Fig 1 - uploaded by Jörg Striessnig
Content may be subject to copyright.
![Properties of ( ϩ )-[ 3 H]-isradipine binding to mouse brain mem-](profile/Joerg-Striessnig/publication/23493186/figure/fig1/AS:276909876367364@1443031867505/Properties-of-3-H-isradipine-binding-to-mouse-brain-mem.png)
Source publication
![Fig. 1. Properties of ( ϩ )-[ 3 H]-isradipine binding to mouse brain mem-](profile/Joerg-Striessnig/publication/23493186/figure/fig1/AS:276909876367364@1443031867505/Properties-of-3-H-isradipine-binding-to-mouse-brain-mem_Q320.jpg)
![Fig. 5. Inhibition of ()-[ 3 H]isradipine binding to native LTCCs in...](profile/Joerg-Striessnig/publication/23493186/figure/fig5/AS:669189031337993@1536558506805/Inhibition-of-3-Hisradipine-binding-to-native-LTCCs-in-mouse-brain-membranes-and-to_Q320.jpg)
The L-type calcium channel (LTCC) isoforms Ca(v)1.2 and Ca(v)1.3 display similar 1,4-dihydropyridine (DHP) binding properties and are both expressed in mammalian brain. Recent work implicates Ca(v)1.3 channels as interesting drug targets, but no isoform-selective modulators exist. It is also unknown to what extent Ca(v)1.1 and Ca(v)1.4 contribute t...
Contexts in source publication
Context 1
... whole-brain microsomal membranes of Ca v 1.2DHP(/) mice, specific binding of the LTCC-selective high affinity probe ()-[ 3 H]isradipine decreased to 15.1 1.9% (mean S.E.M., n 5) of WT values (Fig. 1A). A significant further reduction to 4.4 0.5% (p 0.0006, unpaired t test, n 5) of WT values was observed in Ca v -DM mice. Depending on experimental condi- tions [membrane protein concentration, presence of ()-cis-dil- tiazem, see Fig. 1 and Table 1], this residual specific binding corresponded to 100 to 700 dpm and was reproducible in ...
Context 2
... high affinity probe ()-[ 3 H]isradipine decreased to 15.1 1.9% (mean S.E.M., n 5) of WT values (Fig. 1A). A significant further reduction to 4.4 0.5% (p 0.0006, unpaired t test, n 5) of WT values was observed in Ca v -DM mice. Depending on experimental condi- tions [membrane protein concentration, presence of ()-cis-dil- tiazem, see Fig. 1 and Table 1], this residual specific binding corresponded to 100 to 700 dpm and was reproducible in three individual preparations. These data demonstrate that more than 95% of LTCC-associated DHP binding in mouse brain occurs at Ca v ...
Context 3
... activity is linked to LTCCs or represents specific binding to other proteins, we further examined its properties. A hallmark of DHP interac- tion with LTCC 1 -subunits is the specific stimulation by the structurally unrelated benzothiazepine ()-cis-diltiazem through a noncompetitive interaction mechanism ( Brauns et al., 1997). As illustrated in Fig. 1B, 10 M ()-cis-diltiazem significantly enhanced ()-[ 3 H]isradipine binding to Ca v -DM brain membranes to 323 31% (n 3) of control. Further- more, binding was abolished by 300 nM unlabeled racemic isradipine (corresponding to a 150 nM concentration of the active ()-enantiomer), which indicates that the K d of the residual binding was in the ...
Context 4
... support the residual LTCC-associated binding activity detected in homozygous Ca v -DM mice. There- fore, the mutated Ca v 1.2 1 subunit resulting from their Ca v 1.2DHP(/) genotype remained as the most likely ex- planation for the residual binding. We estimated the lower affinity of the mutant Ca v 1.2 1 subunit as follows: for the experiments in Fig. 1A, we employed ()-[ 3 H]isradipine concen- trations (legend to Fig. 1) that cause similarly high occupancy of 4. Quantitative comparison of different LTCC isoform RNA transcripts in whole brain, brain re- gions, and control tissues of wild-type rats. qPCR assay results are illustrated as in Fig. 3. Relative expression levels of ...
