventricular infusion of cerebrospinal fluid (CSF) in mice. We describe steps to withdraw CSF quickly and abundantly while avoiding blood contamination. Using the Lynch coil technique, we gain functional insights into the collected CSF by slowly infusing minimal amounts of CSF directly to the lateral ventricles of aged mice. This protocol is versatile and can be used to infuse drugs, antibodies, or scarce biological compounds. For complete details on the use and execution of this protocol, please refer to Iram et al. (2022).1.

Chronic intracerebroventricular infusion of angiotensin II causes dose- and sex-dependent effects on intake behaviors and energy homeostasis in C57BL/6J mice.

The renin-angiotensin system (RAS) within the brain is implicated in the control of fluid and electrolyte balance, autonomic functions, blood pressure, and energy expenditure. Mouse models are increasingly used to explore these mechanisms; however, sex and dose dependencies of effects elicited by chronic intracerebroventricular (ICV) angiotensin II (ANG II) infusion have not been carefully established in this species. To examine the interactions among sex, body mass, and ICV ANG II on ingestive behaviors and energy balance, young adult C57BL/6J mice of both sexes were studied in a multiplexed metabolic phenotyping system (Promethion) during chronic infusion of ANG II (0, 5, 20, or 50 ng/h). At these infusion rates, ANG II caused accelerating dose-dependent increases in drinking and total energy expenditure in male mice, but female mice exhibited a complex biphasic response with maximum responses at 5 ng/h. Body mass differences did not account for sex-dependent differences in drinking behavior or total energy expenditure. In contrast, resting metabolic rate was similarly increased by ICV ANG II in a dose-dependent manner in both sexes after correction for body mass. We conclude that chronic ICV ANG II stimulates water intake, resting, and total energy expenditure in male C57BL/6J mice following straightforward accelerating dose-dependent kinetics, but female C57BL/6J mice exhibit complex biphasic responses to ICV ANG II. Furthermore, control of resting metabolic rate by ANG II is dissociable from mechanisms controlling fluid intake and total energy expenditure. Future studies of the sex dependency of ANG II within the brain of mice must be designed to carefully consider the biphasic responses that occur in females.

Validez pronóstica de las amplitudes de presión, tiempo en alcanzar la meseta y la pendiente obtenidas en el test de infusión para el estudio de la hidrocefalia idiopática de presión normal / Prognostic value of the pulse pressure amplitudes, time to reach the plateau and the slope obtained in the lumbar infusion test for the study of idiophatic normal pressure hydrocephalus

Antecedentes y objetivo: Estudiar la validez pronóstica de la resistencia a la salida de líquido cefalorraquídeo (Rout) obtenida en el test de infusión lumbar en el estudio de la hidrocefalia idiopática de presión normal (iNPH), al igual que de las amplitudes en los diferentes tramos del test y otras nuevas variables obtenidas con el software Neuropicture®.Materiales y métodosRevisamos retrospectivamente pacientes con «probable iNPH» a los que se les sometió a un test de infusión lumbar. Se determinó el valor predictivo positivo (VPP) del punto de corte con mayor precisión pronóstica de la Rout, la amplitud de pulso en reposo (AMP0), la amplitud en los primeros 10 min (AMP10min), la amplitud de meseta (AMPmes), la amplitud de Rout (AMPRout), el tiempo en alcanzar la meseta (T) y la pendiente de la curva hasta alcanzar la meseta (P). Se dividió a los pacientes en respondedores y no respondedores.ResultadosEl estudio incluyó a 64 pacientes respondedores y 16, no respondedores. El VPP de Rout >15mmHg/ml/min fue 91,7%; de la AMP0> 2,34mmHg, 91,3%; de la AMP10min> 4,34 mmHG, 83,3%; de AMPmes> 12,44mmHg, 84,6%; de AMPRout> 6,34 mmHG, 85%; de T<634 s, 86,7%, y de P> 0,040mmHg/s, 96,3%.ConclusionesLa Rout sigue siendo un criterio válido para indicar un shunt ventricular. Las amplitudes en diferentes tramos del test, junto a la T y la P son otras variables cuya positividad es indicativa de respuesta valvular y deberían formar parte del protocolo diagnóstico (AU)

