Cerebrospinal Fluid Secretion Research Articles

Changes of cerebrospinal fluid pressure gradient in different body positions under experimental impairment of cerebrospinal fluid pathway: new insight into hydrocephalus development

Changes of cerebrospinal fluid pressure gradient in different body positions under experimental impairment of cerebrospinal fluid pathway: new insight into hydrocephalus development

Paediatric hydrocephalus.

Hydrocephalus is classically considered as a failure of cerebrospinal fluid (CSF) homeostasis that results in the active expansion of the cerebral ventricles. Infants with hydrocephalus can present with progressive increases in head circumference whereas older children often present with signs and symptoms of elevated intracranial pressure. Congenital hydrocephalus is present at or near birth and some cases have been linked to gene mutations that disrupt brain morphogenesis and alter the biomechanics of the CSF-brain interface. Acquired hydrocephalus can develop at any time after birth, is often caused by central nervous system infection or haemorrhage and has been associated with blockage of CSF pathways and inflammation-dependent dysregulation of CSF secretion and clearance. Treatments for hydrocephalus mainly include surgical CSF shunting or endoscopic third ventriculostomy with or without choroid plexus cauterization. In utero treatment of fetal hydrocephalus is possible via surgical closure of associated neural tube defects. Long-term outcomes for children with hydrocephalus vary widely and depend on intrinsic (genetic) and extrinsic factors. Advances in genomics, brain imaging and other technologies are beginning to refine the definition of hydrocephalus, increase precision of prognostication and identify nonsurgical treatment strategies.

TRPV4 Antagonist Treatment of Hydrocephalus Causes Cell and Molecular Changes in Multiple Brain Cell Types

Hydrocephalus is defined by cerebrospinal fluid (CSF) accumulation in the brain’s ventricles causing ventriculomegaly, an imbalance in CSF secretion, flow, and/or absorption. Treatments for hydrocephalus include invasive surgical procedures, which commonly fail throughout a patient’s life. Transient receptor potential vanilloid member 4 (TRPV4) is a mechanosensitive cation channel implicated in osmotic regulation. Our laboratory found that a TRPV4 antagonist, RN1734, ameliorates hydrocephalus in a rat model of congenital hydrocephalus. It was hypothesized that treatment slowed production of CSF by targeting choroid plexus (CP), a contiguous layer of tightly regulated epithelial cells, that is responsible for CSF production. However, hydrocephalus pathology can have various effects on the brain. This study focuses on changes occurring in CP epithelial cells (CPe) and glia, which have roles in brain-barrier maintenance and brain fluid/electrolyte regulation. Interestingly, CPe and glia contain many of the same channels and transporters, including TRPV4, that are important in regulating both CSF and brain interstitial fluid. These cells contain aquaporins (AQP), AQP1 in CPe, and AQP4 in glia. AQPs have been implicated in diseases associated with fluid regulation and may interact with TRPV4. We hypothesize that TRPV4 and AQPs are important in hydrocephalus pathology, and that changes may be attenuated with RN1734 treatment. A point mutation in TMEM67 results in hydrocephalus (hydro). Changes in cell morphology, gene transcription, protein expression, localization of TRPV4, AQP1, and AQP4 were observed. Postnatal day 15 (P15) untreated (unt) and RN1734-treated (RN;2mg/ml DMSO; 4mg/kg intraperitoneal injection daily P7-P14) wildtype and mutant ( Tmem67−/−) rats were utilized in this study. CPe and periventricular (PV) glia were visualized using fluorescent immunohistochemistry (IHC) of GFAP and a plasma membrane marker. Cell volume of CPe’s and process morphology of glia were altered in hydro rats. RN returned these changes to relatively normal in CPe, but not glia. Next, we used IHC to examine localization of TRPV4 and the AQPs. Increased immunoreactivity of TRPV4 and AQP1 was observed in CPe of unt and RN Tmem67−/− rats. AQP4 and TRPV4 immunoreactivity increased in the subventricular zone and PV white matter of hydro rats. TRPV4 immunoreactivity, but not AQP4, was normalized with RN. We then utilized RTqPCR to inspect transcriptional changes. The data showed increased AQP1 and decreased TRPV4 mRNA in PV cortex and CP of unt and RN Tmem67−/− rats. Previous data from our laboratory found no change in TRPV4 protein in unt Tmem67−/− CPe, but we were curious about AQP expression. The amount of AQP1 protein was increased in the CP of unt and RN Tmem67−/− rats. In PV cortex, AQP4, but not TRPV4, protein was increased in hydro rats. With RN, AQP4 protein was not normalized. In summary, TRPV4 changes in the Tmem67−/− rats returned to normal with RN, glial morphology and AQP changes did not. This may indicate residual inflammation in the Tmem67−/− rats, which we aim to address in future studies. To further elucidate TRPV4’s role in hydrocephalus pathology, future studies will explore post-translational and membrane localization changes. Overall, investigating cell and molecular changes that occur in hydrocephalus will help find better pharmacological targets for this disease. Funding: United States Department of Defense Congressionally Directed Medical Research Program Award; Hydrocephalus Association. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Cerebrospinal fluid pH regulation.

