Effects of L-Type Voltage-Gated Calcium Channel (LTCC) Inhibition on Hippocampal Neuronal Death after Pilocarpine-Induced Seizure.

Epilepsy, marked by abnormal and excessive brain neuronal activity, is linked to the activation of L-type voltage-gated calcium channels (LTCCs) in neuronal membranes. LTCCs facilitate the entry of calcium (Ca2+) and other metal ions, such as zinc (Zn2+) and magnesium (Mg2+), into the cytosol. This Ca2+ influx at the presynaptic terminal triggers the release of Zn2+ and glutamate to the postsynaptic terminal. Zn2+ is then transported to the postsynaptic neuron via LTCCs. The resulting Zn2+ accumulation in neurons significantly increases the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, contributing to reactive oxygen species (ROS) generation and neuronal death. Amlodipine (AML), typically used for hypertension and coronary artery disease, works by inhibiting LTCCs. We explored whether AML could mitigate Zn2+ translocation and accumulation in neurons, potentially offering protection against seizure-induced hippocampal neuronal death. We tested this by establishing a rat epilepsy model with pilocarpine and administering AML (10 mg/kg, orally, daily for 7 days) post-epilepsy onset. We assessed cognitive function through behavioral tests and conducted histological analyses for Zn2+ accumulation, oxidative stress, and neuronal death. Our findings show that AML's LTCC inhibition decreased excessive Zn2+ accumulation, reactive oxygen species (ROS) production, and hippocampal neuronal death following seizures. These results suggest amlodipine's potential as a therapeutic agent in seizure management and mitigating seizures' detrimental effects.

Efficient fusion requires a membrane anchor on the vacuolar Qa-SNARE.

As a prelude to fusion, the R-SNARE on one membrane zippers with Qa-, Qb-, and Qc-SNAREs from its apposed fusion partner, forming a four-helical bundle that draws the two membranes together. Because Qa- and Qb-SNAREs are anchored to the same membrane and are adjacent in the 4-SNARE bundle, their two anchors might be redundant. Using the recombinant pure protein catalysts of yeast vacuole fusion, we now report that the specific distribution of transmembrane (TM) anchors on the Q-SNAREs is critical for efficient fusion. A TM anchor on the Qa-SNARE supports rapid fusion even when the other two Q-SNAREs are unanchored, while a TM anchor on the Qb-SNARE is dispensable and is insufficient for rapid fusion as the sole Q-SNARE anchor. This does not depend on which specific TM domain is attached to the Qa-SNARE but rather is due to the Qa-SNARE being anchored per se. The need for Qa-SNARE anchoring is even seen when the homotypic fusion and vacuole protein sorting protein (HOPS), the physiological catalyst of tethering and SNARE assembly, is replaced by an artificial tether. The need for a Qa TM anchor is thus a fundamental property of vacuolar SNARE zippering-induced fusion and may reflect the need for the Qa juxtamembrane (JxQa) region to be anchored between its SNARE and TM domains. This requirement for Qa-SNARE anchoring and correct JxQa position is bypassed by Sec17/Sec18, exploiting a platform of partially zippered SNAREs. Because Qa is the only synaptic Q-SNARE with a TM anchor, the need for Qa-specific anchoring may reflect a general requirement for SNARE-mediated fusion.

Fusion with wild-type SNARE domains is controlled by juxtamembrane domains, transmembrane anchors, and Sec17.

