“…In any case, the changes observed here in mdx mice likely alter the physiological properties of extrasynaptic GABA A Rs and their sensitivity to specific pharmacological compounds such as gaboxadol [ 8 , 52 ]. This may also contribute to a variety of emotional, cognitive, and neuropsychiatric disorders [ 55 , 56 , 57 , 58 , 59 , 60 , 61 ] including those reported in mdx mice and associated with DMD, such as stress reactivity, anxiety, fear memory, and intellectual disability [ 23 ].…”
Duchenne muscular dystrophy (DMD) is a neurodevelopmental disorder primarily caused by the loss of the full-length Dp427 dystrophin in both muscle and brain. The basis of the central comorbidities in DMD is unclear. Brain dystrophin plays a role in the clustering of central gamma-aminobutyric acid A receptors (GABAARs), and its loss in the mdx mouse alters the clustering of some synaptic subunits in central inhibitory synapses. However, the diversity of GABAergic alterations in this model is still fragmentary. In this study, the analysis of in vivo PET imaging of a benzodiazepine-binding site radioligand revealed that the global density of central GABAARs is unaffected in mdx compared with WT mice. In contrast, semi-quantitative immunoblots and immunofluorescence confocal imaging in tissue sections revealed complex and differential patterns of alterations of the expression levels and/or clustered distribution of a variety of synaptic and extrasynaptic GABAAR subunits in the hippocampus, cerebellum, cortex, and spinal cord. Hence, dystrophin loss not only affects the stabilization of synaptic GABAARs but also influences the subunit composition of GABAARs subtypes at both synaptic and extrasynaptic sites. This study provides new molecular outcome measures and new routes to evaluate the impact of treatments aimed at compensating alterations of the nervous system in DMD.
“…In any case, the changes observed here in mdx mice likely alter the physiological properties of extrasynaptic GABA A Rs and their sensitivity to specific pharmacological compounds such as gaboxadol [ 8 , 52 ]. This may also contribute to a variety of emotional, cognitive, and neuropsychiatric disorders [ 55 , 56 , 57 , 58 , 59 , 60 , 61 ] including those reported in mdx mice and associated with DMD, such as stress reactivity, anxiety, fear memory, and intellectual disability [ 23 ].…”
Duchenne muscular dystrophy (DMD) is a neurodevelopmental disorder primarily caused by the loss of the full-length Dp427 dystrophin in both muscle and brain. The basis of the central comorbidities in DMD is unclear. Brain dystrophin plays a role in the clustering of central gamma-aminobutyric acid A receptors (GABAARs), and its loss in the mdx mouse alters the clustering of some synaptic subunits in central inhibitory synapses. However, the diversity of GABAergic alterations in this model is still fragmentary. In this study, the analysis of in vivo PET imaging of a benzodiazepine-binding site radioligand revealed that the global density of central GABAARs is unaffected in mdx compared with WT mice. In contrast, semi-quantitative immunoblots and immunofluorescence confocal imaging in tissue sections revealed complex and differential patterns of alterations of the expression levels and/or clustered distribution of a variety of synaptic and extrasynaptic GABAAR subunits in the hippocampus, cerebellum, cortex, and spinal cord. Hence, dystrophin loss not only affects the stabilization of synaptic GABAARs but also influences the subunit composition of GABAARs subtypes at both synaptic and extrasynaptic sites. This study provides new molecular outcome measures and new routes to evaluate the impact of treatments aimed at compensating alterations of the nervous system in DMD.