Context 5
... Ca v -DM mice. There- fore, the mutated Ca v 1.2 1 subunit resulting from their Ca v 1.2DHP(/) genotype remained as the most likely ex- planation for the residual binding. We estimated the lower affinity of the mutant Ca v 1.2 1 subunit as follows: for the experiments in Fig. 1A, we employed ()-[ 3 H]isradipine concen- trations (legend to Fig. 1) that cause similarly high occupancy of 4. Quantitative comparison of different LTCC isoform RNA transcripts in whole brain, brain re- gions, and control tissues of wild-type rats. qPCR assay results are illustrated as in Fig. 3. Relative expression levels of individual isoforms differed sig- nificantly from each other (not indicated; ...
Context 6
... other (not indicated; one-way ANOVA, Bonferroni post-test), except for compari- sons between Ca v 1.1 and Ca v 1.4. Abbreviations are as in Fig. 3. -Brauns et al., 2004). From the difference in binding density between Ca v 1.2DHP(/) and Ca v -DM mice, the contribution of Ca v 1.3 could be calculated as 10.7% of the total binding activity (see Fig. 1A). Assuming that only Ca v 1.2 contributes to the remaining activity, 89.3% of binding in wild- type brains should be associated with Ca v 1.2; 4.4% of binding were retained in the Ca v -DM mice. If the latter represented lower affinity binding to the mutant Ca v 1.2 1 subunit, it would correspond to a 20.3-fold decrease in occupancy. ...
Context 7
... be estimated as K d2 ((K d1 F) 20.3) F, where K d1 is the K d for the wild-type Ca v 1.2 channel [0.078 nM as previously determined by us in mouse brain preparations under identical experimental condi- tions (Sinnegger-Brauns et al., 2004)] and F is the concentra- tion of free ligand (essentially identical to total ligand, 0.43 nM; see legend to Fig. 1). The 20.3-fold decrease in occupancy there- fore translates into a 127-fold increase in K d from 0.078 nM for the wild-type Ca v 1.2 channel (Sinnegger-Brauns et al., 2004) to K d2 9.88 nM for the mutant channel. This calculation is in agreement with the approximately 150-fold decrease in affinity previously estimated from ...
Similar publications
A growing body of evidence supports the 'calcium hypothesis' of Alzheimer's disease (AD), which postulates that a variety of insults might disrupt the homeostatic regulation of neuronal calcium (Ca(2+)) in the brain, resulting in the progressive symptoms that typify the disease. However, despite ongoing efforts to develop new methods for testing th...
The isradipine is the potent anti hypertensive drug, which is matrix in polymeric nanoparticle by using solvent evaporation method. In this work, 3-factor, 3-level Box-Behnken design was used to optimize the process parameters like polymer concentration (A), sonication frequency (B) and sonication time (C). Three dependent variable's particle size,...
A simple and fast analytical method of ultra-high performance liquid chromatography (UHPLC) was developed and validated in order to assay isradipine in poly(ε-caprolactone) (PCL)/polyethylene glycol (PEG) nanocapsules. Experiments were performed by UHPLC on a C18 chromatographic column at 25°C using a mobile phase composed by methanol and water (85...
The corrosion inhibition of mild steel in 1 M HCl solution by some dihydropyridine has been studied using gravimetric, electrochemical impedance spectroscopy, potentiodynamic polarization techniques and quantum chemical study. The results of weight loss and Tafel polarization measurements showed that among the studied compounds, Isradipine has good...
Citations
... In the heart, CaV1.2 channels activate the ryanodine receptor, promoting the calcium release from the sarcoplasmic reticulum [3] and shaping the cardiac action potential [4]. In the brain, CaV1.2 channels are highly expressed, representing around 90% of all the L-type calcium channels [5], and are located in multiple cerebral regions (especially in the hippocampus) and in the cerebellar cortex. The high expression in some of these regions explain the important role of CaV1.2 channels in neuronal plasticity and long-term potentiation (and, therefore, in learning and memory) [6,7]. ...