Membrane fusion requires tethers, SNAREs of R, Qa, Qb, and Qc families, and chaperones of the SM, Sec17/SNAP, and Sec18/NSF families. SNAREs have N-domains, SNARE domains that zipper into 4-helical RQaQbQc coiled coils, a short juxtamembrane (Jx) domain, and (often) a C-terminal transmembrane anchor. We reconstitute fusion with purified components from yeast vacuoles, where the HOPS protein combines tethering and SM functions. The vacuolar Rab, lipids, and R-SNARE activate HOPS to bind Q-SNAREs and catalyze trans-SNARE associations. With SNAREs initially disassembled, as they are on the organelle, we now report that R- and Qa-SNAREs require their physiological juxtamembrane (Jx) regions for fusion. Swap of the Jx domain between the R- and Qa-SNAREs blocks fusion after SNARE association in trans. This block is bypassed by either Sec17, which drives fusion without requiring complete SNARE zippering, or transmembrane-anchored Qb-SNARE in complex with Qa. The abundance of the trans-SNARE complex is not the sole fusion determinant, as it is unaltered by Sec17, Jx swap, or the Qb-transmembrane anchor. The sensitivity of fusion to Jx swap in the absence of a Qb transmembrane anchor is inherent to the SNAREs, because it remains when a synthetic tether replaces HOPS.

Fusion of tethered membranes can be driven by Sec18/NSF and Sec17/αSNAP without HOPS.

Yeast vacuolar membrane fusion has been reconstituted with R, Qa, Qb, and Qc-family SNAREs, Sec17/αSNAP, Sec18/NSF, and the hexameric HOPS complex. HOPS tethers membranes and catalyzes SNARE assembly into RQaQbQc trans-complexes which zipper through their SNARE domains to promote fusion. Previously, we demonstrated that Sec17 and Sec18 can bypass the requirement of complete zippering for fusion (Song et al., 2021), but it has been unclear whether this activity of Sec17 and Sec18 is directly coupled to HOPS. HOPS can be replaced for fusion by a synthetic tether when the three Q-SNAREs are pre-assembled. We now report that fusion intermediates with arrested SNARE zippering, formed with a synthetic tether but without HOPS, support Sec17/Sec18-triggered fusion. This zippering-bypass fusion is thus a direct result of Sec17 and Sec18 interactions: with each other, with the platform of partially zippered SNAREs, and with the apposed tethered membranes. As these fusion elements are shared among all exocytic and endocytic traffic, Sec17 and Sec18 may have a general role in directly promoting fusion.

Reversible Cerebral Vasoconstriction Syndrome Associated with Levonorgestrel-Releasing Intrauterine System.

Reversible cerebral vasoconstriction syndromes (RCVS) is a rare disease that is characterized by reversible multifocal stenosis of the cerebral arteries with various clinical manifestations. Though the pathomechanism of RCVS was unclear, we reported RCVS related to the levonorgestrel-releasing intrauterine system (IUS). A previous healthy 36-year-old woman had thunderclap headache after implanting the levonorgestrel-releasing IUS a year ago. In the serial angiography, we initially found left vertebra artery (VA), and then additionally new stenosis of both anterior cerebral arteries and middle cerebral arteries (MCA). Bilateral MCA stenosis improved but developed stenosis of right VA after a week. The mean flow velocities of both MCA increased in the first transcranial doppler (TCD), but normalized in the follow up TCD. Levonorgestrel might act as the vasoconstrictitve factor that increased the level of endothelin-1, diminished the release of NO and raised oxidative low-density lipoprotein (LDL). Although the exact pathological mechanisms for RCVS were not yet elucidated, this case might help clinicians understand the mechanisms of RCVS.

Sec17/Sec18 can support membrane fusion without help from completion of SNARE zippering.

Membrane fusion requires R-, Qa-, Qb-, and Qc-family SNAREs that zipper into RQaQbQc coiled coils, driven by the sequestration of apolar amino acids. Zippering has been thought to provide all the force driving fusion. Sec17/αSNAP can form an oligomeric assembly with SNAREs with the Sec17 C-terminus bound to Sec18/NSF, the central region bound to SNAREs, and a crucial apolar loop near the N-terminus poised to insert into membranes. We now report that Sec17 and Sec18 can drive robust fusion without requiring zippering completion. Zippering-driven fusion is blocked by deleting the C-terminal quarter of any Q-SNARE domain or by replacing the apolar amino acids of the Qa-SNARE that face the center of the 4-SNARE coiled coils with polar residues. These blocks, singly or combined, are bypassed by Sec17 and Sec18, and SNARE-dependent fusion is restored without help from completing zippering.