Background and objective: To study the prognostic value of the resistance to the cerebrospinal fluid outflow (Rout) obtained in the lumbar infusion test in idiopathic normal pressure hydrocephalus (iNPH), as well as the pulse pressure amplitudes in the different periods of the test and other new variables extracted by Neuropicture® software.Material and methodsPatients with ́probable iNPH́ who underwent a lumbar infusion test were retrospectively revised. The positive predictive values (PPV) of the cutoff point of the best prognostic accuracy of the Rout, the basal pulse pressure amplitude (AMP0), the pulse pressure amplitude during the first 10minutes (AMP10min), the plateau pulse pressure amplitude (AMPmes), the Rout pulse pressure amplitude (AMPRout), the time to reach the plateau (T), and the slope until reaching the plateau were determined. Patients were categorized either as responders or non-responders.ResultsThe study included 64 responders patients and 16 non-responders patients. The PPV of Rout> 15mmHg/ml/min was 91.7%; AMP0> 2.34mmHg: 91.3%; AMP10min>4.34mmHg: 83.3%; AMPmes>12.44mmHg: 84.6%; AMPRout>6.34mmHg: 85%; T <634seconds: 86.7%; P>0.040mmHg/sec: 96.3%.ConclusionsRout is a valid criterion to indicate a ventricular shunt. Pulse pressure amplitudes in the different periods of the lumbar infusion test, in addition to T and P, are other variables whose positivity is indicative of shunt response and should be considered in the diagnostic protocol of the iNPH (AU)

Pilot Study of the Effects of Chronic Intracerebroventricular Infusion of Human Anti-IgLON5 Disease Antibodies in Mice.

BACKGROUND: Anti-IgLON5 disease is a rare late-onset neurological disease associated with autoantibodies against IgLON5, neuronal accumulation of phosphorylated Tau protein (p-Tau), and sleep, respiratory, and motor alterations. PURPOSE: We performed a pilot study of whether the neuropathological and clinical features of anti-IgLON5 disease may be recapitulated in mice with chronic intracerebroventricular infusion of human anti-IgLON5 disease IgG (Pt-IgG). METHODS: Humanized transgenic hTau mice expressing human Tau protein and wild-type (WT) control mice were infused intracerebroventricularly with Pt-IgG or with antibodies from a control subject for 14 days. The sleep, respiratory, and motor phenotype was evaluated at the end of the antibody infusion and at least 30 days thereafter, followed by immunohistochemical assessment of p-Tau deposition. RESULTS: In female hTau and WT mice infused with Pt-IgG, we found reproducible trends of diffuse neuronal cytoplasmic p-Tau deposits in the brainstem and hippocampus, increased ventilatory period during sleep, and decreased inter-lick interval during wakefulness. These findings were not replicated on male hTau mice. CONCLUSION: The results of our pilot study suggest, but do not prove, that chronic ICV infusion of mice with Pt-IgG may elicit neuropathological, respiratory, and motor alterations. These results should be considered as preliminary until replicated in larger studies taking account of potential sex differences in mice.

Intracerebroventricular infusion of the selective orexin 1 receptor antagonist SB-334867 impairs cognitive flexibility in a sex-dependent manner.

Orexin neuropeptides are well known for their role in sleep/wake cycle, feeding behavior and motivation-related behaviors. However, their role in cognition is not clearly understood. We recently published that orexin deficiency impairs intra-dimensional set shifting in female homozygous orexin-deficient mice but improves the first reversal phase in male homozygous orexin-deficient mice in the attentional set shifting task (ASST), a well-established rodent test for cognitive flexibility. In the present study, we tested if intracerebroventricular injections of the selective orexin 1 receptor antagonist SB-334867 (4 µg/2 µL) affects cognitive flexibility in the different phases of ASST. We found that SB-334867 injections impaired the first and second reversal phases in female C57BL/6J mice but not in males. In addition, we also showed that at this particular dose of SB-334867, the consumption of the reward that was used in the ASST was not affected in both males and females. Our findings indicate that cognitive flexibility is impaired by orexin 1 receptor antagonism in a sex-dependent manner and reiterates the sexually dimorphic role of orexin in cognitive flexibility.

Serotonin-1A receptor activation in the median raphe nucleus improves response learning-based strategy in 192IgG saporin-induced cognitive impairments.