The cerebrospinal fluid (CSF) fills the brain ventricles and the subarachnoid space surrounding the brain and spinal cord. The fluid compartment of the brain ventricles communicates with the interstitial fluid of the brain across the ependyma. In comparison to blood, the CSF contains very little protein to buffer acid-base challenges. Nevertheless, the CSF responds efficiently to changes in systemic pH by mechanisms that are dependent on the CO2/HCO3- buffer system. This is evident from early studies showing that the CSF secretion is sensitive to inhibitors of acid/base transporters and carbonic anhydrase. The CSF is primarily generated by the choroid plexus, which is a well-vascularized structure arising from the pial lining of the brain ventricles. The epithelial cells of the choroid plexus host a range of acid/base transporters, many of which participate in CSF secretion and most likely contribute to the transport of acid/base equivalents into the ventricles. This review describes the current understanding of the molecular mechanisms in choroid plexus acid/base regulation and the possible role in CSF pH regulation.

Modulation of Cerebrospinal Fluid Dysregulation via a SPAK and OSR1 Targeted Framework Nucleic Acid in Hydrocephalus.

Hydrocephalus is one of the most common brain disorders and a life-long incurable condition. An empirical "one-size-fits-all" approach of cerebrospinal fluid (CSF) shunting remains the mainstay of hydrocephalus treatment and effective pharmacotherapy options are currently lacking. Macrophage-mediated ChP inflammation and CSF hypersecretion have recently been identified as a significant discovery in the pathogenesis of hydrocephalus. In this study, a pioneering DNA nano-drug (TSOs) is developed by modifying S2 ssDNA and S4 ssDNA with SPAK ASO and OSR1 ASO in tetrahedral framework nucleic acids (tFNAs) and synthesis via a one-pot annealing procedure. This construct can significantly knockdown the expression of SPAK and OSR1, along with their downstream ion channel proteins in ChP epithelial cells, thereby leading to a decrease in CSF secretion. Moreover, these findings indicate that TSOs effectively inhibit the M0 to M1 phenotypic switch of ChP macrophages via the MAPK pathways, thus mitigating the cytokine storm. In in vivo post-hemorrhagic hydrocephalus (PHH) models, TSOs significantly reduce CSF secretion rates, alleviate ChP inflammation, and prevent the onset of hydrocephalus. These compelling results highlight the potential of TSOs as a promising therapeutic option for managing hydrocephalus, with significant applications in the future.

CSF hyperdynamics in rats mimicking the obesity and androgen excess characteristic of patients with idiopathic intracranial hypertension

BackgroundIdiopathic intracranial hypertension (IIH) is a syndrome exhibiting elevated intracranial pressure (ICP), visual disturbances, and severe headache. IIH primarily affects young obese women, though it can occur in individuals of any age, BMI, and sex. IIH is characterized by systemic metabolic dysregulation with a profile of increased androgen hormones. However, the contribution of obesity/hormonal perturbations to cerebrospinal fluid (CSF) dynamics remains unresolved.MethodsWe employed obese female Zucker rats and adjuvant testosterone to reveal IIH causal drivers. ICP and CSF dynamics were determined with in vivo experimentation and magnetic resonance imaging, testosterone levels assessed with mass spectrometry, and choroid plexus function revealed with transcriptomics.ResultsObese rats had undisturbed CSF testosterone levels and no changes in ICP or CSF dynamics. Adjuvant testosterone treatment of obese rats elevated the CSF secretion rate, although with no effect on the ICP, due to elevated CSF drainage capacity of these rats.ConclusionsObesity in itself therefore does not suffice to recapitulate the IIH symptoms in rats, but modulation of CSF dynamics appears with adjuvant testosterone treatment, which mimics the androgen excess observed in female IIH patients. Obesity-induced androgen dysregulation may thus contribute to the disease mechanism of IIH and could potentially serve as a future therapeutic target.