A Rab prenyl membrane-anchor allows effector recognition to be regulated by guanine nucleotide.

Membrane fusion is catalyzed by conserved proteins R, Qa, Qb, and Qc SNAREs, which form tetrameric RQaQbQc complexes between membranes; SNARE chaperones of the SM, Sec17/αSNAP, and Sec18/NSF families; Rab-GTPases (Rabs); and Rab effectors. Rabs are anchored to membranes by C-terminal prenyl groups, but can also function when anchored by an apolar polypeptide. Rabs are regulated by GTPase-activating proteins (GAPs), activating the hydrolysis of bound GTP. We have reconstituted fusion with pure components from yeast vacuoles including SNAREs, the HOPS (homotypic fusion and vacuole protein sorting) tethering and SNARE-assembly complex, and the Rab Ypt7, bound to membranes by either C-terminal prenyl groups (Ypt7-pr) or a recombinant transmembrane anchor (Ypt7-tm). We now report that HOPS-dependent fusion occurs with Ypt7 anchored by either means, but only Ypt7-pr requires GTP for activation and is inactive either with bound GDP or without bound guanine nucleotide. In contrast, Ypt7-tm is constitutively active for HOPS-dependent fusion, independent of bound guanine nucleotide. Fusion inhibition by the GAP Gyp1-46 is not limited to Ypt7-tm with bound GTP, indicating that this GAP has an additional mode of regulating fusion. Phosphorylation of HOPS by the vacuolar kinase Yck3 renders fusion strictly dependent on GTP-activated Ypt7, whether bound to membranes by prenyl or transmembrane anchor. The binding of GTP or GDP constitutes a selective switch for Ypt7, but with Ypt7-tm, this switch is only read by HOPS after phosphorylation to P-HOPS by its physiological kinase Yck3. The prenyl anchor of Ypt7 allows both HOPS and P-HOPS to be regulated by Ypt7-bound guanine nucleotide.

Asymmetric Rab activation of vacuolar HOPS to catalyze SNARE complex assembly.

Intracellular membrane fusion requires Rab-family GTPases, their effector tethers, soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins, and SNARE chaperones of the Sec1/Munc18 (SM), Sec17/α-SNAP, and Sec18/NSF families. We have developed an assay using fluorescence resonance energy transfer to measure SNARE complex formation in real time. We now show that yeast vacuolar SNAREs assemble spontaneously into RQaQbQc complexes when the R- and Qa-SNAREs are concentrated in the same micelles or in cis on the same membrane. When SNAREs are free in solution or are tethered to distinct membranes, assembly requires catalysis by HOPS, the vacuolar SM and tethering complex. The Rab Ypt7 and vacuole lipids together allosterically activate the bound HOPS for catalyzing SNARE assembly, even if none of the SNAREs are membrane bound. HOPS-dependent fusion between proteoliposomes bearing R- or Qa-SNAREs shows a strict requirement for Ypt7 on the R-SNARE proteoliposomes but not on the Qa-SNARE proteoliposomes. This asymmetry is reflected in the strikingly different capacity of Ypt7 in cis to either the R- or Qa-SNARE to stimulate SNARE complex assembly. Membrane-bound Ypt7 activates HOPS to catalyze 4-SNARE complex assembly when it is on the same membrane as the R-SNARE but not the Qa-SNARE, thus explaining the asymmetric need for Ypt7 for fusion.

HOPS recognizes each SNARE, assembling ternary trans-complexes for rapid fusion upon engagement with the 4th SNARE.