“…1 On the other hand, all nine PQs tested are known to have high-tomoderate affinity for the benzodiazepine site at all α subunit-containing GABAARs, and all but one (DK-I-87-1) are characterized by selective positive modulation of α6-containing GABAARs via the PQ site. 6,7 There is an apparently paradoxical relationship between the α6-containing GABAARs, predominantly expressed in the cerebellum, and motor coordination. In the rotating rod test, α6 knockout mice were significantly more incapacitated by diazepam than wild-type mice, while the impairing effect of ethanol was similar in two cohorts of mice.…”
Section: Discussionmentioning
confidence: 99%
“…Nine PQ ligands, PZ-II-029 (7-methoxy-2-(4-methoxyphenyl)-2,5-dihydro-3H-pyrazolo [4,3-c]quinolin-3-one), DK-I-56-1 (7-methoxy-2-(4-(methoxy-d3)phenyl)-2,5-di-hydro-F I G U R E 1 Subunit composition and arrangement of three classes of GABA A receptors (modified according to Sieghart et al 7 ). At these receptors, selected representatives of three structural groups of pyrazoloquinolinone (PQ) ligands examined (PZ-II-029 and related analogues in red box, LAU 463 and related analogues in green box, and DK-I-87-1 in blue box), as defined in Knutson et al, 6 may act via three types of binding sites represented by rainbow-coloured arrows: DS-BZ-diazepam-sensitive benzodiazepine site; DI-BZ-diazepam-insensitive benzodiazepine site; PQ-pyrazoloquinolinone site.…”
Section: Drugsmentioning
confidence: 99%
“…Functional roles of α6‐containing GABAARs in the central and peripheral nervous system (most conspicuously in the cerebellum and trigeminal ganglia, respectively) have recently been reviewed in detail 7 . Neuroimaging, post‐mortem and genetic studies in human beings, together with animal models mimicking neuropsychiatric phenotypes, support the notion that compounds positively modulating α6‐containing GABAARs could be beneficial in disparate states such as essential tremor and motor disturbances in Tourette's, Angelman and Down syndrome, impaired prepulse inhibition or migraine and trigeminal‐related pain (see Sieghart et al, 7 and numerous references therein).…”
Several pyrazoloquinolinone (PQ) ligands were recently discovered as functionally selective positive modulators at the PQ site of α6‐containing GABAA receptors. PQs are also neutral modulators at the benzodiazepine site. We assessed the influence of PQ compounds from three structural groups (PZ‐II‐029 and related deuterated analogues DK‐I‐56‐1, RV‐I‐029, DK‐I‐60‐3 and DK‐I‐86‐1; LAU 463 and related analogues DK‐I‐58‐1 and DK‐II‐58‐1; and DK‐I‐87‐1), alone and in combination with diazepam, on the behaviour of male Sprague–Dawley rats. An excellent behavioural safety profile of all tested PQs was demonstrated in the spontaneous locomotor activity, rotarod, loss of righting reflex and pentylenetetrazol tests. In interaction studies, only PZ‐II‐029 and its analogues prevented the ataxic effects of the benzodiazepine, as assessed in the rotarod test and during monitoring of rat locomotor activity after awakening from the loss of righting reflex. Published electrophysiological profiles of PQ ligands imply that positive modulation elicited at α6‐GABAA receptors that contain the γ2 and δ subunit, rather than their neutral modulatory action at the benzodiazepine site, may prevent the ataxic action of diazepam. Thus, PZ‐II‐029 and its deuterated analogues are not prone to untoward interactions with benzodiazepines and may indeed completely abolish their ataxic action, seen at therapeutic, and especially toxic concentrations.
“…It is known that Cl − influx mediated by the γ-aminobutyric acid type A A (GABA A ) receptor is an important way for the brain to calm neuronal activity (Sieghart et al, 2022). The decrease in GABA A receptor function may be an important mechanism for the development of neuronal hyperactivity.…”
Section: Pharmacological Effects Of Sinomenine In Disorders Assocaite...mentioning
Sinomenine is a natural compound extracted from the medicinal plant Sinomenium acutum. Its supplementation has been shown to present benefits in a variety of animal models of central nervous system (CNS) disorders, such as cerebral ischemia, intracerebral hemorrhage, traumatic brain injury (TBI), Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy, depression, multiple sclerosis, morphine tolerance, and glioma. Therefore, sinomenine is now considered a potential agent for the prevention and/or treatment of CNS disorders. Mechanistic studies have shown that inhibition of oxidative stress, microglia-or astrocyte-mediated neuroinflammation, and neuronal apoptosis are common mechanisms for the neuroprotective effects of sinomenine. Other mechanisms, including activation of nuclear factor E2-related factor 2 (Nrf2), induction of autophagy in response to inhibition of protein kinase B (Akt)-mammalian target of rapamycin (mTOR), and activation of cyclic adenosine monophosphate-response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF), may also mediate the anti-glioma and neuroprotective effects of sinomenine. Sinomenine treatment has also been shown to enhance dopamine receptor D2 (DRD2)mediated nuclear translocation of αB-crystallin (CRYAB) in astrocytes, thereby suppressing neuroinflammation via inhibition of Signal Transducer and Activator of Transcription 3 (STAT3). In addition, sinomenine supplementation can suppress N-methyl-D-aspartate (NMDA) receptormediated Ca 2+ influx and induce γ-aminobutyric acid type A (GABA A ) receptor-mediated Cl − influx, each of which contributes to the improvement of morphine dependence and sleep disturbance. In this review, we outline the pharmacological effects and possible mechanisms of sinomenine in CNS disorders to advance the development of sinomenine as a new drug for the treatment of CNS disorders.
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