Pharmacological properties of SAK3, a novel T-type voltage-gated Ca2+ channel enhancer

Yabuki, Yasushi; Matsuo, Keitaro; Izumi, Hisanao; Haga, Hidaka; Yoshida, Takashi; Wakamori, Minoru; Kakei, Akikazu; Sakimura, Kenji; Fukuda, Takahiro; Fukunaga, Kohji

doi:10.1016/j.neuropharm.2017.01.011

Cited by 38 publications

(58 citation statements)

References 49 publications

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“…In support of this hypothesis, we previously demonstrated that application of the T-type calcium channel inhibitor NNC 55-0396 (1 μmol/L) blocks elevated CaMKII autophosphorylation levels by SAK3 (0.1 nmol/L) treatment in the mouse hippocampal slice [20]. SAK3 partially antagonized the reduction of phosphorylated ERK2, but not ERK1, levels in the mPFC of MMI-treated mice, suggesting that decreased CaMKII activity in the mPFC and hippocampus is critical for SAK3-induced cognitive improvement in MMI-treated mice.…”

Section: Discussionmentioning

confidence: 67%

“…Dr. Abe et al [22] generously provided the SAK3 used in the experiments [20]. Based on previous studies [14,20], we chose a SAK3 dose of 1.0 mg/kg for the present study. SAK3 was prepared by dissolving it in double-distilled water.…”

Section: Experimental Designmentioning

confidence: 99%

“…ST101 promotes nicotine-induced acetylcholine (ACh) release in the hippocampus via enhancement of Cav3.1 T-type calcium channel activity [18,19]. Recently, we developed a novel spiroimidazopyridine derivative called SAK3 (ethyl-8'-m e t h y l -2 ' , 4 -d i o x o -2 -[ p i p e r i d i n -1 -y l ] -2 ' Hspiro[cyclopentane-1, 3′-imidazo[1, 2-α]pyridin]-2-ene-3,carboxylate) that is a more effective T-type calcium channel enhancer than ST101 [20]. Acute administration of SAK3, but not ST101, significantly promotes basal ACh release in the hippocampus, an effect blocked by treatment with the T-type calcium channel inhibitor NNC 55-0396 and/or Cav3.1 channel deficiency [20].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, we developed a novel spiroimidazopyridine derivative called SAK3 (ethyl-8'-m e t h y l -2 ' , 4 -d i o x o -2 -[ p i p e r i d i n -1 -y l ] -2 ' Hspiro[cyclopentane-1, 3′-imidazo[1, 2-α]pyridin]-2-ene-3,carboxylate) that is a more effective T-type calcium channel enhancer than ST101 [20]. Acute administration of SAK3, but not ST101, significantly promotes basal ACh release in the hippocampus, an effect blocked by treatment with the T-type calcium channel inhibitor NNC 55-0396 and/or Cav3.1 channel deficiency [20]. Chronic SAK3 administration prevents neuronal loss following transient brain ischemia in the hippocampal CA1 region through activation of nicotinic ACh receptor (nAChR) signaling [21].…”

Section: Introductionmentioning

confidence: 99%

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Acute Treatment with T-Type Calcium Channel Enhancer SAK3 Reduces Cognitive Impairments Caused by Methimazole-Induced Hypothyroidism Via Activation of Cholinergic Signaling

Noreen¹,

Yabuki²,

Shinoda³

et al. 2018

Pharmacology

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Hypothyroidism is a common disorder that is associated with psychological disturbances such as dementia, depression, and psychomotor disorders. We recently found that chronic treatment with the T-type calcium channel enhancer SAK3 prevents the cholinergic neurodegeneration induced by a single intraperitoneal (i.p.) injection of methimazole (MMI; 75 mg/kg), thereby improving cognition. Here, we evaluated the acute effect of SAK3 on cognitive impairments and its mechanism of action following the induction of hypothyroidism. Hypothyroidism was induced by 2 injections of MMI (75 mg/kg, i.p.) administered once per week. Four weeks after the final MMI treatment, MMI-treated mice showed reduced serum thyroxine (T4) levels and cognitive impairments without depression-like behaviors. Although acute SAK3 (1.0 mg/kg, p.o.) administration failed to ameliorate the decreased T4 levels and histochemical destruction of the glomerular structure, acute SAK3 (1.0 mg/kg, p.o.) administration significantly reduced cognitive impairments in MMI-treated mice. Importantly, the α7 nicotinic acetylcholine receptor (nAChR)-selective inhibitor methyllycaconitine (MLA; 12 mg/kg, i.p.) and T-type calcium channel-specific blocker NNC 55–0396 (25 mg/kg, i.p.) antagonized the acute effect of SAK3 on memory deficits in MMI-treated mice. We also confirmed that acute SAK3 administration does not rescue reduced olfactory marker protein or choline acetyltransferase immunoreactivity levels in the olfactory bulb or medial septum. Taken together, these results suggest that SAK3 has the ability to improve the cognitive decline caused by hypothyroidism directly through activation of nAChR signaling and T-type calcium channels.