Yeast vacuole fusion requires R-SNARE, Q-SNAREs, and HOPS. A HOPS SM-family subunit binds the R- and Qa-SNAREs. We now report that HOPS binds each of the four SNAREs. HOPS catalyzes fusion when the Q-SNAREs are not pre-assembled, ushering them into a functional complex. Co-incubation of HOPS, proteoliposomes bearing R-SNARE, and proteoliposomes with any two Q-SNAREs yields a rapid-fusion complex with 3 SNAREs in a trans-assembly. The missing Q-SNARE then induces sudden fusion. HOPS can 'template' SNARE complex assembly through SM recognition of R- and Qa-SNAREs. Though the Qa-SNARE is essential for spontaneous SNARE assembly, HOPS also assembles a rapid-fusion complex between R- and QbQc-SNARE proteoliposomes in the absence of Qa-SNARE, awaiting Qa for fusion. HOPS-dependent fusion is saturable at low concentrations of each Q-SNARE, showing binding site functionality. HOPS thus tethers membranes and recognizes each SNARE, assembling R+Qa or R+QbQc rapid fusion intermediates.

Tethering guides fusion-competent trans-SNARE assembly.

R-SNAREs (soluble N-ethylmaleimide-sensitive factor receptor), Q-SNAREs, and Sec1/Munc18 (SM)-family proteins are essential for membrane fusion in exocytic and endocytic trafficking. The yeast vacuolar tethering/SM complex HOPS (homotypic fusion and vacuole protein sorting) increases the fusion of membranes bearing R-SNARE to those with 3Q-SNAREs far more than it enhances their trans-SNARE pairings. We now report that the fusion of these proteoliposomes is also supported by GST-PX or GST-FYVE, recombinant dimeric proteins which tether by binding the phosphoinositides in both membranes. GST-PX is purely a tether, as it supports fusion without SNARE recognition. GST-PX tethering supports the assembly of new, active SNARE complexes rather than enhancing the function of the fusion-inactive SNARE complexes which had spontaneously formed in the absence of a tether. When SNAREs are more disassembled, as by Sec17, Sec18, and ATP (adenosine triphosphate), HOPS is required, and GST-PX does not suffice. We propose a working model where tethering orients SNARE domains for parallel, active assembly.

Blockade of AMPA Receptor Regulates Mitochondrial Dynamics by Modulating ERK1/2 and PP1/PP2A-Mediated DRP1-S616 Phosphorylations in the Normal Rat Hippocampus.

N-Methyl-D-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activations induce fast and transient mitochondrial fragmentation under pathophysiological conditions. However, it is still unknown whether NMDAR or AMPAR activity contributes to mitochondrial dynamics under physiological conditions. In the present study, MK801 (a non-competitive NMDAR antagonist) did not affect mitochondrial length in hippocampal neurons as well as phosphorylation levels of dynamin-related protein 1 (DRP1)-serine (S) 616, extracellular-signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38 MAPK) and AMPAR. In contrast, perampanel (a non-competitive AMPAR antagonist) elongated mitochondrial length in neurons concomitant with diminishing phosphorylations of DRP1-S616, ERK1/2, and JNK, but not p38 MAPK. Perampanel also reduced protein phosphatase (PP) 1, PP2A and PP2B phosphorylations, indicating activations of these PPs which were unaffected by MK801. U0126 (an ERK1/2 inhibitor) elongated mitochondrial length, accompanied by the reduced DRP1-S616 phosphorylation. SP600125 (a JNK inhibitor) did not influence mitochondrial length and DRP1 phosphorylations. Okadaic acid (a PP1/PP2A inhibitor) reduced mitochondrial length with the up-regulated DRP1-S616 phosphorylation, while CsA (a PP2B inhibitor) increased it with the elevated DRP1-S637 phosphorylation. Co-treatment of okadaic acid or CsA with perampanel attenuated the reductions in DRP1-S616 and -S637 phosphorylation without changing DRP1 expression level, respectively. GYKI 52466 (another non-competitive AMPAR antagonist) showed the similar effects of perampanel on phosphorylations of DRP1, ERK1/2, JNK, PPs, and GluR1 AMPAR subunits. Taken together, our findings suggest that a blockade of AMPAR may regulate the cooperation of ERK1/2- and PP1/PP2A for the modulation of DRP1 phosphorylations, which facilitate mitochondrial fusion.

