Development of an efficacious, non-addicting analgesic has been challenging. Discovery of novel mechanisms underlying addiction may present a solution. Here we target the neurokinin system, which is ...involved in both pain and addiction. Morphine exerts its rewarding actions, at least in part, by inhibiting GABAergic input onto substance P (SP) neurons in the ventral tegmental area (VTA), subsequently increasing SP release onto dopaminergic neurons. Genome editing of the neurokinin 1 receptor (NK1R) in the VTA renders morphine non-rewarding. Complementing our genetic approach, we demonstrate utility of a bivalent pharmacophore with dual activity as a μ/δ opioid agonist and NK1R antagonist in inhibiting nociception in an animal model of acute pain while lacking any positive reinforcement. These data indicate that dual targeting of the dopaminergic reward circuitry and pain pathways with a multifunctional opioid agonist–NK1R antagonist may be an efficacious strategy in developing future analgesics that lack abuse potential.
The X-linked gene encoding MECP2 is involved in two severe and complex neurodevelopmental disorders. Loss of function of the MeCP2 protein underlies Rett syndrome, whereas duplications of the MECP2 ...locus cause MECP2 duplication syndrome. Research on the mechanisms by which MeCP2 exerts effects on gene expression in neurons, studies of animal models bearing different disease-causing mutations, and more in-depth observations of clinical presentations have clarified some issues even as they have raised further questions. Yet there is enough evidence so far to suggest possible approaches to therapy for these two diseases that could go beyond attempting to address specific signs and symptoms (of which there are many) and instead target the pathophysiology underlying MECP2 disorders. Further work could bring antisense oligonucleotides, deep brain stimulation, and gene therapy into the clinic within the next decade or so.
Traumatic brain injury (TBI) is a leading cause of disability in the US. Angiotensin 1-7 (Ang-1-7), an endogenous peptide, acts at the G protein coupled MAS1 receptors (MASR) to inhibit inflammatory ...mediators and decrease reactive oxygen species within the CNS. Few studies have identified whether Ang-(1-7) decreases cognitive impairment following closed TBI. This study examined the therapeutic effect of Ang-(1-7) on secondary injury observed in a murine model of mild TBI (mTBI) in a closed skull, single injury model.
Male mice (
= 108) underwent a closed skull, controlled cortical impact injury. Two hours after injury, mice were administered either Ang-(1-7) (
= 12) or vehicle (
= 12), continuing through day 5 post-TBI, and tested for cognitive impairment on days 1-5 and 18. pTau, Tau, GFAP, and serum cytokines were measured at multiple time points. Animals were observed daily for cognition and motor coordination
novel object recognition. Brain sections were stained and evaluated for neuronal injury.
Administration of Ang-(1-7) daily for 5 days post-mTBI significantly increased cognitive function as compared to saline control-treated animals. Cortical and hippocampal structures showed less damage in the presence of Ang-(1-7), while Ang-(1-7) administration significantly changed the expression of pTau and GFAP in cortical and hippocampal regions as compared to control.
These are among the first studies to demonstrate that sustained administration of Ang-(1-7) following a closed-skull, single impact mTBI significantly improves neurologic outcomes, potentially offering a novel therapeutic modality for the prevention of long-term CNS impairment following such injuries.
Clonidine is an imidazoline sympatholytic, acting on both α
-adrenergic and imidazoline receptors in the brainstem to induce antihypertensive and negative chronotropic effects in the vasculature and ...heart respectively.
A 69-year-old gentleman with hypertension presented to the emergency department after multiple syncopal episodes over the past 12 months. Electrocardiogram demonstrated sinus bradycardia with a heart rate of 42 beats per minute. It was hypothesized that the antihypertensive agent clonidine was responsible for inducing symptomatic bradycardia. Clonidine was thus gradually tapered and then discontinued over five days restoring normal sinus rhythm rates while avoiding hypertensive rebound related to sympathetic surge. His heart rate and blood pressure remained within normal limits after the clonidine taper and subsequent adjustments to his other hypertensive medications and he was discharged.
While clonidine has fallen out of favor for its indication as an antihypertensive, it remains a viable option for the use of opioid withdrawal, chronic pain, and smoking cessation, necessitating the appropriate clinical and pharmacological competencies for a physician to prescribe. A discussion of the clinical effects of clonidine brainstem receptor activation follows.
We report results from a search for strangelets (small chunks of strange quark matter) in lunar soil using the Yale WNSL accelerator as a mass spectrometer. We have searched over a range in mass from ...A = 42 to A = 70 amu for nuclear charges 5, 6, 8, 9, and 11. No strangelets were found in the experiment. For strangelets with nuclear charge 8, a concentration in lunar soil higher than 10(-16) is excluded at the 95% confidence level. The implied limit on the strangelet flux in cosmic rays is the most sensitive to date for the covered range and is relevant to both recent theoretical flux predictions and a strangelet candidate event found by the AMS-01 experiment.