Deficits in the translation between egocentric-allocentric strategies may become another diagnostic mark for neurodegenerative disorders, especially Alzheimer's disease. Regarding the specific regional distribution of serotonin-1A receptor in brain areas mediating allocentric (externally-centered) spatial navigation to the escape location, here we studied the effects of median raphe nucleus serotonin-1A autoreceptors stimulation, [8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT); 4 µg/0.5 µl saline], of a selective cholinergic denervation by intracerebroventricular administration of the 192IgG saporin (1µl/each ventricle), on male Wistar rats search strategies in a Morris maze during acquisition, and before probe sessions. Despite some evidence of spatial hippocampal dependent knowledge to those PBS/Saline animals, their performance dropped to chance levels on probe trial. Therefore, we considered two probabilities and first analyzed the ability of the rats to make better use of one or more strategies. We showed statistically significant increases in the distances associated with egocentric (body-centered) non-spatial strategies, random searching in particular, in 192IgG/8OH rats, which led to their improved performance. Second, considering to what extent a shift in search strategy use improves performance indicated that 8-OH-DPAT alone did not affect learning since it appeared the related performance was impaired over days. However, the strategy choices made by 192IgG/8OH rats increased performance by more than 12% compared to 192IgG/Saline rats, an effect reversed with pre-treatment by serotonin-1A receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane-carboxamide (WAY 100635). The results strongly suggest the potential role of serotonergic system, via the serotonin-1A receptors, in spatial navigation. We argue that the receptors are of interest as therapeutic targets that can be used against age-related cognitive decline.

Ghrelin signaling in dCA1 suppresses neuronal excitability and impairs memory acquisition via PI3K/Akt/GSK-3ß cascades.

Ghrelin is a circulating peptide hormone that promotes feeding and regulates metabolism in humans and rodents. The action of ghrelin is mediated by the growth hormone secretagogue receptor type 1a (GHSR-1a) that is widely distributed in the brain, including the hippocampus. Studies have demonstrated the critical role of hippocampal ghrelin/GHS-R1a signaling in synaptic physiology and memory. However, those findings are controversial, and the mechanism underlying ghrelin modulation of learning and memory is uncertain. Here, we report that micro-infusion of ghrelin in the CA1 region of the dorsal hippocampus during training specifically impairs memory acquisition. The activation of GHS-R1a and the subsequent PI3K/Akt/GSK3ß signaling cascades are involved in this process. Moreover, we report that bath application of ghrelin suppresses the intrinsic excitability of dCA1 pyramidal neurons through activating GHS-R1a, and PI3K inhibitor LY294002 blocks ghrelin's effect. However, LY294002 fails to rescue ghrelin-induced LTP impairment. Our findings support an adverse effect of ghrelin-dependent activation of GHS-R1a on memory acquisition, and suggest that PI3K/Akt/GSK3ß signaling-dependent repression of neuronal intrinsic excitability is an important novel mechanism underlying memory inhibition of ghrelin in the hippocampus.

Activation of GPR55 attenuates cognitive impairment and neurotoxicity in a mouse model of Alzheimer's disease induced by Aß1-42 through inhibiting RhoA/ROCK2 pathway.

The accumulation of amyloid-ß (Aß) peptides in the brain is considered to be the initial event in the Alzheimer's disease (AD). Neurotoxicity mediated by Aß has been demonstrated to damage the cognitive function. In the present study, we sought to determine the effects of O-1602, a specific G-protein coupled receptor 55 (GPR55) agonist, on the impairment of learning and memory induced by intracerebroventricular (i.c.v.) of Aß1-42 (400 pmol/mouse) in mice. Our results showed that i.c.v. injection of aggregated Aß1-42 into the brain of mice resulted in cognitive impairment and neurotoxicity. In contrast, O-1602 (2.0 or 4.0 µg/mouse, i.c.v.) can improve memory impairment induced by Aß1-42 in the Morris water maze (MWM), and novel object recognition (NOR) tests. Besides, we found that O-1602 reduced the activity of ß-secretase 1 (BACE1) and the level of soluble Aß1-42 in the hippocampus and frontal cortex. Importantly, O-1602 treatment reversed Aß1-42-induced GPR55 down-regulation, decreased pro-inflammatory cytokines, and the level of malondialdehyde (MDA), increased the levels of glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT), as well as suppressed apoptosis as indicated by decreased TUNEL-positive cells, and increased the ratio of Bcl-2/Bax. O-1602 treatment also pronouncedly ameliorated synaptic dysfunction by promoting the upregulation of PSD-95 and synaptophysin (SYN) proteins. Moreover, O-1602 concurrently down regulated the protein levels of RhoA, and ROCK2, the critical proteins in the RhoA/ROCK2 pathway. This study indicates that O-1602 may reverse Aß1-42-induced cognitive impairment and neurotoxicity in mice by inhibiting RhoA/ROCK2 pathway. Taken together, these findings suggest that GPR55 could be a novel and promising target for the treatment of AD.