Concomitant Psychiatric Symptoms in Neurological Outpatients.

To estimate the prevalence of concomitant psychiatric disorders in neurological outpatients and to assess the value of simple screening questionnaires in the identification of psychiatric symptoms, we analyzed a total of 803 patients who visited neurology clinics with neurological symptoms over a six-month period. Using self-reported questionnaires, we assessed psychiatric symptoms, such as stress (Perceived Stress Scale, PSS), depression (Patient Health Question 9, PHQ9), and anxiety (Generalized Anxiety Disorder 7, GAD7). According to the disease subtypes, we analyzed the psychiatric scales based on gender and age group. The prevalence of psychiatric comorbidities was lowest in patients with cerebrovascular disease (CVD) and highest among patients with cognitive decline and epilepsy. The overall prevalence of psychiatric symptoms markedly decreased with age. This decline was statistically significant for all questionnaires (PSS ≥ 14, p for trend = 0.027; PQH9 ≥ 10, p for trend = 0.005; GAD7 ≥ 10, p for trend = 0.002) and was more pronounced in males. Considering the high incidence of undetected psychiatric comorbidities and their associated burden, proactive psychiatric management should be included in neurological care. Psychiatric questionnaires could also be an effective screening tool for identifying psychiatric symptoms accompanying neurological symptoms.

Perampanel Affects Up-Stream Regulatory Signaling Pathways of GluA1 Phosphorylation in Normal and Epileptic Rats.

To elucidate the pharmacological properties of perampanel [2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile, a novel non-competitive antagonist of AMPA receptor], we investigated its effects on the up-stream regulatory pathways of GluA1 phosphorylation including protein kinase C (PKC), Ca2+-calmodulin-dependent protein kinase II (CAMKII), protein kinase A (PKA), extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), protein phosphatase (PP) 1, PP2A, and PP2B in normal and pilocarpine-induced epileptic rat model using Western blot analysis. In normal animals, perampanel affected GluA1 expression/phosphorylation, PKC, CAMKII, PKA, ERK1/2, JNK, and PPs activities. In epileptic rats, perampanel effectively inhibited spontaneous seizure activities. Perampanel enhanced phospho (p)-GluA1-S831 and -S845 ratios (phosphoprotein/total protein), while it reduced GluA1 expression. Perampanel also increased pCAMKII and pPKA ratios, which phosphorylate GluA1-S831 and -S845 site, respectively. Perampanel elevated pJNK and pPP2B ratios, which phosphorylates and dephosphorylates both GluA1-S831 and -S845 sits. Perampanel also increased pERK1/2 ratio in epileptic animals, while U0126 (an ERK1/2 inhibitor) did not affect pGluA1 ratios. Perampanel did not influence PKC, PP1, and PP2A expression levels and their phosphorylation ratios. In addition, perampanel did not have a detrimental impact on cognitive abilities of epileptic and normal rats in Morris water maze test. These findings suggest that perampanel may regulate AMPA receptor functionality via not only blockade of AMPA receptor but also the regulations of multiple molecules (CAMKII, PKA, JNK, and pPP2B)-mediated GluA1 phosphorylations without negative effects on cognition, although the effects of perampanel on PKC, PP1, and PP2A activities were different between normal and epileptic rats.

Unusual Intracranial Arterial Calcification and Vitamin D Deficiency.

Although intracranial arterial calcifications (IACs) are encountered in approximately 85% of patients with acute ischemic stroke (IS), the significance of IAC in plaque instability is still controversial. Because most tissues including brain tissue have vitamin D receptors, vitamin D deficiency might play multiple roles in variable sites. Here, we report a novel presentation of IS with IAC including anterior cerebral artery involvement due to vitamin D deficiency. In conclusion, although the role of IAC in cerebral infarction is still controversial, we suggest that insufficient vitamin D should be examined and treated appropriately in all patients with IS. We believe that this article provides important implications for the treatment of vitamin D deficiency in patients with IS.

