-
Brain Research Dec 2023Epileptic activity is known to cause a lowering of intraneuronal pH, which has been suggested to serve as a feedback signal to terminate seizures. The mechanism of such...
Epileptic activity is known to cause a lowering of intraneuronal pH, which has been suggested to serve as a feedback signal to terminate seizures. The mechanism of such signaling is unclear, but likely involves an altered function of several types of ligand- and voltage-gated channels in postsynaptic membranes caused by increasing cytosolic and extracellular [H]. In addition, axonal conduction properties may be altered by endogenous pH signals, but this has not been investigated. In the present study, we have recorded the axonal compound action potential (fiber volley) in hippocampal slices in the presence of glutamatergic and GABAergic antagonists. During high-frequency stimulation (HFS) of the Schaffer collaterals, the fiber volley was depressed and its latency from stimulus to peak increased. In the CA1 stratum radiatum these changes were enhanced when the carbonic anhydrase inhibitor acetazolamide (1 mM) was co-perfused. The enhancing effect of acetazolamide was absent after lowering of [Ca] in the perfusion medium. Acetazolamide had no detectable effect on HFS-evoked fiber volleys recorded from a more proximal site along the Schaffer collaterals (at the CA2-CA3 border) or from axons in the alveus of CA1. Intracellular acidification imposed by washout of NHCl (5 mM) had qualitatively similar effects on fiber volleys evoked at low frequency as those observed with acetazolamide during HFS in CA1 stratum radiatum. The results suggest that carbonic anhydrase-dependent pH regulation counteracts activity-induced reduction of the excitability of Schaffer collateral axons in CA1. A possible influence from local synaptic terminals on this effect is discussed.
Topics: Acetazolamide; Action Potentials; Hippocampus; Axons; CA1 Region, Hippocampal; Electric Stimulation
PubMed: 37748571
DOI: 10.1016/j.brainres.2023.148604 -
Cancers Sep 2023Aquaporin (AQP) channels in endometrial cancer (EC) cells are of interest as pharmacological targets to reduce tumor progression. A panel of compounds, including AQP1...
Aquaporin (AQP) channels in endometrial cancer (EC) cells are of interest as pharmacological targets to reduce tumor progression. A panel of compounds, including AQP1 ion channel inhibitors (AqB011 and 5-(phenoxymethyl) furan-2-carbaldehyde, PMFC), were used to test the hypothesis that inhibition of key AQPs can limit the invasiveness of low- and high-grade EC cells. We evaluated the effects on transwell migration in EC cell lines (Ishikawa, MFE-280) and primary EC cells established from surgical tissues ( = 8). Quantitative PCR uncovered classes of not previously reported in EC that are differentially regulated by hormonal signaling. With estradiol, Ishikawa showed increased , , , and decreased and ; MFE-280 showed increased , , , , , and decreased . Protein expression was confirmed by Western blot and immunocytochemistry. AQPs 1, 4, and 11 were colocalized with plasma membrane marker; AQP8 was intracellular in Ishikawa and not detectable in MFE-280. AQP1 ion channel inhibitors (AqB011; PMFC) reduced invasiveness of EC cell lines in transwell chamber and spheroid dispersal assays. In Ishikawa cells, transwell invasiveness was reduced ~41% by 80 µM AqB011 and ~55% by 0.5 mM 5-PMFC. In MFE-280, 5-PMFC inhibited invasion by ~77%. In contrast, proposed inhibitors of AQP water pores (acetazolamide, ginsenoside, KeenMind, TGN-020, IMD-0354) were not effective. Treatments of cultured primary EC cells with AqB011 or PMFC significantly reduced the invasiveness of both low- and high-grade primary EC cells in transwell chambers. We confirmed the tumors expressed moderate to high levels of AQP1 detected by immunohistochemistry, whereas expression levels of AQP4, AQP8, and AQP11 were substantially lower. The anti-invasive potency of AqB011 treatment for EC tumor tissues showed a positive linear correlation with AQP1 expression levels. In summary, AQP1 ion channels are important for motility in both low- and high-grade EC subtypes. Inhibition of AQP1 is a promising strategy to inhibit EC invasiveness and improve patient outcomes.
PubMed: 37760476
DOI: 10.3390/cancers15184507 -
Cureus Apr 2024The morning glory (MG) disc anomaly is a congenital excavation of the posterior globe involving the optic disc, with a distinct appearance reminiscent of the MG flower....