Chronic infusions of mecamylamine into the medial habenula: Effects on nicotine self-administration in rats.

The habenula is an epithalamic structure through which descending connections go from the telencephalon to the brainstem, putting it in a key location to provide feedback control over the ascending projections from the brainstem to the telencephalon. The medial habenula has a high concentration of nicotinic receptors. We assessed the role of medial habenular nicotinic receptors for nicotine self-administration (SA) in female young adult Sprague-Dawley rats. The rats had bilateral chronic infusion cannulae placed into the medial habenula nucleus. Each cannula was connected to a slow delivery osmotic minipump to chronically infuse mecamylamine (100 µg/side/day) or vehicle for four consecutive weeks. The rats were tested for nicotine SA for the first two weeks of mecamylamine infusion. Then, they had one week of enforced abstinence, during which they had no access to the nicotine SA. Finally, they had one week of resumed nicotine SA access. There was a significantly differential mecamylamine effects in animals with lower and higher pretreatment baseline nicotine SA. Rats with lower baseline nicotine SA levels showed a nearly significant mecamylamine-induced reduction in SA while those with higher baseline levels of SA showed a significant mecamylamine-induced increase in nicotine SA. This study determined that medial habenular nicotinic receptors are important for nicotine reinforcement. Baseline level of performance makes a crucial difference for the involvement of habenular mechanisms in nicotine reinforcement with nicotinic activation being important for maintaining nicotine self-administration for those with lower levels of baseline self-administration and the opposite effect with subjects with higher levels of baseline self-administration.

A survival analysis of ventricular access devices for delivery of cerliponase alfa.

OBJECTIVE: Late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) is a rare autosomal recessive disease caused by tripeptidyl peptidase 1 enzyme deficiency. At the authors' center, the medication cerliponase alfa is administered every 2 weeks via the intracerebroventricular (ICV) route. This requires the placement of a ventricular access device (VAD) or reservoir and frequent percutaneous punctures of this device over the child's lifetime. In this study, the authors audited the longevity and survival of these VADs and examined the causes of device failure. METHODS: A single-center survival analysis of VAD insertions and revisions (January 2014 through June 2020) was conducted. All children received cerliponase alfa infusions through a VAD. Patient characteristics and complications were determined from a prospectively maintained surgical database and patient records. For the VAD survival analysis, the defined endpoint was when the device was removed or changed. Reservoir survival was assessed using Kaplan-Meier curves and the log-rank (Cox-Mantel) test. RESULTS: A total of 17 patients had VADs inserted for drug delivery; median (range) age at first surgery was 4 years 4 months (1 year 8 months to 15 years). Twenty-six VAD operations (17 primary insertions and 9 revisions) were required among these 17 patients. Twelve VAD operations had an associated complication, including CSF infection (n = 6) with Propionibacterium and Staphylococcus species being the most prevalent organisms, significant surgical site swelling preventing infusion (n = 3), leakage/wound breakdown (n = 2), and catheter obstruction (n = 1). There were no complications or deaths associated with VAD insertion. The median (interquartile range) number of punctures was 59.5 (7.5-82.0) for unrevised VADs (n = 17) versus 2 (6-87.5) for revised VADs (n = 9) (p = 0.70). The median survival was 301 days for revisional reservoirs (n = 9) versus 2317 days for primary inserted reservoirs (n = 17) (p = 0.019). CONCLUSIONS: In the context of the current interest in intrathecal drug delivery for rare metabolic disorders, the need for VADs is likely to increase. Auditing the medium- to long-term outcomes associated with these devices will hopefully result in their wider application and may have potential implications on the development of new VAD technologies. These results could also be used to counsel parents prior to commencement of therapy and VAD implantation.