Cycle-dependent sex differences in expression of membrane proteins involved in cerebrospinal fluid secretion at rat choroid plexus

BackgroundFemale sex is a known risk factor of brain disorders with raised intracranial pressure (ICP) and sex hormones have been suggested to alter cerebrospinal fluid (CSF) dynamics, thus impairing ICP regulation in CSF disorders such as idiopathic intracranial hypertension (IIH). The choroid plexus (CP) is the tissue producing CSF and it has been hypothesized that altered hormonal composition could affect the activity of transporters involved in CSF secretion, thus affecting ICP. Therefore, we aimed to investigate if expression of various transporters involved in CSF secretion at CP were different between males and females and between females in different estrous cycle states. Steroid levels in serum was also investigated.MethodsFemale and male rats were used to determine sex-differences in the genes encoding for the transporters Aqp1 and 4, NKCC1, NBCe2, NCBE; carbonic anhydrase enzymes II and III (CA), subunits of the Na+/K+-ATPase including Atp1a1, Atp1b1 and Fxyd1 at CP. The estrous cycle stage metestrus (MET) and estrous (ES) were determined before euthanasia. Serum and CP were collected and subjected to RT-qPCR analysis and western blots. Serum was used to measure steroid levels using liquid chromatography tandem mass spectrometry (LC–MS/MS).ResultsSignificant differences in gene expression and steroid levels between males and ES females were found, while no differences were found between male and MET females. During ES, expression of Aqp1 was lower (p < 0.01) and NKCC1 was higher in females compared to males. CAII was lower while CAIII was higher in ES females (p < 0.0001). Gene expression of Atp1a1 was lower in ES compared to male (p = 0.0008). Several of these choroidal genes were also significantly different in MET compared to females in ES. Differences in gene expression during the estrus cycle were correlated to serum level of steroid hormones. Protein expression of AQP1 (p = 0.008) and CAII (p = 0.035) was reduced in ES females compared to males.ConclusionsThis study demonstrates for the first time that expression at CP is sex-dependent and markedly affected by the estrous cycle in female rats. Further, expression was related to hormone levels in serum. This opens a completely new avenue for steroid regulation of the expression of CSF transporters and the close link to the understanding of CSF disorders such as IIH.

The relationship between myodural bridge, atrophy and hyperplasia of the suboccipital musculature, and cerebrospinal fluid dynamics

The Myodural Bridge (MDB) is a physiological structure that is highly conserved in mammals and many of other tetrapods. It connects the suboccipital muscles to the cervical spinal dura mater (SDM) and transmits the tensile forces generated by the suboccipital muscles to the SDM. Consequently, the MDB has broader physiological potentials than just fixing the SDM. It has been proposed that MDB significantly contributes to the dynamics of cerebrospinal fluid (CSF) movements. Animal models of suboccipital muscle atrophy and hyperplasia were established utilizing local injection of BTX-A and ACE-031. In contrast, animal models with surgical severance of suboccipital muscles, and without any surgical operation were set as two types of negative control groups. CSF secretion and reabsorption rates were then measured for subsequent analysis. Our findings demonstrated a significant increase in CSF secretion rate in rats with the hyperplasia model, while there was a significant decrease in rats with the atrophy and severance groups. We observed an increase in CSF reabsorption rate in both the atrophy and hyperplasia groups, but no significant change was observed in the severance group. Additionally, our immunohistochemistry results revealed no significant change in the protein level of six selected choroid plexus-CSF-related proteins among all these groups. Therefore, it was indicated that alteration of MDB-transmitted tensile force resulted in changes of CSF secretion and reabsorption rates, suggesting the potential role that MDB may play during CSF circulation. This provides a unique research insight into CSF dynamics.