CACNA1C gene encodes the alpha 1 subunit of the CaV1.2 L-type Ca2+ channel. Pathogenic variants in this gene have been associated with cardiac rhythm disorders such as long QT syndrome, Brugada syndrome and Timothy syndrome. Recent evidence has suggested the possible association between CACNA1C mutations and neurologically-isolated (in absence of cardiac involvement) phenotypes in children, giving birth to a wider spectrum of CACNA1C-related clinical presentations. However, to date, little is known about the variety of both neurological and non-neurological signs/symptoms in the neurologically-predominant phenotypes. Methods and results: We conducted a systematic review of neurologically-predominant presentations without cardiac conduction defects, associated with CACNA1C mutations. We also reported a novel de novo missense pathogenic variant in the CACNA1C gene of a children patient presenting with constructional, dressing and oro-buccal apraxia associated with behavioral abnormalities, mild intellectual disability, dental anomalies, gingival hyperplasia and mild musculoskeletal defects, without cardiac conduction defects. Conclusions: The present study highlights the importance of considering the investigation of the CACNA1C gene in children’s neurological isolated syndromes, and expands the phenotype of the CACNA1C related conditions. In addition, the present study highlights that, even in absence of cardiac conduction defects, nuanced clinical manifestations of the Timothy syndrome (e.g., dental and gingival defects) could be found. These findings suggest the high variable expressivity of the CACNA1C gene and remark that the absence of cardiac involvement should not mislead the diagnosis of a CACNA1C related disorder.
... We selected ISR for our study because it has been widely used in preclinical in vitro and in vivo studies. In contrast to some other DHPs it lacks lower affinity targets, such as adenosine transporters (inhibited by nimodipine [26]), inner mitochondrial membrane proteins (interaction with nitrendipine [27]) and binds to Cav1.2 and Cav1.3 with subnanomolar affinity [28]. Moreover, Vascal® uno is to our knowledge the only extended-release formulation of a DHP that can be added to food while preserving its modified-release properties. ...
Studies in genetically modified animals and human genetics have recently provided new insight into the role of voltage-gated L-type Ca²⁺ channels in human disease. Therefore, the inhibition of L-type Ca²⁺ channels in vivo in wildtype and mutant mice by potent dihydropyridine (DHP) Ca²⁺ channel blockers serves as an important pharmacological tool. These drugs have a short plasma half-life in humans and especially in rodents and show high first-pass metabolism upon oral application. In the vast majority of in vivo studies, they have therefore been delivered through parenteral routes, mostly subcutaneously or intraperitoneally. High peak plasma concentrations of DHPs cause side effects, evident as DHP-induced aversive behaviors confounding the interpretation of behavioral readouts. Nevertheless, pharmacokinetic data measuring the exposure achieved with these applications are sparse. Moreover, parenteral injections require animal handling and can be associated with pain, discomfort and stress which could influence a variety of physiological processes, behavioral and other functional readouts. Here, we describe a noninvasive oral application of the DHP isradipine by training mice to quickly consume small volumes of flavored yogurt that can serve as drug vehicle. This procedure does not require animal handling, allows repeated drug application over several days and reproducibly achieves peak plasma concentrations over a wide range previously shown to be well-tolerated in humans. This protocol should facilitate ongoing nonclinical studies in mice exploring new indications for DHP Ca²⁺ channel blockers.
... ACE inhibitors mainly act on angiotensin-converting enzyme [27][28][29] and the 72 kDa type IV collagenase encoded by MMP2 [30][31][32]. Calcium channel blockers mainly act on Voltage-dependent L-type calcium channel [33,34]. ...
Background and objectives
Proteinuria is a common complication after the application of bevacizumab therapy in patients with metastatic colorectal cancer, and severe proteinuria can lead to discontinuation of the drug. There is a lack of sophisticated means to predict bevacizumab-induced proteinuria, so the present study aims to predict bevacizumab-induced proteinuria using peripheral venous blood samples.
Methods
A total of 122 subjects were enrolled and underwent pre-treatment plasma markers, and we followed them for six months with proteinuria as the endpoint event. We then analyzed the clinical features and plasma markers for grade ≥ 2 proteinuria occurrence using machine learning to construct a model with predictive utility.