Association Between Intraventricular Alteplase Use and Parenchymal Hematoma Volume in Patients With Spontaneous Intracerebral Hemorrhage and Intraventricular Hemorrhage.

Importance: Intraventricular thrombolysis reduces intraventricular hemorrhage (IVH) volume in patients with spontaneous intracerebral hemorrhage (ICH), but it is unclear if a similar association with parenchymal ICH volume exists. Objective: To evaluate the association between intraventricular alteplase use and ICH volume as well as the association between a change in parenchymal ICH volume and long-term functional outcomes. Design, Setting, and Participants: This cohort study was a post hoc exploratory analysis of data from the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage phase 3 randomized clinical trial with blinded outcome assessments. Between September 1, 2009, and January 31, 2015, patients with ICH and IVH were randomized to receive either intraventricular alteplase or normal saline via an external ventricular drain. Participants with primary IVH were excluded. Data analyses were performed between January 1 and June 30, 2021. Exposure: Randomization to receive intraventricular alteplase. Main Outcomes and Measures: The primary outcome was the change in parenchymal ICH volume between the hematoma stability and end-of-treatment computed tomography scans. Secondary outcomes were a modified Rankin Scale score higher than 3 and mortality, both of which were assessed at 6 months. The association between alteplase and change in parenchymal ICH volume was assessed using multiple linear regression, whereas the associations between change in parenchymal ICH volume and 6-month outcomes were assessed using multiple logistic regression. Prespecified subgroup analyses were performed for baseline IVH volume, admission ICH volume, and ICH location. Results: A total of 454 patients (254 men [55.9%]; mean [SD] age, 59 [11] years) were included in the study. Of these patients, 230 (50.7%) were randomized to receive alteplase and 224 (49.3%) to receive normal saline. The alteplase group had a greater mean (SD) reduction in parenchymal ICH volume compared with the saline group (1.8 [0.2] mL vs 0.4 [0.1] mL; P < .001). In the primary analysis, alteplase use was associated with a change in the parenchymal ICH volume in the unadjusted analysis per 1-mL change (ß, 1.37; 95% CI, 0.92-1.81; P < .001) and in multivariable linear regression analysis that was adjusted for demographic characteristics, stability ICH and IVH volumes, ICH location, and time to first dose of study drug per 1-mL change (ß, 1.20; 95% CI, 0.79-1.62; P < .001). In the secondary analyses, no association was found between change in parenchymal ICH volume and poor outcome (odds ratio [OR], 0.97; 95% CI 0.87-1.10; P = .64) or mortality (OR, 0.97; 95% CI 0.99-1.08; P = .59). Similar results were observed in the subgroup analyses. Conclusions and Relevance: This study found that intraventricular alteplase use in patients with a large IVH was associated with a small reduction in parenchymal ICH volume, but this association did not translate into improved functional outcomes or mortality. Intraventricular thrombolysis should be examined in patients with moderate to large ICH with IVH, especially in a thalamic location.

The role for intra-arterial chemotherapy for refractory retinoblastoma: a systematic review

Background Intra-arterial chemotherapy is a new retinoblastoma treatment associated with high rates of globe salvage that has been widely adopted for primary treatment of retinoblastoma but is less frequently used as secondary treatment for refractory retinoblastoma. This systematic review aims to summarize the reported outcomes of intra-arterial chemotherapy for refractory retinoblastoma. Methods We conducted a systematic review of studies published on PubMed, Medline, and Embase from 2011 to 2021 reporting globe salvage rates following intra-arterial chemotherapy for secondary treatment of refractory retinoblastoma. Results Our search yielded 316 studies, and 24 met inclusion criteria. The 24 included studies were comprised of 1366 patients and 1757 eyes. Among these, 1184 (67%) eyes received secondary indication treatment, and globe salvage was achieved for 776 of these 1184 eyes (64%). Sixteen studies reported cannulation success rates from 71.8 to 100%. Pooled analysis of subjects revealed 21 patients (2.6%) with metastatic disease and 26 deaths (3%) during study follow-up periods (7–74 months). The most common ocular complications were vitreous hemorrhage (13.2%), loss of eyelashes (12.7%), and periocular edema (10.5%). The most common systemic complications were nausea/vomiting (20.5%), neutropenia (14.1%), fever (8.2%), and bronchospasm (6.2%). Conclusions Intra-arterial chemotherapy is associated with high rates of globe salvage and low rates of serious complications in patients with refractory retinoblastoma. Unfortunately, current literature is predominantly comprised of retrospective case studies, and further high-quality evidence is necessary to inform clinical practice (AU)

Protective effects of octylseleno-xylofuranoside in a streptozotocin-induced mouse model of Alzheimer's disease.