In vitro investigation of the effect of proinflammatory cytokines on mouse choroid plexus membrane transporters Ncbe and NKCC1

Intraventricular hemorrhage is a potentially life-threatening condition. Approximately 20% of patients develop posthemorrhagic hydrocephalus with increased ventricular volume and intracranial pressure. Hydrocephalus develops partially due to increased secretion of cerebrospinal fluid by the choroid plexus. During hemorrhage a multitude of factors are released into the cerebrospinal fluid. Many of these have been implicated in the hypersecretion. In this study, we have investigated the isolated effect of inflammatory components, on the abundance of two membrane transporters involved in cerebrospinal fluid secretion by the choroid plexus: the Na+-dependent Cl−/HCO3− exchanger, Ncbe, and the Na+, K+, 2Cl− cotransporter, NKCC1. We have established a primary choroid plexus epithelial cell culture from 1 to 7 days old mouse pups. Seven days after seeding, the cells formed a monolayer. The cells were treated with either tumor necrosis factor alpha (TNFα), interleukin 1 beta (IL-1β), or interleukin 6 (IL-6) to mimic inflammation. The data show that treatment with TNFα, and IL-1β only transiently increased NKCC1 abundance whereas the effect on Ncbe abundance was a transient decrease. IL-6 however significantly increased NKCC1 (242%), the phosphorylated NKCC1 (147%), as well as pSPAK (406%) abundance, but had no effect on Ncbe. This study suggests that the inflammatory pathway involved in hypersecretion primarily is mediated by activation of basolateral receptors in the choroid plexus, mainly facilitated by IL-6. This study highlights the complexity of the pathophysiological circumstances occurring during intraventricular hemorrhage.

Effects of caffeine on intracranial pressure and pain perception in freely moving rats.

Caffeine, a non-selective adenosine receptor (AR) antagonist, is the most consumed psychostimulant in the world. Caffeine has been suggested to regulate cerebrospinal fluid secretion and is known both to alleviate and to trigger headache; however, its effect on the regulation of intracranial pressure (ICP) is not known. Therefore, we aimed to investigate the effects of caffeine on ICP and nociceptive responses. Female Sprague-Dawley rats were implanted with a novel telemetric device for continuous ICP recordings, which allowed for continuous recordings in freely moving rats. A single dose of caffeine (30 or 120 mg/kg intraperitoneally) was given. In a second group (non-implanted), the acute effects of 30 mg/kg caffeine on periorbital threshold using Von Frey testing and spontaneous behavior were utilized using an automated behavioral registration platform (Laboratory, Animal, Behavior, Observation, Registration and Analysis System) in a randomized cross-over study. Quantitative polymerase chain reaction and immunofluorescence were used to localize ARs in the choroid plexus. A single dose of 30 mg/kg caffeine lowered the ICP by 35% at 165 min after administration (saline: 0.16 ± 0.9 vs caffeine: -1.18 ± 0.9 ΔmmHg, p = 0.0098) and lasted up to 12 h. Administration of 120 mg/kg caffeine showed a faster onset of decrease in ICP within 15 min by 50% (p = 0.0018) and lasted up to 12 h. The periorbital pain thresholds were higher after 1 h (saline: 224.6 ± 15.1 vs caffeine: 289.5 ± 8.7 g, p = 0.005) and lasted up to 5 h. Caffeine-treated rats had increased locomotor activity, speed, and changed grooming behavior. Expression of AR1 was found in the choroid plexus. This study demonstrates that caffeine has a lowering effect on ICP as an acute treatment. Interestingly, caffeine acutely caused an increased response in cephalic thresholds supporting hypoalgesic effects. Future studies investigating the beneficial effects of caffeine for elevated ICP are warranted.

Dual function of the choroid plexus: Cerebrospinal fluid production and control of brain ion homeostasis

The choroid plexus is a small monolayered epithelium located in the brain ventricles and serves to secrete the cerebrospinal fluid (CSF) that envelops the brain and fills the central ventricles. The CSF secretion is sustained with a concerted effort of a range of membrane transporters located in a polarized fashion in this tissue. Prominent amongst these are the Na+/K+-ATPase, the Na+,K+,2Cl− cotransporter (NKCC1), and several HCO3− transporters, which together support the net transepithelial transport of the major electrolytes, Na+ and Cl−, and thus drive the CSF secretion. The choroid plexus, in addition, serves an important role in keeping the CSF K+ concentration at a level compatible with normal brain function. The choroid plexus Na+/K+-ATPase represents a key factor in the barrier-mediated control of the CSF K+ homeostasis, as it increases its K+ uptake activity when faced with elevated extracellular K+ ([K+]o). In certain developmental or pathological conditions, the NKCC1 may revert its net transport direction to contribute to CSF K+ homeostasis. The choroid plexus ion transport machinery thus serves dual, yet interconnected, functions with its contribution to electrolyte and fluid secretion in combination with its control of brain K+ levels.

Acetazolamide and topiramate lower intracranial pressure through differential mechanisms: The effect of acute and chronic administration.