Results
One hundred sixteen subjects were included in the statistical analysis. We found that high baseline systolic blood pressure, low baseline HGF, high baseline ET1, high baseline MMP2, and high baseline ACE1 were risk factors for the development of grade ≥ 2 proteinuria in patients with metastatic colorectal cancer who received bevacizumab. Then, we constructed a support vector machine model with a sensitivity of 0.889, a specificity of 0.918, a precision of 0.615, and an F1 score of 0.727.
Conclusion
We constructed a machine learning model for predicting grade ≥ 2 bevacizumab-induced proteinuria, which may provide proteinuria risk assessment for applying bevacizumab in patients with metastatic colorectal cancer.
... Our model carries a mutation equivalent to the human Ile770Met mutation found in aldosterone-producing adenomas and in PASNA syndrome (Cacna1d Ile772Met/+ ). We choose the calcium channel blocker isradipine for this study, as it combines high affinity for CaV1.3 with high brain penetration (28,29). ...
... mutations. Isradipine appears particularly suited because it has previously been shown to be one of the dihydropyridines with the greatest affinity towards CaV1.3 (28,29). Different CaV1.3 mutations vary in their response to calcium channel inhibitors, and it would be interesting to correlate clinical responses with the sensitivity of variants identified by sequencing after adrenalectomy (17). ...
... These patients often have debilitating neurological impairment, and even minor improvements could be clinically relevant. Use of amlodipine and nifedipine, respectively, has been described in two cases (8, 48), but few details were provided, and these substances show only low affinity towards CaV1.3 (29). Carefully designed protocols (perhaps using isradipine, which can be administered in yogurt to patients with difficulty 22 swallowing) and detailed documentation could be a step forward, perhaps followed by the development of more specific CaV1.3 ...
Somatic gain-of-function mutations in the L-type calcium channel CaV1.3 (CACNA1D gene) cause adrenal aldosterone-producing adenomas and micronodules. De novo germline mutations are found in a syndrome of primary aldosteronism, seizures, and neurologic abnormalities (PASNA) as well as in autism spectrum disorder. Using CRISPR/Cas9, we here generated mice with a Cacna1d gain-of-function mutation found in both adenomas and PASNA syndrome (Cacna1dIle772Met/+). These mice show reduced body weight and increased mortality from weaning to approximately 100 days of age. Male mice do not breed, likely due to neuromotor impairment, and the offspring of female mice die perinatally, likely due to lack of maternal care. Mice generated by in vitro fertilization showed elevated intracellular calcium in the aldosterone-producing zona glomerulosa, an elevated aldosterone/renin ratio, and persistently elevated serum aldosterone on a high-salt diet as signs of primary aldosteronism. Anesthesia with ketamine and xylazine induced tonic-clonic seizures. Neurologic abnormalities included hyperlocomotion, impaired performance in the rotarod test, impaired nest building, and slight changes in social behavior. Intracellular calcium in the zona glomerulosa, aldosterone levels, and rotarod performance responded to treatment with the calcium channel blocker isradipine, with implications for the therapy of patients with aldosterone-producing lesions and with PASNA syndrome.
... Likewise, C-terminal splicing in the Ca v 1.3-channel, which occurs outside the drug binding domains but causes profound changes in channel inactivation and voltage-dependence of gating, strongly affects sensitivity for the DHP nimodipine (Huang et al., 2013), later also confirmed for isradipine (Ortner et al., 2017). In contrast to isradipine, some DHPs, such as nitrendipine and nifedipine, also have lower binding affinity for Ca v 1.3, indicating subtle differences in the coordination within the two binding pockets (Sinnegger-Brauns et al., 2009). ...
... In these mice, DHPs are 'Ca v 1.3-selective' which allowed the detailed pharmacological analysis of the role of native Cav1.3 channels for many physiological functions (including behaviour, cardiac and endocrine functions) using DHPs without interference from Ca v 1.2-inhibition(Zamponi et al., 2015). Radioligand binding in these mice found that Ca v 1.3-channels comprise only about 10% of the total DHP binding sites in brain and confirmed essentially identical K D values for isradipine in brain membranes as compared to heterologously expressed Ca v 1.3 channels(Sinnegger-Brauns et al., 2009). The differences in DHP-sensitivity between Ca v 1.3 and Ca v 1.2 observed in functional studies must therefore involve conformational changes induced by changes of membrane-voltage, protein interactions and/or alternative splicing. ...