Citation Classics in Stroke: The Top-100 Cited Articles on Hemorrhagic Stroke.

BACKGROUND: Stroke is a disastrous disease and a major health burden worldwide, especially in Korea. Hemorrhagic stroke (HS) accounts for approximately 20% of all the types of strokes. It is important to be able to evaluate stroke diagnoses and evolving treatments. OBJECTIVE: We aimed to identify the top-100 cited articles and assess a paradigm shift that occurred in the field of HS. METHODS: We searched all articles that had been cited more than 100 times using the Web of Science citation search tool during January 2016. Among a total of 2,651 articles, we identified the top-100 cited articles on HS. RESULTS: The number of citations for the articles analyzed in this study ranged from 1,746 to 211, and the number of annual citations ranged from 125.6 to 5.5. Most of the articles that were published in Stroke (35%) and Journal of Neurosurgery (22%), originated in the United States (n = 56), were original articles (64%), and dealt with the natural history or etiology (n = 37) and vasospasm in subarachnoid hemorrhage (n = 8). CONCLUSIONS: We analyzed the top-100 cited articles in the field of HS based on citation rates. The results provide a unique perspective on historical and academic developments in this field.

Sec17/Sec18 act twice, enhancing membrane fusion and then disassembling cis-SNARE complexes.

At physiological protein levels, the slow HOPS- and SNARE-dependent fusion which occurs upon complete SNARE zippering is stimulated by Sec17 and Sec18:ATP without requiring ATP hydrolysis. To stimulate, Sec17 needs its central residues which bind the 0-layer of the SNARE complex and its N-terminal apolar loop. Adding a transmembrane anchor to the N-terminus of Sec17 bypasses this requirement for apolarity of the Sec17 loop, suggesting that the loop functions for membrane binding rather than to trigger bilayer rearrangement. In contrast, when complete C-terminal SNARE zippering is prevented, fusion strictly requires Sec18 and Sec17, and the Sec17 apolar loop has functions beyond membrane anchoring. Thus Sec17 and Sec18 act twice in the fusion cycle, binding to trans-SNARE complexes to accelerate fusion, then hydrolyzing ATP to disassemble cis-SNARE complexes.

A short region upstream of the yeast vacuolar Qa-SNARE heptad-repeats promotes membrane fusion through enhanced SNARE complex assembly.

Whereas SNARE (soluble N -ethylmaleimide-sensitive factor attachment protein receptor) heptad-repeats are well studied, SNAREs also have upstream N-domains of indeterminate function. The assembly of yeast vacuolar SNAREs into complexes for fusion can be studied in chemically defined reactions. Complementary proteoliposomes bearing a Rab:GTP and either the vacuolar R-SNARE or one of the three integrally anchored Q-SNAREs were incubated with the tethering/SM protein complex HOPS and the two other soluble SNAREs (lacking a transmembrane anchor) or their SNARE heptad-repeat domains. Fusion required a transmembrane-anchored R-SNARE on one membrane and an anchored Q-SNARE on the other. The N-domain of the Qb-SNARE was completely dispensable for fusion. Whereas fusion can be promoted by very high concentrations of the Qa-SNARE heptad-repeat domain alone, at physiological concentrations the Qa-SNARE heptad-repeat domain alone has almost no fusion activity. The 181-198 region of Qa, immediately upstream of the SNARE heptad-repeat domain, is required for normal fusion activity with HOPS. This region is needed for normal SNARE complex assembly.

HOPS catalyzes the interdependent assembly of each vacuolar SNARE into a SNARE complex.