Diseases of raised intracranial pressure (ICP) cause severe morbidity and mortality. Multiple drugs are utilised to lower ICP including acetazolamide and topiramate. However, the evidence for their use is unclear. We aimed to assess the ICP modulatory effects and molecular effects at the choroid plexus (CP) of acetazolamide and topiramate. Female rats were implanted with telemetric ICP probes for physiological, freely moving 24/7 ICP recordings. Randomised cross-over studies were performed, where rats received acute (24 h) high doses of acetazolamide and topiramate, and chronic (10days) clinically equivalent doses of acetazolamide and topiramate, all via oral gavage. Cerebrospinal fluid (CSF) secretion assays, and RT-qPCR and western blots on in vitro and in vivo CP, were used to investigate drug actions. We demonstrate that acetazolamide and topiramate achieved maximal ICP reduction within 120 min of administration, and in combination doubled the ICP reduction over a 24-h period. Chronic administration of acetazolamide or topiramate lowered ICP by 25%. Topiramate decreased CSF secretion by 40%. Chronic topiramate increased the gene expression of Slc12a2 and Slc4a10 and protein expression of the sodium-dependent chloride/bicarbonate exchanger (NCBE), whereas chronic acetazolamide did not affect the expression of assessed genes. Acetazolamide and topiramate are effective at lowering ICP at therapeutic levels. We provide the first evidence that topiramate lowers CSF secretion and that acetazolamide and topiramate may lower ICP via distinct molecular mechanisms. Thus, the combination of acetazolamide and topiramate may have utility for treating raised ICP.

Determining the role of novel metabolic pathways in driving intracranial pressure reduction after weight loss.

Idiopathic intracranial hypertension, a disease classically occurring in women with obesity, is characterized by raised intracranial pressure. Weight loss leads to the reduction in intracranial pressure. Additionally, pharmacological glucagon-like peptide-1 agonism reduces cerebrospinal fluid secretion and intracranial pressure. The potential mechanisms by which weight loss reduces intracranial pressure are unknown and were the focus of this study. Meal stimulation tests (fasted plasma sample, then samples at 15, 30, 60, 90 and 120 min following a standardized meal) were conducted pre- and post-bariatric surgery [early (2 weeks) and late (12 months)] in patients with active idiopathic intracranial hypertension. Dynamic changes in gut neuropeptides (glucagon-like peptide-1, gastric inhibitory polypeptide and ghrelin) and metabolites (untargeted ultra-high performance liquid chromatography-mass spectrometry) were evaluated. We determined the relationship between gut neuropeptides, metabolites and intracranial pressure. Eighteen idiopathic intracranial hypertension patients were included [Roux-en-Y gastric bypass (RYGB) n = 7, gastric banding n = 6 or sleeve gastrectomy n = 5]. At 2 weeks post-bariatric surgery, despite similar weight loss, RYGB had a 2-fold (50%) greater reduction in intracranial pressure compared to sleeve. Increased meal-stimulated glucagon-like peptide-1 secretion was observed after RYGB (+600%) compared to sleeve (+319%). There was no change in gastric inhibitory polypeptide and ghrelin. Dynamic changes in meal-stimulated metabolites after bariatric surgery consistently identified changes in lipid metabolites, predominantly ceramides, glycerophospholipids and lysoglycerophospholipids, which correlated with intracranial pressure. A greater number of differential lipid metabolites were observed in the RYGB cohort at 2 weeks, and these also correlated with intracranial pressure. In idiopathic intracranial hypertension, we identified novel changes in lipid metabolites and meal-stimulated glucagon-like peptide-1 levels following bariatric surgery which were associated with changes in intracranial pressure. RYGB was most effective at reducing intracranial pressure despite analogous weight loss to gastric sleeve at 2 weeks post-surgery and was associated with more pronounced changes in these metabolite pathways. We suggest that these novel perturbations in lipid metabolism and glucagon-like peptide-1 secretion are mechanistically important in driving a reduction in intracranial pressure following weight loss in patients with idiopathic intracranial hypertension. Therapeutic targeting of these pathways, for example with glucagon-like peptide-1 agonist infusion, could represent a therapeutic strategy.