Octylseleno-xylofuranoside (OSX) is an organic selenium compound which has previously shown antioxidant and antidepressant-like activities, trough the modulation of monoaminergic system and synaptic plasticity pathways. Since recent studies have suggested Major Depressive Disorder (MDD) as a potential risk factor or condition that precedes and correlates with Alzheimer's Disease (AD), this study aimed to evaluate the protective effects of OSX in an AD mouse model induced by intracerebroventricular injection of streptozotocin (STZ). To address this protective effect, mice were pre-treated with intragastrical OSX (0.1 mg/kg) or vehicle for 20 days. After the pre-treatment, mice were submitted to two alternated intracerebroventricular infusions of STZ (days 21 and 23) or saline. 15 days after the last STZ injection, cognitive and memory skills of the treated mice were evaluated on object recognition test, Y-maze, stepdown passive avoidance and social recognition paradigms. Added to that, measurements of oxidative stress markers and gene expression were evaluated in brain samples of the same mice groups. Mice pre-treatment with OSX protected mice from cognitive and memory decline elicited by STZ. This effect was attributed to the prevention of lipid peroxidation and modulation of acetylcholinesterase and monoamine oxidase activities in cerebral cortices and hippocampi by OSX treatment. Furthermore, OSX treatment demonstrated reduction of amyloidogenic pathway genes expression when compared to the control groups. Besides that, OSX treatment showed no hepatic and renal toxicity in the protocol used for treatment. Considering the antidepressant-like effect of OSX, together with the ability to prevent memory and cognitive impairment, this new compound may be an interesting strategy for targeting the comorbidity between MDD and AD, in a multitarget drug paradigm.

Tauroursodeoxycholic Acid Attenuates Diet-Induced and Age-Related Peripheral Endoplasmic Reticulum Stress and Cerebral Amyloid Pathology in a Mouse Model of Alzheimer's Disease.

BACKGROUND: Obesity and diabetes are well-established risk factors of Alzheimer's disease (AD). In the brains of patients with AD and model mice, diabetes-related factors have been implicated in the pathological changes of AD. However, the molecular mechanistic link between the peripheral metabolic state and AD pathophysiology have remained elusive. Endoplasmic reticulum (ER) stress is known as one of the major contributors to the metabolic abnormalities in obesity and diabetes. Interventions aimed at reducing ER stress have been shown to improve the systemic metabolic abnormalities, although their effects on the AD pathology have not been extensively studied. OBJECTIVES: We examined whether interventions targeting ER stress attenuate the obesity/diabetes-induced Aß accumulation in brains. We also aimed to determine whether ER stress that took place in the peripheral tissues or central nervous system was more important in the Aß neuropathology. Furthermore, we explored if age-related metabolic abnormalities and Aß accumulation could be suppressed by reducing ER stress. METHODS: APP transgenic mice (A7-Tg), which exhibit Aß accumulation in the brain, were used as a model of AD to analyze parameters of peripheral metabolic state, ER stress, and Aß pathology in the brain. Intraperitoneal or intracerebroventricular administration of taurodeoxycholic acid (TUDCA), a chemical chaperone, was performed in high-fat diet (HFD)-fed A7-Tg mice for ~1 month, followed by analyses at 9 months of age. Mice fed a normal diet were treated with TUDCA by drinking water for 4 months and intraperitoneally for 1 month in parallel, and analyzed at 15 months of age. RESULTS: Intraperitoneal administration of TUDCA suppressed ER stress in the peripheral tissues and ameliorated the HFD-induced obesity and insulin resistance. Concomitantly, Aß levels in the brain were significantly reduced. In contrast, intracerebroventricular administration of TUDCA had no effect on the Aß levels. Peripheral administration of TUDCA was also effective against the age-related obesity and insulin resistance, and markedly reduced amyloid accumulation. CONCLUSIONS: Interventions that target peripheral ER stress might be beneficial therapeutic and prevention strategies against brain Aß pathology associated with metabolic overload and aging.