The morning glory (MG) disc anomaly is a congenital excavation of the posterior globe involving the optic disc, with a distinct appearance reminiscent of the MG flower. Various intracranial and ocular associations with MG have been documented. Conditions such as trans-sphenoidal encephalocele and hypoplasia of the intracranial vasculature have been observed in association with this anomaly. In this report, we present a case of MG optic disc anomaly accompanied by serous macular detachment.
PubMed: 38721220
DOI: 10.7759/cureus.57817 -
American Journal of Ophthalmology Case... Dec 2023Papilledema is a very rare complication of leukemia therapies, and particularly tyrosine kinase inhibitor (TKI) therapy. Targeted oncologic therapies are becoming...
PURPOSE
Papilledema is a very rare complication of leukemia therapies, and particularly tyrosine kinase inhibitor (TKI) therapy. Targeted oncologic therapies are becoming increasingly popular, so it is increasingly important to report rare adverse effects. We present a case of probable papilledema in the setting of ponatinib therapy for acute lymphoblastic leukemia.
OBSERVATIONS
Our patient is a 48-year-old male who was diagnosed with acute lymphocytic leukemia. He underwent stem cell transplantation and shortly after was placed on ponatinib therapy. After initiation of ponatinib, he began to note decreased clarity in the inferonasal visual field of his right eye, corroborated on Humphrey visual field (HVF) testing. Neuroimaging was only notable for a partially empty sella. Lumbar puncture demonstrated opening pressures at the upper limit of normal (23 cm H2O) but with normal cellular constituents and chemistry. Slit lamp exam did not reveal any signs of ocular inflammation. Dilated funduscopic examination (DFE) revealed 360-degree blurring of the right optic disc margin as well as 270-degree blurring of the left optic disc (sparing the temporal border). Optical coherence tomography of the retinal nerve fiber layer (OCT-RNFL) showed increased RNFL thickness of 272 μm in the right eye and 113 μm in the left eye. In the absence of evidence for other possible etiologies of optic disc edema, ponatinib-induced papilledema was suspected. No changes to the ponatinib regimen were made; however, the patient was started on acetazolamide 500 mg twice a day. At three-month follow up, the patient reported resolution of his right eye blurriness and his repeat HVF, OCT-RNFL, and DFE showed resolution of optic disc edema, supporting that his initial bilateral optic disc swelling was likely ponatinib-induced papilledema.
CONCLUSIONS AND IMPORTANCE
This is the first report of probable ponatinib-induced papilledema. This case expands on the literature of TKI induced papilledema and demonstrates successful treatment with an oral acetazolamide regimen.
PubMed: 38077783
DOI: 10.1016/j.ajoc.2023.101933 -
Pharmaceutics Mar 2024Human carbonic anhydrase IX (hCA IX) is a zinc(II)-dependent metalloenzyme that plays a critical role in the conversion of carbon dioxide and water to protons and...
Human carbonic anhydrase IX (hCA IX) is a zinc(II)-dependent metalloenzyme that plays a critical role in the conversion of carbon dioxide and water to protons and bicarbonate. It is a membrane-bound protein with an extracellular catalytic center that is predominantly overexpressed in solid hypoxic tumors. Sulfamates and sulfonamides, for example acetazolamide (AZA), have been used to inhibit hCA IX in order to improve the response to solid hypoxic tumors. In the present study, we propose a new drug targeting approach by attaching the natural cytotoxic substances betulin and betulinic acid (BA) via a linker to sulfonamides. The conjugate was designed with different spacer lengths to accumulate at the target site of hCA IX. Computational and cell biological studies suggest that the length of the linker may influence hCA IX inhibition. Cytotoxicity tests of the newly synthesized bifunctional conjugates 3, 5, and 9 show effective cytotoxicity in the range of 6.4 and 30.1 µM in 2D and 3D tumor models. The hCA IX inhibition constants of this conjugates, measured using an in vitro enzyme assay with -nitrophenyl acetate, were determined in a low µM-range, and all compounds reveal a significant inhibition of hypoxia-induced CA activity in a cell-based assay using the Wilbur-Anderson method. In addition, the cells respond with G1 increase and apoptosis induction. Overall, the dual strategy to produce cytotoxic tumor therapeutics that inhibit tumor-associated hCA IX was successfully implemented.
PubMed: 38543295
DOI: 10.3390/pharmaceutics16030401 -
Journal of Pediatric Genetics Dec 2023Hyperphosphatemic familial tumoral calcinosis (HFTC) presents with varied neurological manifestations that have been reported in the literature like facial palsy, vision...