Rab GTPases, their effectors, SNAREs of the R, Qa, Qb, and Qc families, and SM SNARE-binding proteins catalyze intracellular membrane fusion. At the vacuole/lysosome, they are integrated by the homotypic fusion and vacuole protein sorting (HOPS) complex. Two HOPS subunits bind vacuolar Rabs for tethering, another binds the Qc SNARE, and a fourth HOPS subunit, an SM protein, has conserved grooves that bind R- and Qa-SNARE domains. Spontaneous quaternary SNARE complex assembly is very slow. We report an assay of SNARE complex assembly that does not rely on fusion and for which tethering does not coenrich the four SNAREs. HOPS is required in this assay for rapid SNARE complex assembly. Optimal assembly needs HOPS, lipid membranes to which the R- or Qa-SNARE and Ypt7:GTP are integrally bound, and each of the other three SNAREs. Each SNARE assembles into this complex relying on the others, suggesting four-SNARE complex assembly rather than direct binding of each to HOPS. SNAREs can be disassociated by Sec 17/Sec 18/ATP, completing a catalyzed cycle of SNARE assembly and disassembly.

The effect of recurrent seizures on cognitive, behavioral, and quality-of-life outcomes after 12 months of monotherapy in adults with newly diagnosed or previously untreated partial epilepsy.

PURPOSE: The purpose of this study was to determine whether seizure recurrence has a negative impact on cognition, psychological function, and health-related quality of life (HRQoL) over a 12-month period of monotherapy in adults with newly diagnosed or previously untreated partial epilepsy. METHODS: Seizure freedom (SF) was defined as no seizure recurrence during the 40-week maintenance period of medication. Neuropsychological tests, the Symptom Checklist-90 (SCL-90), and the Quality of Life in Epilepsy-31 (QOLIE-31) were administered at baseline and after 48 weeks of carbamazepine or lamotrigine monotherapy. Seventy-three patients successfully continued treatment until the 48-week follow-up time point. Fifty patients (68.5%) had SF, and the remaining 23 were not seizure-free (NSF). A seizure outcome group-by-time interaction was analyzed using a linear mixed model. RESULTS: A group-by-time interaction was identified for the total QOLIE-31 score (p<0.05) and score on two QOLIE-31 subscales (social function: p<0.001 and seizure worry: p<0.001), with a significant improvement over time only present in the SF group (all p<0.001). There was no significant group-by-time interaction for most cognitive function tests, with the exception of the serial clustering score (p<0.01) and number of recognition hits on the California Verbal Learning Test (p<0.05). Serial clustering did not differ between the SF and NSF groups at baseline, but was significantly more used in the NSF group than in the SF group at 48 weeks (p<0.01). There was no significant group-by-time interaction for any dimension of the SCL-90. CONCLUSION: Recurrent seizures had a significant effect on HRQoL, a subtle effect on cognitive performance, and no effect on psychological symptoms over one year in newly diagnosed or previously untreated adults with partial epilepsy.

Cellular and regional specific changes in multidrug efflux transporter expression during recovery of vasogenic edema in the rat hippocampus and piriform cortex.

In the present study, we investigated the characteristics of drug efflux transporter expressions following status epilepticus (SE). In the hippocampus and piriform cortex (PC), vasogenic edema peaked 3-4 days after SE. The expression of breast cancer resistance protein (BCRP), multidrug resistance protein-4 (MRP4), and p-glycoprotein (p-GP) were decreased 4 days after SE when vasogenic edema was peaked, but subsequently increased 4 weeks after SE. Multidrug resistance protein-1 (MRP1) expression gradually decreased in endothelial cells until 4 weeks after SE. These findings indicate that SE-induced vasogenic edema formation transiently reduced drug efflux pump expressions in endothelial cells. Subsequently, during recovery of vasogenic edema drug efflux pump expressions were differentially upregulated in astrocytes, neuropils, and endothelial cells. Therefore, we suggest that vasogenic edema formation may be a risk factor in pharmacoresistent epilepsy.