Addition of Neostigmine and Atropine to Conventional Management of Postdural Puncture Headache in Patients Undergoing Lower Abdominal Surgeries

Abstract Background Postdural puncture headache (PDPH) is a complication of spinal anesthesia or lumbar puncture and is an unpleasant experience for the patient as well as the anesthetist. It is thought to result from meningeal traction related to low cerebrospinal fluid (CSF) pressure or cerebral vasodilation as an indirect effect of decreased CSF pressure. Neostigmine is a reversible inhibitor of the enzyme cholinesterase, which results in an increased concentration of the neurotransmitter acetylcholine. It produces cholinergic-mediated analgesia and has been used as an adjunct analgesic postoperatively. Neostigmine can pass through the choroid plexus but not the blood–brain barrier, the central effect of both neostigmine and atropine influence both CSF secretion and cerebral vascular tone which are the primary pathophysiological changes in PDPH. Objective Assess the effectiveness of postdural anesthesia with addition of Neostigmine and Atropine versus conventional postdural anesthesia. Patients and Methods A 90 patients were included in our prospective randomized controlled double-blind study that was conducted at Ain Shams University Hospitals for 4 months on patients who fulfilled the inclusion criteria: patients with ASA Grade I &amp; II, aged from (18 to 40) years old and scheduled for cesarean section. All patients aged &amp;gt;18 or &amp;lt;40, body weight &amp;gt;50, ASA III, IV, patients with uncontrolled chronic diseases such as hypertension, cardiac, renal, hepatic, cerebral diseases and peripheral vascular diseases, patients with history of PDPH, chronic headache, cluster headache, migraine, convulsions, cerebrovascular accident, signs of meningismus, preeclampsia, eclampsia coagulopathy, and previous neurological diseases and patients with history of bronchial asthma were excluded. Patients were divided into 2 groups: Group I (experimental group): neostigmine and atropine and Group II (placebo group): Saline placebo. Results The results of this study showed that incidence of postoperative headache was significantly lower among the intervention group, furthermore, VAS was significantly lower in the experimental arm versus placebo one. However, there was no significant difference regarding demographic, vital signs, and need for post-operative analgesia. The presented study showed that there is statistically non-significant difference between the studied groups regarding age, weight, and height and body mass index. There is statistically non-significant difference between the studied groups regarding duration of surgery. Conclusion After demonstrating many management options for post dural puncture headache (PDPH), in this study, we tried to prove the value of the use of neostigmine as a new management option that looks promising to alleviate the symptoms of such distressing condition. The current study results proved that the drug reduced the number of cases that experienced (PDPH) after spinal anesthesia for lower segment caesarean section, and how it prevent &amp;control headache. A combination of neostigmine and atropine are effective in managing PDPH by reducing the associated VAS score and preventing persistence of headache.

Addition of Neostigmine and Atropine to Conventional Management of Postdural Puncture Headache after Cesarean Section: A Randomized Controlled Study

Abstract Background Post dural puncture headache (PDPH) is a known side effect following spinal anesthesia occurring in 2.5-40% of patients, it typically starts after 2 days but may be delayed up to 2 weeks and almost resolves spontaneously within a few days. Classic symptoms of PDPH consist of photophobia, nausea, vomiting, neck stiffness, tinnitus, diplopia and dizziness. Objective The aim of the study is to know if the neostigmine and atropine can improve PDPH treatment when added to conventional management after cesarean sections. Patients and Methods After obtaining approval from research ethics committee of Faculty of Medicine, Ain Shams University and after obtaining informed written consents from the patients. The study was conducted in the operating theaters of Ain Shams University Hospitals. The study period was 6 months after approval of the protocol, computer generated simple randomization. Patients with PDPH and a VAS &amp;lt; 5 were randomly allocated to receive either: Group 1: Slow intravenous injection with 20 µg/Kg neostigmine and 10 µg/Kg atropine in 20 ml 0.9% Saline given over 5 minutes every 8 hours up to 72 hours, Group 2: 20 ml of 0.9% saline intravenous every 8 hours. Results In this study, we compared the efficacy of neostigmine versus placebo (Both groups received the conventional management) in treating the PDPH, All of the 2 groups (neostigmine and Placebo) were effective in lowering VAS scores at 24, 48 and 72 h after headache's onset but neostigmine alleviated the pain more effectively and with rapid onset. The mean VAS score was significantly lower in neostigmine group compared with other group 6, 12, 24, 36, 48 and 72 h after start of medications (p &amp;lt; 0.001 for all of them) Placebo group 6, 12, 24, 36, 48, and 72 h (p &amp;lt; 0.001 for all of them). This may cause the drug to be one of the potential new drug therapies for such distressing condition, especially with its different mechanism of action that differs from other drugs. Conclusion Neostigmine/atropine was effective in treating PDPH after only 2 doses. Neostigmine can pass the choroid plexus but not the blood–brain barrier. The central effects of both drugs influence both cerebrospinal fluid secretion and cerebral vascular tone, which are the primary pathophysiological changes in PDPH. The results are consistent with previous studies and clinical reports of neostigmine activity.