Hyperphosphatemic familial tumoral calcinosis (HFTC) presents with varied neurological manifestations that have been reported in the literature like facial palsy, vision and hearing impairment, stroke, and headache. In this article, we reported a 12-year-old girl child patient with recurrent facial weakness with bilateral hearing impairment and multiple ulcerative lesions on lower limbs and elbows. On examination, she had lower motor neuron (LMN) facial palsy with conductive hearing loss. The investigations showed hyperphosphatemia (9.3 mg/dL) with normal serum calcium (10.4 mg/dL), alkaline phosphatase (147.9 U/L), parathyroid hormone (23.12 pg/mL), and renal function tests. Elevated serum calcium and phosphorus product (96.72 mg /mL ) and elevated renal tubular reabsorption of phosphate (TMPxGFR) value (9.16) were noted. Skeletal survey showed hyperostosis in the long bone diaphysis, vertebrae, ribs, pelvic bone, skull, and facial bones with narrowing of cranial ostium, characteristically without any peri-articular soft tissue calcifications. An angiogram showed multiple intravascular calcifications. She was managed with a low-phosphate diet, sevelamer, niacinamide, acetazolamide, sucroferric oxyhydroxide to lower serum phosphate level, and topical sodium thiosulfate ectopic cutaneous calcification. Exome sequencing showed novel homozygous inframe deletion of ACG in gene exon 3 at c.374_376 delins position (p. Asp125del) in the proband and a mutation in the heterozygous state in the mother and elder sibling, thus confirming a molecular diagnosis of HFTC. Our case had a unique neurological presentation of recurrent bilateral lower motor nerve facial palsy, hearing loss, multiple ectopic cutaneous calcifications without peri-articular deposits, multiple intravascular, intracranial, and vertebral endplate calcification, which has not been reported earlier. The proband showed a novel pathogenic variant suggesting an expanding phenotype of HFTC.
PubMed: 38162162
DOI: 10.1055/s-0041-1741522 -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... Dec 2023To explore the effects of hypoxic and hypobaric conditions on blood gas and erythrocyte-related indicators in rats.
OBJECTIVES
To explore the effects of hypoxic and hypobaric conditions on blood gas and erythrocyte-related indicators in rats.
METHODS
SD male rats were exposed to low-pressure hypoxic conditions simulating an altitude of 6500 m in a small or a large experimental cabin. Abdominal aortic blood samples were collected and blood gas indicators, red blood cells (RBCs) count, and hemoglobin (Hb) content were measured. The effects of exposure to different hypoxia times, different hypoxia modes, normal oxygen recovery after hypoxia, and re-hypoxia after hypoxia preconditioning on blood gas indicators, RBCs count and Hb content were investigated.
RESULTS
The effect of blood gas indicators was correlated with the length of exposure time of hypoxia and the reoxygenation after leaving the cabin. Hypoxia caused acid-base imbalance and its severity was associated with the duration of hypoxia; hypoxia also led to an increase in RBCs count and Hb content, and the increase was also related to the time exposed to hypoxia. The effects of reoxygenation on acid-base imbalance in rats caged in a small animal cabin were more severe that those in a large experimental cabin. Acetazolamide alleviated the effects of reoxygenation after leaving the cabin. Different hypoxia modes and administration of acetazolamide had little effect on RBCs count and Hb content. Normal oxygen recovery can alleviate the reoxygenation and acid-base imbalance of hypoxic rats after leaving the cabin and improve the increase in red blood cell and hemoglobin content caused by hypoxia. The improvement of hypoxia preconditioning on post hypoxia reoxygenation is not significant, but it can alleviate the acid-base imbalance caused by hypoxia in rats and to some extent improve the increase in red blood cell and hemoglobin content caused by hypoxia.
CONCLUSIONS
Due to excessive ventilation and elevated RBCs count and Hb content after hypoxia reoxygenation, oxygen partial pressure and other oxygenation indicators in hypoxic rats are prone to become abnormal, while blood gas acid-base balance indicators are relatively stable, which are more suitable for evaluating the degree of hypoxia injury and related pharmacological effects in rats.
Topics: Rats; Animals; Male; Acetazolamide; Hypoxia; Oxygen; Erythrocytes; Hemoglobins; Acid-Base Imbalance
PubMed: 38105680
DOI: 10.3724/zdxbyxb-2023-0352 -
Journal of Vitreoretinal Diseases 2024To present a rare case of subfoveal choroidal neovascular membrane (CNVM) secondary to idiopathic intracranial hypertension. A case was evaluated. A 21-year-old woman...