Addiction is a chronic disorder in which consumption of a substance or a habitual behavior becomes compulsive and often recurrent, despite adverse consequences. Substance p (SP) is an undecapeptide ...and was the first neuropeptide of the neurokinin family to be discovered. The subsequent decades of research after its discovery implicated SP and its neurokinin relatives as neurotransmitters involved in the modulation of the reward pathway. Here, we review the neurokinin literature, giving a brief historical perspective of neurokinin pharmacology, localization in various brain regions involved in addictive behaviors, and the functional aspects of neurokinin pharmacology in relation to reward in preclinical models of addiction that have shaped the rational drug design of neurokinin antagonists that could translate into human research. Finally, we will cover the clinical investigations using neurokinin antagonists and discuss their potential as a therapy for drug abuse.
Management of traumatic brain injury (TBI) is focused on minimizing or preventing secondary brain injury. Remote ischemic conditioning (RIC) is an established treatment modality that has been shown ...to improve patient outcomes in different clinical settings by influencing inflammatory insults. In a clinical trial, RIC showed amelioration of SB100 and neuron-specific enolase. The aim of our study was to further elucidate the mechanisms and outcome when applying RIC in a mouse model of traumatic brain injury.
We subjected 100 male C57BL mice to a closed-skull cortical-controlled impact injury. Two hours after the TBI, the animals were allocated to either the RIC group (n = 50) or the sham group (n = 50). By clamping the exposed femoral artery, we induced RIC by six 4-minute cycles of ischemia and reperfusion. Circulating levels of S100-B, neuron-specific enolase, and glial fibrillary acidic protein were measured at multiple time points. Animals were additionally observed daily for cognition and motor coordination via novel object recognition and rotarod. Brain sections were stained and evaluated for neuronal injury at post-TBI Day 5.
The RIC animals had a significantly higher recognition index than did sham at 24, 48, and 72 hours after intervention. Rotarod latency was higher in the RIC animals compared to the sham animals at all-time points, and statistically significant at 120 hours after intervention. The RIC group demonstrated preserved cognitive function and motor coordination compared to the sham. On hematoxylin and eosin and immunohistochemical staining of brain sections, there was less area of neuronal degeneration and astrocytosis, respectively, in the RIC group compared to the sham group. There was no significant difference in systemic neuronal markers between the RIC and sham animals.
Remote ischemic conditioning 2 hours after injury preserved cognitive functions and motor coordination in a mouse model of TBI. Remote ischemic conditioning can preserve viability of neurons and astrocytes after TBI and has potential as a clinically noninvasive and relatively easy method to improve outcome after TBI.
Therapeutic studies, randomized controlled trial, level I.
Anti-N-methyl-d-aspartate receptor autoimmune encephalitis (NMDAR AE) is an antibody-mediated neurological disorder that may be caused by post-herpes simplex virus-1 meningoencephalitis (HSV ME) and ...ovarian teratomas, although most pediatric cases are idiopathic. We sought to evaluate if other infections precede NMDAR AE by conducting a single-center, retrospective, case-control study of 86 pediatric cases presenting to Texas Children's Hospital between 2006 and 2022. HSV ME (HSV-1 and HSV-2) was a significantly more common preceding infection in the experimental group compared to control patients with idiopathic intracranial hypertension, while there was no difference in remote HSV infection between the two groups. Recent Epstein-Barr virus infection was evident in 8/42 (19%) tested experimental patients in comparison to 1/25 (4%) tested control patients which provided evidence for a genuine measure of effect but was not statistically significant due to small sample size (p = 0.07). The other 25 infectious etiologies were not different among the two groups and not all variables were clinically indicated or obtained in every subject, highlighting the need for future standardized, multi-institutional studies on underlying infectious precursors of autoimmune encephalitis.
•In addition to HSV- 1, HSV- 2 meningoencephalitis is a likely precipitant of anti-NMDAR encephalitis.•Other Herpesviridae like EBV may predispose to NMDAR AE greater than previously appreciated, requiring further study.•Frequently detected concomitant infections with NMDAR AE like common respiratory viruses are less likely triggers of NMDAR AE.
We describe a cohort of children with severe myelin oligodendrocyte glycoprotein (MOG)-IgG-associated cerebral cortical encephalitis (CCE), manifesting with bilateral cortical cytotoxic edema and ...critical neurological illness.
We retrospectively reviewed our pediatric MOG antibody-associated disease (MOGAD) database and identified patients with specific radiographic pattern of bilateral, multifocal cortical cytotoxic lesions. We collected demographic, clinical, and outcomes data from these patients and compared select variables with radiographically distinct cerebral MOGAD syndromes (case-control analysis). We assessed the correlation of quantitative clinical variables with severity/outcomes measures using simple linear regression.
Sixty-five of 88 total MOGAD cases had cerebral disease, and six of 88 met inclusion criteria for fulminant CCE (f-CCE). Age range was 2 to 7 years; five of six were male. Six of six were critically ill with severe encephalopathy and seizures, two of six required barbiturate coma, and two of six required invasive intracranial pressure monitoring. Six of six required treatment escalation beyond steroids. Four of six had favorable outcome; two of six had moderate-severe disability. Compared with other cerebral MOGAD cases (n = 59), children with f-CCE were more likely to have critical illness and poor neurological outcomes scores. Neurofilament light chain and treatment latency positively correlated with intensive care unit length of stay and outcomes scores; cerebrospinal fluid (CSF) white blood cell count and neutrophil-to-lymphocyte ratio did not.
Pediatric CCE with bilateral cytotoxicity is associated with more fulminant disease and worse outcomes than other cerebral MOGAD syndromes.
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