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Section: Discussionmentioning

confidence: 67%

Section: Experimental Designmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Acute Treatment with T-Type Calcium Channel Enhancer SAK3 Reduces Cognitive Impairments Caused by Methimazole-Induced Hypothyroidism Via Activation of Cholinergic Signaling

Noreen¹,

Yabuki²,

Shinoda³

et al. 2018

Pharmacology

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“…This suggests that, depending on the biophysical mechanism for tremor frequency oscillations in the VIM, blocking T-type Ca 2+ channels would have opposite effects. However, tremor frequency activity in both networks was paradoxically reduced by increases in T-type Ca 2+ , suggesting that T-type Ca 2+ agonists such as ST101 or SAK3 [55,64] may work to reduce tremor in either case.…”

Section: Tremor Frequency Activity Depended On T-type Ca 2+ In Vim Cellsmentioning

confidence: 99%

Biophysical modeling of VIM to assess contributions of oscillatory activity to essential tremor

Lee

Segar

Asaad

et al. 2018

Preprint

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Essential tremor (ET) is the most common movement disorder, in which the primary symptom is a prominent, involuntary 4-10 Hz rhythmic movement. The presence of tremor frequency activity in the ventral intermediate nucleus of the thalamus (VIM) is well established, but it is often assumed that it is driven by cerebellar tremor frequency activity, while the role of intrinsic oscillatory activity in VIM is not clear. An improved understanding of the mechanisms of tremor and non-tremor activity in the VIM may lead to better pharmacological and neuromodulatory therapies. We recorded local field activity during tremor in the VIM from 5 patients during deep brain electrode implantation surgery to constrain a biophysically-principled computational model of tremor field activity in the VIM, coupled with the thalamic reticular nucleus (TRN). We compared tremor frequency activity in the model generated either by extrinsic tremor-periodic drive or by intrinsic VIM-TRN interaction. Extrinsic and intrinsic tremor frequency oscillations in the model depended on T-type Ca 2+ channels in different ways. Both also depended on GABA modulation in a site-and type-specific manner. These results suggested that efficacy of pharmacological manipulations may depend upon the mechanisms generating tremor activity in VIM. Simulated non-tremor-related cerebellar drive decreased extrinsic tremor activity but increased intrinsic tremor activity. Intrinsic tremor power was increased with an external tremor frequency drive, suggesting that both mechanisms may be important to understand the emergence and cessation of tremor activity in VIM. Our results lead to experimentally testable predictions on modulating tremor frequency activity that can help to improve future treatment strategies for ET. 2. CC-BY-NC-ND 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/339846 doi: bioRxiv preprint first posted online Jun. 7, 2018; Biophysical Modeling of VIM Activity in ET S. Lee et al. Significance StatementEssential Tremor (ET) is a movement disorder in which the primary symptom is a prominent, involuntary, and rhythmic shaking, often of the arms. Electrical activity in many areas of the brain exhibit rhythmicity that is related to the patient's tremor. One such area resides in a brain structure called the thalamus, but it is not fully known what gives rise to the tremor-related activity. Here, we recorded electrical activity from the thalamus in ET patients and created a computational model of this activity in the thalamus. Model results suggest how to differentiate tremor mechanisms and how these differences may contribute to other impairments in ET. Knowledge of the biophysical mechanisms contributing to tremor can ultimately lead to improvements in treatments to improve symptoms of ET.

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SAK3-Induced Neuroprotection Is Mediated by Nicotinic Acetylcholine Receptors

Fukunaga

Yabuki

2018

Nicotinic Acetylcholine Receptor Signaling in Neuroprotection

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Cholinergic neurotransmission plays a critical role in neuronal plasticity and cell survival in the central nervous system (CNS). Two types of acetylcholine receptors (AChRs), muscarinic AChRs (mAChRs) and nicotinic AChRs (nAChRs), trigger intracellular signaling through G protein activity and ion influx, respectively. To assess mechanisms underlying neuroprotection through nAChRs, we developed SAK3, a novel modulator of nAChR activity. Recently, we found that SAK3 enhances T-type calcium channel activity, promoting ACh release in the hippocampal CA1 region of olfactory-bulbectomized mice. Here, we observed potent SAK3 neuroprotective activity in mice with 20-min bilateral common carotid artery occlusion (BCCAO) or hypothyroidism. Treatment of mice with the α7 nAChR-selective inhibitor methyllycaconitine (0.5 mg/kg/day, p.o.) antagonized SAK3-mediated neuroprotection and memory improvement in BCCAO mice. Single administration of the anti-Graves' disease therapeutic methimazole (MMI) to female mice disrupted olfactory bulb (OB) glomerular structure, and cholinergic neurons largely disappeared in the medial septum followed by memory loss. Chronic SAK3 (0.5-1 mg/kg, p.o.) administration significantly rescued the number of cholinergic medial septum neurons in MMI-treated mice and improved cognitive deficits seen in those mice. Overall, our study suggests that, in mice, the novel nAChR modulator SAK3 can rescue neurons impaired by transient ischemia and hypothyroidism. We also address mechanisms common to SAK3-induced neuroprotection in both conditions.

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Pharmacological properties of SAK3, a novel T-type voltage-gated Ca2+ channel enhancer

Cited by 38 publications

References 49 publications

Acute Treatment with T-Type Calcium Channel Enhancer SAK3 Reduces Cognitive Impairments Caused by Methimazole-Induced Hypothyroidism Via Activation of Cholinergic Signaling

Acute Treatment with T-Type Calcium Channel Enhancer SAK3 Reduces Cognitive Impairments Caused by Methimazole-Induced Hypothyroidism Via Activation of Cholinergic Signaling

Biophysical modeling of VIM to assess contributions of oscillatory activity to essential tremor

SAK3-Induced Neuroprotection Is Mediated by Nicotinic Acetylcholine Receptors

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