Voltage‐gated L‐type Ca²⁺‐channels (LTCCs) are the target of Ca²⁺‐channel blockers (CCBs), which are in clinical use for the evidence‐based treatment of hypertension and angina. Their cardiovascular effects are largely mediated by the Cav1.2‐subtype. However, based on our current understanding of their physiological and pathophysiological roles, Cav1.3 LTCCs also appear as attractive drug targets for the therapy of various diseases, including treatment‐resistant hypertension, spasticity after spinal cord injury and neuroprotection in Parkinson's disease. Since CCBs inhibit both Cav1.2 and Cav1.3, Cav1.3‐selective inhibitors would be valuable tools to validate the therapeutic potential of Cav1.3 channel inhibition in preclinical models. Despite a number of publications reporting the discovery of Cav1.3‐selective blockers, their selectivity remains controversial. We conclude that at present no pharmacological tools exist that are suitable to confirm or refute a role of Cav1.3 channels in cellular responses. We also suggest essential criteria for a small molecule to be considered Cav1.3‐selective.
... Unfortunately, these compounds are not subtype specific and have a higher affinity for Ca V 1.2 (Sinnegger-Brauns et al., 2009). However, because of its pathological role in Parkinson's disease (Surmeier et al., 2017) there is an ongoing effort to develop Ca V 1.3 specific ...
The calcium dysregulation hypothesis of brain aging posits that an age‐related increase in neuronal calcium concentration is responsible for alterations in a variety of cellular processes that ultimately result in learning and memory deficits in aged individuals. We previously generated a novel transgenic mouse line, in which expression of the L‐type voltage‐gated calcium, CaV1.3, is increased by ~50% over wild‐type littermates. Here, we show that, in young mice, this increase is sufficient to drive changes in neuronal physiology and cognitive function similar to those observed in aged animals. Specifically, there is an increase in the magnitude of the postburst afterhyperpolarization, a deficit in spatial learning and memory (assessed by the Morris water maze), a deficit in recognition memory (assessed in novel object recognition), and an overgeneralization of fear to novel contexts (assessed by contextual fear conditioning). While overexpression of CaV1.3 recapitulated these key aspects of brain aging, it did not produce alterations in action potential firing rates, basal synaptic communication, or spine number/density. Taken together, these results suggest that increased expression of CaV1.3 in the aged brain is a crucial factor that acts in concert with age‐related changes in other processes to produce the full complement of structural, functional, and behavioral outcomes that are characteristic of aged animals. Here we revisit the hypothesis that dysregulation of calcium homeostasis in neurons underlies age‐related changes in neuronal function and cognition. To test this hypothesis, we examined the post burst afterhyperpolarization and spatial memory in young mice genetically engineered to overexpress the L‐VGCC CaV1.3 in glutamatergic neurons in the hippocampus and forebrain.
... Other groups of Ca V that contribute to HVA currents and are abundantly expressed at soma and dendrites of mPFC neurons are Ca V 1.2 and Ca V 1.3 [43,44]; therefore, we explored if the in vivo administration of CPZ impacts Ca V 1 currents. We measured the sensitivity of native HVA calcium currents to nifedipine (10 µM), a L-type channel blocker of the dihydropyridine family [45,46], in layer 5/6 pyramidal neurons of the mPFC. ...
