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Background: Given that changes in brain water content are often correlated with disease, investigating water content non‐invasively and in vivo could lead to a better understanding of the pathogenesis of several neurologic diseases. Purpose: To adapt a super‐resolution‐based technique, previously developed for humans, to the rat brain and report in vivo high‐resolution (HR) water content maps in comparison with ex vivo wet/dry methods. Study Type: Prospective. Animal Model: Eight healthy male Wistar rats. Field Strength/Sequence: 9.4‐T, multi‐echo gradient‐echo (mGRE) sequence. Assessment: Using super‐resolution reconstruction (SRR), a HR mGRE image (200 μm isotropic) was reconstructed from three low‐resolution (LR) orthogonal whole‐brain images in each animal, which was followed by water content mapping in vivo. The animals were subsequently sacrificed, the brains excised and divided into five regions (front left, front right, middle left, middle right, and cerebellum–brainstem regions), and the water content was measured ex vivo using wet/dry measurements as the reference standard. The water content values of the in vivo and ex vivo methods were then compared for the whole brain and also for the different regions separately. Statistical Tests: Friedman's non‐parametric test was used to test difference between the five regions, and Pearson's correlation coefficient was used for correlation between in vivo and ex vivo measurements. A P‐value <0.05 was considered statistically significant. Results: Water content values derived from in vivo MR measurements showed strong correlations with water content measured ex vivo at a regional level (r = 0.902). Different brain regions showed significantly different water content values. Water content values were highest in the frontal brain, followed by the midbrain, and lowest in the cerebellum and brainstem regions. Data Conclusion: An in vivo technique to achieve HR isotropic water content maps in the rat brain using SRR was adopted in this study. The MRI‐derived water content values obtained using the technique showed strong correlations with water content values obtained using ex vivo wet/dry methods. Level of Evidence: 1 Technical Efficacy: Stage 1 [ABSTRACT FROM AUTHOR]

Background and Purpose: Neuropathic pain affects up to 10% of the global population and is caused by an injury or a disease affecting the somatosensory, peripheral, or central nervous system. NP is characterized by chronic, severe and opioid‐resistant properties. Therefore, its clinical management remains very challenging. The N‐type voltage‐gated calcium channel, Cav2.2, is a validated target for therapeutic intervention in chronic and neuropathic pain. The conotoxin ziconotide (Prialt®) is an FDA‐approved drug that blocks Cav2.2 channel but needs to be administered intrathecally. Thus, although being principally efficient, the required application route is very much in disfavour. Experimental Approach and Key Results: Here, we describe an orally available drug candidate, RD2, which competes with ziconotide binding to Cav2.2 at nanomolar concentrations and inhibits Cav2.2 almost completely reversible. Other voltage‐gated calcium channel subtypes, like Cav1.2 and Cav3.2, were affected by RD2 only at concentrations higher than 10 μM. Data from sciatic inflammatory neuritis rat model demonstrated the in vivo proof of concept, as low‐dose RD2 (5 mg·kg‐1) administered orally alleviated neuropathic pain compared with vehicle controls. High‐dose RD2 (50 mg·kg‐1) was necessary to reduce pain sensation in acute thermal response assessed by the tail flick test. Conclusions and Implications: Taken together, these results demonstrate that RD2 has antiallodynic properties. RD2 is orally available, which is the most convenient application form for patients and caregivers. The surprising and novel result from standard receptor screens opens the room for further optimization into new promising drug candidates, which address an unmet medical need. [ABSTRACT FROM AUTHOR]

ClC-3 Cl-/H+ exchangers are expressed in multiple endosomal compartments and likely modify intra-endosomal pH and [Cl-] via the stoichiometrically coupled exchange of two Cl- ions and one HC. We studied pain perception in Clcn3-/- mice and found that ClC-3 not only modifies the electrical activity of peripheral nociceptors but is also involved in inflammatory processes in the spinal cord. We demonstrate that ClC-3 regulates the number of Nav and Kv ion channels in the plasma membrane of dorsal root ganglion (DRG) neurons and that these changes impair the age-dependent decline in excitability of sensory neurons. To distinguish the role of ClC-3 in Cl-/H+ exchange from its other functions in pain perception, we used mice homozygous for the E281Q ClC-3 point mutation (Clcn3E281Q=E281Q), which completely eliminates transport activity. Since ClC-3 forms heterodimers with ClC-4, we crossed these animals with Clcn4-/- to obtain mice completely lacking in ClC-3-associated endosomal chloride-proton transport. The electrical properties of Clcn3E281Q=E281Q/Clcn4-/- DRG neurons were similar to those of wild-type cells, indicating that the age-dependent adjustment of neuronal excitability is independent of ClC-3 transport activity. Both Clcn3=and Clcn3E281Q=E281Q/Clcn4-/- animals exhibited microglial activation in the spinal cord, demonstrating that competent ClC-3 transport is needed to maintain glial cell homeostasis. Our findings illustrate how reduced Cl/HC exchange contributes to inflammatory responses and demonstrate a role for ClC-3 in the homeostatic regulation of neuronal excitability beyond its function in endosomal ion balance. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons, thus, progressing to complete muscle loss until the patient dies from respiratory arrest. The disease is not curable, and patients die approximately 2–5 years after diagnosis. Studying the underlying disease mechanisms to get access to new treatment options is, therefore, essential for patients' benefit. However, so far, only three drugs that alleviate the symptoms have been approved by the U.S. Food and Drug Administration (FDA). A new drug candidate for the treatment of ALS is the all-d-enantiomeric peptide RD2RD2. In this study, we investigated the therapeutic effect of RD2RD2 in two setups. First, we analyzed disease progression and survival in 7 week-old B6.Cg-Tg(SOD1*G93A)1Gur/J mice. Second, we confirmed the result of the survival analysis in the B6SJL-Tg(SOD1*G93A)1Gur/J mouse line. Shortly before disease onset, the mice were treated daily with an oral dose of 50 mg/kg body weight. Treatment with RD2RD2 led to a delayed disease onset and reduced motor phenotype as shown using the SHIRPA test, the splay reflex test, and the pole test, but did not affect survival. In conclusion, RD2RD2 has the ability to delay the onset of symptoms. [ABSTRACT FROM AUTHOR]