Intracerebroventricular asprosin administration strongly stimulates hypothalamic-pituitary-testicular axis in rats.

Asprosin, a protein-based secretary product of white adipose tissue, stimulates appetite hepatic glucose production. It crosses blood-brain barrier and stimulates appetite center and causes sperm chemotaxis but exact role of this endogenous agent is not completely known. This study was conducted to investigate possible effects of central asprosin infusion on the hormones involved in the hypothalamic-pituitary-testicular (HPT) axis and sperm cells. Spraque Dawley male rats were divided into four groups; control, sham, low asprosin (34) and high asprosin (68 nM) groups, (n = 10 for each group). Control group remain intact while a brain infusion kit was placed in the lateral ventricles of the rats in the sham group (artificial cerebrospinal fluid) and asprosin (34 and 68 nM) was infused for 14 days. At the end of the experiment, the hypothalamus, blood, and epididymis tissues of the rats were collected. Gonadotropin-releasing hormone (GnRH) mRNA and tissue protein levels were determined in the hypothalamus tissue by RT-PCR and Western Blot methods. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels were examined using the ELISA method from blood samples and sperm cells were examined in the epididymis tissue. GnRH mRNA and protein expressions of asprosin administered groups were higher than control and sham groups (p < 0.05). Asprosin infusion was also found to increase serum FSH, LH, and testosterone levels (p < 0.05). In addition, sperm density, motility, and progressive movement were observed to increase in asprosin administered groups (p < 0.05). This study suggests that central asprosin stimulate the HPT axis and also epididymis tissue. Our results implicates potential role for asprosin in male infertility.

C-Type Natriuretic Peptide Ameliorates Vascular Injury and Improves Neurological Outcomes in Neonatal Hypoxic-Ischemic Brain Injury in Mice.

C-type natriuretic peptide (CNP) is an important vascular regulator that is present in the brain. Our previous study demonstrated the innate neuroprotectant role of CNP in the neonatal brain after hypoxic-ischemic (HI) insults. In this study, we further explored the role of CNP in cerebrovascular pathology using both in vivo and in vitro models. In a neonatal mouse HI brain injury model, we found that intracerebroventricular administration of recombinant CNP dose-dependently reduces brain infarct size. CNP significantly decreases brain edema and immunoglobulin G (IgG) extravasation into the brain tissue, suggesting a vasculoprotective effect of CNP. Moreover, in primary brain microvascular endothelial cells (BMECs), CNP dose-dependently protects BMEC survival and monolayer integrity against oxygen-glucose deprivation (OGD). The vasculoprotective effect of CNP is mediated by its innate receptors NPR2 and NPR3, in that inhibition of either NPR2 or NPR3 counteracts the protective effect of CNP on IgG leakage after HI insult and BMEC survival under OGD. Of importance, CNP significantly ameliorates brain atrophy and improves neurological deficits after HI insults. Altogether, the present study indicates that recombinant CNP exerts vascular protection in neonatal HI brain injury via its innate receptors, suggesting a potential therapeutic target for the treatment of neonatal HI brain injury.

Primary Nocardia brain abscesses and role of intraventricular antibiotic therapy.

Intracranial infections caused by Nocardia Farcinica are challenging to treat and potentially lethal because of the organism's tendency to resist antibiotics and high relapse rates. Such infections usually occur in immunocompromised patients who have predisposing factors. Nocardia brain abscesses carry a higher morbidity and mortality rate than other bacterial brain abscesses, with reported mortality rates of 55% (even up to 90% in cases of late diagnosis) in immunocompromised patients. An aggressive therapeutic approach is required and an early identification of the microorganism is paramount. Given the high microbial resistance, it is usually an infection with a low cure rate. We present the case of a patient with primary brain abscesses due to Nocardia Farcinica, successfully treated with intrathecal Amikacin administration through ventricular drain, in addition to surgical evacuation and intravenous antibiotic therapy. In this case, clinical and radiological improvement were observed once the intrathecal treatment was started. To our best knowledge, no cases of intraventricular use of Amikacin have been previously reported to treat this type of infection and we believe that it may be useful in properly selected patients.