Amyloid-β slows cilia movement along the ventricle, impairs fluid flow, and exacerbates its neurotoxicity in explant culture

Alzheimer’s disease (AD) is characterized by extensive and selective death of neurons and deterioration of synapses and circuits in the brain. The Aβ1–42 concentration is higher in an AD brain than in cognitively normal elderly individuals, and Aβ1–42 exhibits neurotoxicity. Brain-derived Aβ is transported into the cerebrospinal fluid (CSF), and CSF flow is driven in part by the beating of cilia and CSF secretion into ventricles. Ventricles are lined with ependyma whose apical surface is covered with motile cilia. Herein, we constructed an experimental system to measure the movement of ependymal cilia and examined the effects of Aβ1–42 to the beating of cilia and neurons. The circadian rhythm of the beating frequency of ependymal cilia was detected using brain wall explant-cultures containing ependymal cilia and neurons; the beating frequency was high at midday and low at midnight. Aβ1–42 decreased the peak frequency of ciliary beating at midday and slightly increased it at midnight. Aβ1–42 exhibited neurotoxicity to neurons on the non-ciliated side of the explant culture, while the neurotoxicity was less evident in neurons on the ciliated side. The neurotoxic effect of Aβ1–42 was diminished when 1 mPa of shear stress was generated using a flow chamber system that mimicked the flow by cilia. These results indicate that Aβ1–42 affects the circadian rhythm of ciliary beating, decreases the medium flow by the cilia-beating, and enhances the neurotoxic action of Aβ1–42 in the brain explant culture.

Resistance pattern of isolated microorganisms from 783 clinical specimen cultures in patients admitted to Yasuj Educational Hospitals, Iran

BackgroundInfectious diseases are still one of the leading causes of morbidity and mortality in resource-limited settings. Serious infection caused mostly by gram-negative pathogens causes significant morbidity. According to the Centers for Disease Control and Prevention, antimicrobial resistance kills over 700,000 people worldwide. Antibiotic resistance is on the rise, and as a consequence, serious public health issues are arising. The present study investigated isolated clinical samples from Yasuj teaching hospitals to determine the antimicrobial resistance profile to various antibiotics.Materials and methodsMicrobial isolates regarding cultures from urine, blood, wound, abdominal tap, throat, stool, cerebrospinal fluid, endotracheal tube, sputum, skin lesion, nasal, and mouth secretion were collected from patients admitted to hospitals affiliated with Yasuj teaching hospitals. Antibiotic susceptibility profiles were determined by using the Kirby-Bauer disc diffusion method. Data were tabulated and analyzed with SPSS version 26.0.ResultsA total of 783 samples were evaluated in our study, with an average of 30.6 years and 54.5% female patients. Most of the bacterial isolates were gram-negative (64.2%). The majority of cultures were Escherichia coli (49.9%), mainly among urine samples (64.2%). The frequency distribution of norfloxacin antibiotic resistance was more common in internal medicine (66.7%), infectious (63.6%), and emergency wards (58.8%). The frequency distribution of penicillin antibiotic resistance was statistically significant in different wards. All cases of oxacillin were resistant.ConclusionOur data showed a high level of antibiotic resistance among bacterial isolates in our center. Considering widespread empirical antibiotic therapy in Iran, the rate of increasing resistance to common antibiotics prescribed for ambulatory and hospitalized patients is concerning. We recommend providing more strict guidelines and policies to control the overuse and overprescription of antimicrobials by health policy-making organizations.

Day-night fluctuations in choroid plexus transcriptomics and cerebrospinal fluid metabolomics.