The dopamine receptor type 1 (D1R) and the dopamine receptor type 5 (D5R), which are often grouped as D1R-like due to their sequence and signaling similarities, exhibit high levels of constitutive activity. The molecular basis for this agonist-independent activation has been well characterized through biochemical and mutagenesis in vitro studies. In this regard, it was reported that many antipsychotic drugs act as inverse agonists of D1R-like constitutive activity. On the other hand, D1R is highly expressed in the medial prefrontal cortex (mPFC), a brain area with important functions such as working memory. Here, we studied the impact of D1R-like constitutive activity and chlorpromazine (CPZ), an antipsychotic drug and D1R-like inverse agonist, on various neuronal CaV conductances, and we explored its effect on calcium-dependent neuronal functions in the mouse medial mPFC. Using ex vivo brain slices containing the mPFC and transfected HEK293T cells, we found that CPZ reduces CaV2.2 currents by occluding D1R-like constitutive activity, in agreement with a mechanism previously reported by our lab, whereas CPZ directly inhibits CaV1 currents in a D1R-like activity independent manner. In contrast, CPZ and D1R constitutive activity did not affect CaV2.1, CaV2.3, or CaV3 currents. Finally, we found that CPZ reduces excitatory postsynaptic responses in mPFC neurons. Our results contribute to understanding CPZ molecular targets in neurons and describe a novel physiological consequence of CPZ non-canonical action as a D1R-like inverse agonist in the mouse brain.
... Neuronal LTCCs are either Ca V 1.2 or Ca V 1.3 subtype, while the Ca V 1.2 subtype is mostly expressed in the cardiovascular system (Little, 2021). Most dihydropyridine LTCC blockers display selectivity for the Ca V 1.2 subtype to mediate the antihypertensive effect (Sinnegger-Brauns et al., 2009). Isradipine has relatively similar affinity for Ca V 1.2 and Ca V 1.3 subtypes, thus it has been favored in many recent studies probing the function of neuronal LTCCs via systemic administration. ...
... Isradipine has relatively similar affinity for Ca V 1.2 and Ca V 1.3 subtypes, thus it has been favored in many recent studies probing the function of neuronal LTCCs via systemic administration. For the clinical studies discussed in this article, most proposed mechanisms fall into two categories: (a) isradipine's antagonistic effects on drug-induced dopamine (DA) release on the mesolimbic dopaminergic pathway, and (b) isradipine's hemodynamic effects on cerebral blood flow (CBF), particularly in DA-rich areas (Gaggi et al., 1995;Johnson et al., 2001;Ooboshi et al., 1993;Sauter et al., 1989). Through these mechanisms, it has been postulated that isradipine interferes with the rewarding effects, positive subject effects, and hemodynamic effects of psychostimulants, such as cocaine, d-amphetamine, and methamphetamine, and other substances. ...
Given the personal and public health burden of addictive disorders, innovative approaches to treatment are sorely needed. This systematic review examined the use of the pharmacological agent isradipine in the context of potential applications for addiction treatment. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guided a comprehensive search of PubMed, Cochrane Library, and PsycINFO between the years 1985 to July 2022. Studies were included if isradipine was administered to adults with a current Diagnostic and Statistical Manual of Mental Disorders-5th edition diagnosis of a substance use disorder and/or to healthy volunteers alone and in conjunction with a substance (i.e, cocaine, methamphetamine, alcohol). A total of 16 studies with 252 participants were included in this review. Substantial variability was identified with study designs, isradipine dosages/dosing, and addictive substance of interest. Outcomes clustered in four categories: (a) cerebral blood flow (CBF), (b) hemodynamic effects, (c) subjective effects, and (d) cognitive effects. Isradipine was found to improve CBF in individuals with cocaine-induced hypoperfusion and in several studies was found to reduce parameters of blood pressure elevation after stimulant use. There were no significant findings on isradipine's effect on subjective reporting (i.e., craving, mood, drug affect) or cognition/attention. Given the limited number of studies identified in this review, there is insufficient data to draw clear conclusions. The direct effects of isradipine as a pharmacologic agent for addictive disorder treatment appear minimal, however, future work may benefit from examining the impact of isradipine as an augmentative agent within existing cue exposure paradigms for preventing cue-induced drug relapse. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
... Neuronal LTCCs are either Ca V 1.2 or Ca V 1.3 subtype, while the Ca V 1.2 subtype is mostly expressed in the cardiovascular system (Little, 2021). Most dihydropyridine LTCC blockers display selectivity for the Ca V 1.2 subtype to mediate the antihypertensive effect (Sinnegger-Brauns et al., 2009). Isradipine has relatively similar affinity for Ca V 1.2 and Ca V 1.3 subtypes, thus it has been favored in many recent studies probing the function of neuronal LTCCs via systemic administration. ...