To present a rare case of subfoveal choroidal neovascular membrane (CNVM) secondary to idiopathic intracranial hypertension. A case was evaluated. A 21-year-old woman presented with a 2-week history of painless blurred vision in the right eye. She described initial metamorphopsia and intermittent bitemporal headaches lasting 30 minutes. She denied pain with eye movements and a history of trauma. Her body mass index was 49 kg/m. The visual acuity (VA) was 20/320 OD and 20/20 OS; there was no relative afferent pupillary defect. A dilated fundus examination showed bilateral optic disc edema and a subfoveal CNVM in the right eye. The patient was started on oral acetazolamide 500 mg twice daily and treated with 2 intravitreal antivascular endothelial growth factor (anti-VEGF) injections. Three months later, the VA was 20/30 in the right eye and the disc edema had improved. CNVMs in the setting of idiopathic intracranial hypertension-related papilledema may be subfoveal and have an excellent response to anti-VEGF agents.
PubMed: 38465349
DOI: 10.1177/24741264231218539 -
Cureus Aug 2023Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is the most common immune-mediated inflammatory polyneuropathy, defined as progressive or relapsing...
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is the most common immune-mediated inflammatory polyneuropathy, defined as progressive or relapsing symptoms for over two months with pathological or electrophysiological evidence of peripheral nerve demyelination. Papilledema is optic nerve head edema secondary to increased intracranial pressure or infiltrative/infectious etiologies. Regardless of the cause, visual loss is one of the feared manifestations due to optic nerve damage. We present a 50-year-old female patient with CIDP who developed papilledema that was secondary to increased intracranial pressure from high protein content in the cerebrospinal fluid (CSF) and elevated body mass index (BMI) secondary to prednisone use. Treatment with acetazolamide completely resolved the papilledema and headaches, and the patient was later maintained on mycophenolate, intravenous immunoglobulin (IVIG), rituximab, and prednisone. To the best of our knowledge, this is the first case that describes successful medical management of increased intracranial pressure in the setting of CIDP.
PubMed: 37719616
DOI: 10.7759/cureus.43648 -
Frontiers in Physiology 2023We aimed to demonstrate non-invasive measurements of regional oxygen extraction fraction (OEF) from quantitative BOLD MRI modeling at baseline and after pharmacological...
We aimed to demonstrate non-invasive measurements of regional oxygen extraction fraction (OEF) from quantitative BOLD MRI modeling at baseline and after pharmacological vasodilation. We hypothesized that OEF decreases in response to vasodilation with acetazolamide (ACZ) in healthy conditions, reflecting compensation in regions with increased cerebral blood flow (CBF), while cerebral metabolic rate of oxygen (CMRO) remained unchanged. We also aimed to assess the relationship between OEF and perfusion in the default mode network (DMN) regions that have shown associations with vascular risk factors and cerebrovascular reactivity in different neurological conditions. Eight healthy subjects (47 ± 13 years, 6 female) were scanned on a 3 T scanner with a 32-channel head coil before and after administration of 15 mg/kg ACZ as a pharmacological vasodilator. The MR imaging acquisition protocols included: 1) A Gradient Echo Slice Excitation Profile Imaging Asymmetric Spin Echo scan to quantify OEF, deoxygenated blood volume, and reversible transverse relaxation rate (R ) and 2) a multi-post labeling delay arterial spin labeling scan to measure CBF. To assess changes in each parameter due to vasodilation, two-way -tests were performed for all pairs (baseline versus vasodilation) in the DMN brain regions with Bonferroni correction for multiple comparisons. The relationships between CBF versus OEF and CBF versus R' were analyzed and compared across DMN regions using linear, mixed-effect models. During vasodilation, CBF significantly increased in the medial frontal cortex (), posterior cingulate gyrus (pCG) (), precuneus cortex (PCun) (), and occipital pole (). Concurrently, a significant decrease in OEF was observed only in the pCG (8.8%, ) and PCun (). CMRO showed a trend of increased values after vasodilation, but these differences were not significant after correction for multiple comparisons Although R' showed a slightly decreasing trend, no statistically significant changes were found in any regions in response to ACZ. The CBF response to ACZ exhibited a stronger negative correlation with OEF (; ), than with R' (; ). Quantitative BOLD modeling can reliably measure OEF across multiple physiological conditions and captures vascular changes with higher sensitivity than R' values. The inverse correlation between OEF and CBF across regions in DMN, suggests that these two measurements, in response to ACZ vasodilation, are reliable indicators of tissue health in this healthy cohort.
PubMed: 37869717
DOI: 10.3389/fphys.2023.1231793