The cerebrospinal fluid (CSF) provides mechanical protection for the brain and serves as a brain dispersion route for nutrients, hormones, and metabolic waste. The CSF secretion rate is elevated in the dark phase in both humans and rats, which could support the CSF flow along the paravascular spaces that may be implicated in waste clearance. The similar diurnal CSF dynamics pattern observed in the day-active human and the nocturnal rat suggests a circadian regulation of this physiological variable, rather than sleep itself. To obtain a catalog of potential molecular drivers that could provide the day-night-associated modulation of the CSF secretion rate, we determined the diurnal fluctuation in the rat choroid plexus transcriptomic profile with RNA-seq and in the CSF metabolomics with ultraperformance liquid chromatography combined with mass spectrometry. We detected significant fluctuation of 19 CSF metabolites and differential expression of 2,778 choroid plexus genes between the light and the dark phase, the latter of which encompassed circadian rhythm-related genes and several choroid plexus transport mechanisms. The fluctuating components were organized with joint pathway analysis, of which several pathways demonstrated diurnal regulation. Our results illustrate substantial transcriptional and metabolic light-dark phase-mediated changes taking place in the rat choroid plexus and its encircling CSF. The combined data provide directions toward future identification of the molecular pathways governing the fluctuation of this physiological process and could potentially be harnessed to modulate the CSF dynamics in pathology.

Spontaneously hypertensive rats can become hydrocephalic despite undisturbed secretion and drainage of cerebrospinal fluid

BackgroundHydrocephalus constitutes a complex neurological condition of heterogeneous origin characterized by excessive cerebrospinal fluid (CSF) accumulation within the brain ventricles. The condition may dangerously elevate the intracranial pressure (ICP) and cause severe neurological impairments. Pharmacotherapies are currently unavailable and treatment options remain limited to surgical CSF diversion, which follows from our incomplete understanding of the hydrocephalus pathogenesis. Here, we aimed to elucidate the molecular mechanisms underlying development of hydrocephalus in spontaneously hypertensive rats (SHRs), which develop non-obstructive hydrocephalus without the need for surgical induction.MethodsMagnetic resonance imaging was employed to delineate brain and CSF volumes in SHRs and control Wistar-Kyoto (WKY) rats. Brain water content was determined from wet and dry brain weights. CSF dynamics related to hydrocephalus formation in SHRs were explored in vivo by quantifying CSF production rates, ICP, and CSF outflow resistance. Associated choroid plexus alterations were elucidated with immunofluorescence, western blotting, and through use of an ex vivo radio-isotope flux assay.ResultsSHRs displayed brain water accumulation and enlarged lateral ventricles, in part compensated for by a smaller brain volume. The SHR choroid plexus demonstrated increased phosphorylation of the Na+/K+/2Cl− cotransporter NKCC1, a key contributor to choroid plexus CSF secretion. However, neither CSF production rate, ICP, nor CSF outflow resistance appeared elevated in SHRs when compared to WKY rats.ConclusionHydrocephalus development in SHRs does not associate with elevated ICP and does not require increased CSF secretion or inefficient CSF drainage. SHR hydrocephalus thus represents a type of hydrocephalus that is not life threatening and that occurs by unknown disturbances to the CSF dynamics.

Nocturnal increase in cerebrospinal fluid secretion as a circadian regulator of intracranial pressure

BackgroundIt is crucial to maintain the intracranial pressure (ICP) within the physiological range to ensure proper brain function. The ICP may fluctuate during the light-dark phase cycle, complicating diagnosis and treatment choice in patients with pressure-related disorders. Such ICP fluctuations may originate in circadian or sleep-wake cycle-mediated modulation of cerebrospinal fluid (CSF) flow dynamics, which in addition could support diurnal regulation of brain waste clearance.MethodsICP was monitored continuously in patients who underwent placement of an external ventricular drain (EVD) and by telemetric monitoring in experimental rats. CSF was collected via the EVD in patients and the rodent CSF secretion rate determined by in vivo experimentation. Rodent choroid plexus transporter transcripts were quantified with RNAseq and transport activity with ex vivo isotope transport assays.ResultsWe demonstrated that ICP increases by 30% in the dark phase in both species, independently of vascular parameters. This increase aligns with elevated CSF collection in patients (12%) and CSF production rate in rats (20%), the latter obtained with the ventriculo-cisternal perfusion assay. The dark-phase increase in CSF secretion in rats was, in part, assigned to increased transport activity of the choroid plexus Na+,K+,2Cl- cotransporter (NKCC1), which is implicated in CSF secretion by this tissue.ConclusionCSF secretion, and thus ICP, increases in the dark phase in humans and rats, irrespective of their diurnal/nocturnal activity preference, in part due to altered choroid plexus transport activity in the rat. Our findings suggest that CSF dynamics are modulated by the circadian rhythm, rather than merely sleep itself.