The Epileptic Gerbil. Neuronal Networks and Actions of Antiepileptic Drugs
Carl L. Faingold, Gerhard H. Fromm in Drugs for Control of Epilepsy:, 2019
As discussed above, there is strong evidence from neurochemical studies that GABAergic neurotransmission may be impaired in gerbil brain, especially in SN. This may explain the high anticonvulsant potency of GABAmimetic drugs in this species. Löscher et al.31 reported that GABAmimetics, such as the GABA pro-drug cetyl GABA, the GABA degradation inhibitors aminooxyacetic acid (AOAA), and gamma-acetylenic GABA (GAG), the GABA receptor agonist THIP, and the GABA uptake blocker (-)-nipecotic acid ethyl ester, were strikingly more potent to suppress seizures in gerbils than in other genetic animal models of epilepsy and in traditional electrical or chemical mouse or rat models of epilepsy, such as maximal electroshock seizures (MES) or seizures induced by pentylenetetrazol (PTZ). Subsequent studies showed that the same was true for other GABA uptake blockers, such as the novel N-4,4-diphenyl-3-butenyl derivatives of nipecotic acid and guvacine, SKF 89976-A and SKF 100330-A,30 the GABA receptor agonist muscimol,32 and the GABA aminotransferase (GABA-T) inhibitors ethanolamine-O-sulfate (EOS)32 and gamma-vinyl GABA (GVG).33 Interestingly, the effective doses of GVG in gerbils are in the range known to be effective in patients with epilepsy.34 With respect to seizure types in gerbils, the GABA receptor agonists THIP and progabide were almost equally effective to protect against minor and major seizures.35
Prefrontal Inhibitory Signaling in the Control of Social Behaviors
Tian-Le Xu, Long-Jun Wu in Nonclassical Ion Channels in the Nervous System, 2021
The above studies provide convincing evidence that mPFC neuronal activities are good correlates of social interaction behavior. Echoing these observations, complex human social interaction is compromised in patients whose frontal lobes are damaged as a consequence of diseases (Bechara et al. 2000; Saver and Damasio 1991). Among subdivisions of the frontal lobe, selective lesion of the anterior cingulate gyrus in male macaque monkeys disrupts the normal patterns of social interest in other male or female macaque individuals, indicating that the anterior cingulate cortex (ACC, a subregion of the mPFC) is particularly important for social evaluation (Rudebeck et al. 2006). In contrast, focal lesions of the medial orbitofrontal cortex (mOFC) of macaque monkeys, another subregion of the mPFC, induce mild impairments in decision making but do not induce alterations in evaluation of social information (Noonan et al. 2010). These lesion studies suggest that mPFC subregions do not uniformly contribute to social behavior regulation but there exists a division of labor. In agreement with lesion studies in monkeys, pharmacological inactivation of the prefrontal cortical region with GABA receptor agonist reduces frequency and duration of social play in rats (van Kerkhof et al. 2013), and decreases the time of social interaction in mice assessed with a three-chamber social preference test (Xu et al. 2019). Together, on top of correlative observations, these findings establish a causal relationship between the mPFC and social interaction behavior.
Advances in molecular therapies for targeting pathophysiology in spinal cord injury
Published in Expert Opinion on Therapeutic Targets, 2023
Ha Neui Kim, Madeline R. McCrea, Shuxin Li
When mice with transection SCI were housed in an enriched environment, treatment with CSP-TTK21, a CBP/p300 activator, between 12 and 22 weeks after SCI stimulated motor and sensory axon growth, sprouting, and synaptic plasticity, but did not promote sensorimotor recovery [111]. A recent genomics study indicated that REST might be an upstream suppressor of a pro-regenerative gene program associated with CNS axon regeneration [112]. Upregulating Inpp5k, an enzyme to remove the phosphate on position 5 of inositol rings, could stimulate CST axon regrowth after pyramidotomy, stroke, and acute and chronic contusion injuries [113]. A genetic study showed that some synaptic vesicle priming proteins in the presynaptic active zone, including RIMs and Munc13s, suppressed the axon growth of adult neurons by activating voltage-gated Ca channels [114]. Systemic treatment with Baclofen, a GABA receptor agonist, could reduce voltage-dependent Ca influx in sensory neurons and promote their regeneration after SCI. PARP1 was upregulated by several growth inhibitors or CNS injury and its deletion or inhibition has been shown to facilitate axon regeneration of CNS neurons [115,116]. However, a recent study showed that PARP deletion or inhibition by systemic veliparib failed to induce axon regrowth and functional recovery in mice with either SCI or ONC [117].
Current and emerging pharmacotherapeutic strategies for Tourette syndrome
Published in Expert Opinion on Pharmacotherapy, 2022
Finally, complementary and alternative medicines have been reported for the treatment of TS, although the evidence is limited because of a lack of randomized control trials. These include dietary or nutritional supplements (mainly minerals and vitamins), as well as Chinese traditional medicine [23]. For example, vitamin D supplementation was found to be associated with significant improvement in tic severity [94]. Taurine, a naturally occurring sulfur-containing amino acid with GABA-receptor agonist properties, was found to significantly improve tic severity when used as add-on to tiapride, as compared to placebo [95]. An ongoing trial is currently investigating the possible tic-modulating properties of Lactobacillus plantarum PS128, a probiotic that can affect brain neurotransmitter levels. Beyond Western medicine, there have been recent reports that traditional Chinese compounds might have clinically significant tic-reducing properties [96,97]. Polyherbal products called Ningdong granules, Choudongning capsules, 5-Ling granules, and Changma Xifeng tablets have been tested for the treatment of TS with promising preliminary results. The possible generalizability of these early findings in other populations of patients with TS still needs to be established. Moreover, the underlying mechanism(s) for the tic-reduction properties of Chinese herbal supplements is unknown.
Brain circuits and neurochemical systems in essential tremor: insights into current and future pharmacotherapeutic approaches
Published in Expert Review of Neurotherapeutics, 2018
Sara M Schaefer, Ana Vives Rodriguez, Elan D Louis
Progabide is a GABAA receptor agonist that has shown not to work in ET [62,63]. It is not clear which subunits progabide may or may not act upon, as it has not been explored in ET since the 1980s. Tiagabine is a GABA reuptake inhibitor (rather than a GABA receptor agonist) that is also ineffective for the treatment of ET [64]. Zolpidem has high affinity for α1–3 and γ subunits, like benzodiazepines, but does not act on α5 subunits as benzodiazepines do [20]. It has not been studied in ET. Baclofen, a selective GABAB receptor agonist, has shown an effect in harmaline-induced tremor in rats, but has not been studied in ET patients [65].
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