Over the past three decades, L-type Ca²⁺ channel (LTCC) blockers have been considered a potential therapeutic drug to alleviate the symptoms of drug addiction. This idea has been supported, in part, by 1) expression of LTCCs in the brain dopaminergic circuits that are thought to play critical roles in the development and expression of addictive behaviors and 2) common usage of LTCC blockers in treating hypertension, which may enable off-label use of these drugs with good brain penetration as therapeutics for brain disorders. Addiction can be viewed as a maladaptive form of learning where powerful memories of drug-associated stimuli and actions drive compulsive drug intake. Largely under this framework, we will focus on the dopaminergic system that is thought be critically involved in drug-associated learning and memory and provide a brief overview of the past and recent studies testing the therapeutic potential of LTCC blockers for addictive disorders in animal models and humans and offer a future perspective on the use of LTCC blockers in drug addiction and, possibly, addiction to other non-drug rewards (e.g., gambling, eating, shopping). Interested readers can refer to other related articles in this issue and a comprehensive review available elsewhere (Little, 2021) to gain further insights into the roles of LTCCs in drug addiction and withdrawal symptoms associated with dependence.
This article is part of the Special Issue on ‘L-type calcium channel mechanisms in neuropsychiatric disorders’.
... These are expressed especially in the hippocampus, amygdala, and substantia nigra, though at a different extent (approximately 90% Cav1.2 and 10% Cav1.3). 166,167 Initial pharmacological assessments, complemented by studies in genetic animal models, have dissected the role of the Cav1.2 and Cav1.3 isoforms in synaptic plasticity and learning and memory processes in CA1 pyramidal neurones in the hippocampus. 168 These studies showed the specific involvement of Cav1.2 in the consolidation or reconsolidation of spatial memory. ...
... 160 Since Cav1.2 and Cav1.3 channels have very similar pharmacological properties, CCBs discriminate between these channels only weakly. 160,166 However, the analysis of the binding of different dihydropyridines to both channels suggested some selectivity for Cav1.2 of nifedipine and nitrendipine. 160,176 The data obtained by the genetic modification of brain LTCCs suggest behavioural effects and anxiolytic-like features for CCBs, which are possibly related to the modulation of neurotransmitters release. ...
A bidirectional relationship exists between hypertension and psychiatric disorders, including unipolar and bipolar depression, anxiety, post-traumatic stress disorder (PTSD), psychosis, schizophrenia, mania, and dementia/cognitive decline. Repurposing of antihypertensive drugs to treat mental disorders is thus being explored. A systematic knowledge of the mechanisms of action and clinical consequences of the use of antihypertensive agents on neuropsychiatric functions has not been achieved yet. In this article, we review the putative role of antihypertensive agents in psychiatric disorders, discuss the targets and mechanisms of action, and examine how and to what extent specific drug classes/molecules may trigger, worsen, or mitigate psychiatric symptoms. In addition, we review pharmacokinetics (brain penetration of drugs) and pharmacogenetics data that add important information to assess risks and benefits of antihypertensive drugs in neuropsychiatric settings.
The scientific literature shows robust evidence of a positive effect of α1 blockers on PTSD symptoms, nightmares and sleep quality, α2 agonists on core symptoms, executive function and quality of life in Attention-Deficit/Hyperactivity Disorder, PTSD, Tourette’s syndrome, and β blockers on anxiety, aggression, working memory, and social communication. Renin-angiotensin system modulators exert protective effects on cognition, depression, and anxiety, and the loop diuretic bumetanide reduced the core symptoms of autism in a subset of patients. There is no evidence of clear benefits of calcium channel blockers in mood disorders in the scientific literature.
These findings are mainly from preclinical studies; clinical data are still insufficient or of anecdotal nature, and seldom systematic. The information herewith provided can support a better therapeutic approach to hypertension, tailored to patients with, or with high susceptibility to, psychiatric illness. It may prompt clinical studies exploring the potential benefit of antihypertensive drugs in selected patients with neuropsychiatric comorbidities that include outcomes of neuropsychiatric interest and specifically assess undesirable effects or interactions.
