Outzenbender2086
Epilepsy is a neurological disease recognized as the consequence of excessive neuronal excitability. Endocannabinoid system, the critical regulator of synaptic inhibition in brain, was supposed to be closely involved in epilepsy. CQ211 solubility dmso Cannabinoid receptors mostly locate on presynaptic terminals of both excitatory and inhibitory neurons, but with characteristic distribution varying in different brain areas and synapses. Endocannabinoids are synthesized in postsynaptic neurons and retrogradely act on presynaptic cannabinoid receptors. Accumulating evidence suggest that the expression of cannabinoid receptors and synthesis or breakdown of endocannabinoids were cell-type specifically altered and spatiotemporally regulated in seizures, and intervention of the expression of cannabinoid receptors or the level of endocannabinoids could affect seizure actions. Further in clinic, cannabidiol as an add-on treatment could reduce seizures in patients with treatment-resistant epilepsy, but the underlying mechanisms are still unclear and independent of the endocannabinoid system. Therefore, we review recent advances from bench to bedside, to address the cannabinoid control on seizures, discuss the existing confusion in current studies and provide directions for further research, which may be clinically important for the design of cannabinoid-based precise therapeutic interventions for epilepsy.Vitamin D (Vt. D) is one of the vital hormone having multiple functions in various tissues, including brain. Several evidences reported that Vt. D plays a significant part in memory and cognition as its inadequate amount may accelerate cognitive impairment. This study shows for the first time the antioxidant potential of Vt. D against D-Galactose (D-gal) induced oxidative stress mediated Alzheimer disease (AD) pathology in male adult albino mice. The result reveals that the mice exposed to D-gal (120 mg/kg) for eight weeks have pre-and post-synaptic dysfunction and impaired memory investigated through Morris water maze and Y-maze tests. This is followed by the suppressed Nuclear factor erythroid 2-related factor 2 (NRF2), Heme Oxygenase-1 (HO-1) and elevated expressions of Nuclear Factor kappa B (NF-kB), Tumor Necrosis Factor alpha (TNF-α) and Interleukin 1 beta (IL-1β) proteins in the brain homogenates evaluated through western blotting technique. On the other hand Vt. D (100 μg/kg) administration (three times a week for 4 weeks) activated Silent mating type information regulation 2 homolog 1 (SIRT1) and significantly improved both the neuronal synapse and memory, reduced oxidative stress by upregulating NRF-2 and HO-1 and downregulating NF-kB, TNF-α and IL-1β proteins expression. Most importantly, Vt. D significantly abrogate the amyloidogenic pathway of amyloid beta (Aβ) production against D-gal in the brains of adult male albino mice. These results reveal that Vt. D being an antioxidant agent plays a vital role in reducing the AD pathophysiology in D-gal induced animal model of aging, therefore act as a potential drug candidate in neurodegenerative diseases.Cocaine, amphetamine, and methamphetamine abuse disorders are serious worldwide health problems. To date, there are no FDA-approved medications for the treatment of these disorders. Elucidation of the biochemical underpinnings contributing to psychostimulant addiction is critical for the development of effective therapies. Excitatory signaling and glutamate homeostasis are well known pathophysiological substrates underlying addiction-related behaviors spanning multiple types of psychostimulants. To alleviate relapse behavior to psychostimulants, considerable interest has focused on GLT-1, the major glutamate transporter in the brain. While many brain regions are implicated in addiction behavior, this review focuses on two regions well known for their role in mediating the effects of cocaine and amphetamines, namely the nucleus accumbens (NAc) and the ventral tegmental area (VTA). In addition, because many investigators have utilized Cre-driver lines to selectively control gene expression in defined cell populations relevant for psychostimulant addiction, we discuss potential off-target effects of Cre-recombinase that should be considered in the design and interpretation of such experiments.
Denture fracture is one of the most common complications in prosthodontics and implant overdentures are reported to be at higher risk of fractures. Therefore, the aim of this study was to assess the incidence and factors associated with the occurrence of fractures in patients treated with a single implant mandibular overdenture (SIMO) opposed by a conventional maxillary complete denture.
A cohort of 152 patients, 65.1% female and 34.9% male, mean age 65.4 ± 8.5 years, were prospectively followed-up for a minimum of 1 year and up to 6.7 years. Patients received a single midline mandibular implant with a retention system incorporated in the overdenture Straumann ball abutment and gold elliptical matrix (n = 37), Neodent ball/nylon matrix (n = 83), or Neodent Equator/nylon matrix (n = 32). Fracture was defined as a complete separation of denture parts and classified as midline fracture (over the implant region), or elsewhere. No metal reinforcement was incorporated into the overdenture. Incidence rates, lifed that single-implant mandibular overdentures are at high risk of midline fractures. Proper post-insertion monitoring and the identification and management of patient's individual risk factors are essential for the successful treatment in the long-term.
Compounds that selectively target orexin-1 receptors may be beneficial for the treatment of various disorders. The role of selective orexin-1 receptor antagonists (1-SORAs) in addictive behavior and stress/anxiety-related disturbances has been demonstrated in animals. ACT-539313, an orally active, potent 1-SORA, has been assessed in a clinical single-ascending dose study and exhibited good safety and tolerability. In the two reported studies on ACT-539313, multiple-dose pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability were investigated and in a proof-of-mechanism study a CO
challenge was applied as pharmacological model for induction of anxiety and panic symptoms (sequential inhalation of air, 7.5% CO
, and 35% CO
).
Two double-blind, placebo-controlled, randomized, multiple-dose studies included 58 healthy male and female subjects. In Study 1, multiple-ascending oral doses of 30, 100, and 200mg twice daily (b.i.d.) ACT-539313 were investigated in 3 dose groups of 8 or 12 subjects (of whom 2 received placebo per dose group).
