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Inhibition of phosphodiesterase type 1 may lead to phosphorylation of AMPA receptors and its incorporation to the synapse. AC, adenyl cyclase; GC, guanylate cyclase.
Source publication
Neuronal plasticity is an essential property of the brain that is impaired in different neurological conditions. Phosphodiesterase type 1 (PDE1) inhibitors can enhance levels of the second messengers cAMP/cGMP leading to the expression of neuronal plasticity-related genes, neurotrophic factors, and neuroprotective molecules. These neuronal plastici...
Citations
... 88 In Europe, it has been approved for the treatment of dementia. 89 Its preclinical data indicated some signicant effects, such as repairing cognitive impairment in a rodent AD model, 90 downregulating BACE1, 90 decreasing oxidative stress, 91,92 and reducing mitochondrial dysfunction. 93 Despite the signicant preclinical ndings, the results of clinical studies were disappointing with regard to the improvement of AD patients. ...
Alzheimer is an irreversible progressive neurodegenerative disease that causes failure of cerebral neurons and disability of the affected person to practice normal daily life activities. There is no concrete evidence to identify the exact reason behind the disease, so several relevant hypotheses emerged, highlighting many possible therapeutic targets, such as acetylcholinesterase, cholinergic receptors, N-methyl d-aspartate receptors, phosphodiesterase, amyloid β protein, protein phosphatase 2A, glycogen synthase kinase-3 beta, β-secretase, γ-secretase, α-secretase, serotonergic receptors, glutaminyl cyclase, tumor necrosis factor-α, γ-aminobutyric acid receptors, and mitochondria. All of these targets have been involved in the design of new potential drugs. An extensive number of these drugs have been studied in clinical trials. However, only galantamine, donepezil, and rivastigmine (ChEIs), memantine (NMDA antagonist), and aducanumab and lecanemab (selective anti-Aβ monoclonal antibodies) have been approved for AD treatment. Many drugs failed in the clinical trials to such an extent that questions have been posed about the significance of some of the aforementioned targets. On the contrary, the data of other drugs were promising and shed light on the significance of their targets for the development of new potent anti-alzheimer drugs.
... In the last two decades, many pharmacological agents have been tried that can improve in better neurological outcome after stroke. [6,7] Few important agents which were tested as neuroprotective agents are selective serotonin reuptake inhibitors, [8][9][10] citicoline, [11,12] edaravone, [13,14] cerebrolysin, [15][16][17] and Phosphodiesterase Inhibitors (PDEIs) [18][19][20] Other newer neuroprotective therapies described in literature are growth factors, monoclonal antibodies, drugs, cell-based therapies, activity-based therapies, and brain stimulation-based therapies. [21] Unfortunately, after such extensive search, none of the neuroprotective agents had failed to get the approval by American, European, and Indian stroke guidelines. ...
... [18] Activation of the CREB pathway can enhance the motor recovery after stroke while blocking it can prevent stroke recovery and there are evidence that PDE1 inhibitor like vinpocetine is able to increase the expression of plasticity-related gene through activation of CREB pathway. [18,19] The cyclic AMP and cyclic GMP are rapidly converted to AMP and GMP by enzyme phosphodiesterase (PDE) at cellular level; therefore, the wanted action does not take place and we need PDEIs for blocking this conversion. PDEIs were classified into five types according to the organs they found and physiological role. ...
... [6] Therefore, type 1 PDEIs (vinpocetine) found to act through upregulation of CREB pathway through cyclic AMP and cyclic GMP modulation and result in better stroke recovery. [19,20] The role of vinpocetine in acute ischemic stroke had been reviewed in experimental and human studies, and it was proved that vinpocetine also acts though multimodal mechanisms of action like anti-inflammatory and anti-oxidative activity along with activation of CREB pathway. [20,[36][37][38][39][40][41][42] Along with the above-mentioned mechanism, vinpocetine also acts through nuclear factor kappa B (NF-κB), voltage-gated calcium and sodium channels, interleukin-8, and tumor necrosis factor-α which are overexpressed during ischemic stroke which play a potential role in the initiation of inflammation and apoptosis. ...
BACKGROUND
Stroke is a leading cause of morbidity and mortality worldwide and a leading cause of disability. None of the neuroprotective agents have been approved internationally except edaravone in Japanese guidelines in acute ischemic stroke. We here discuss that there are two types of endogenous defense mechanisms (EDMs) after acute stroke for neuromodulation and neuroregeneration, and if both can be activated simultaneously, then we can have better recovery in stroke.
AIMS AND OBJECTIVES
We aimed to study the effect of combination of neuroprotection therapies acting on the two wings of EDM in acute large-vessel middle cerebral artery (LMCA) ischemic stroke.
METHODS
Sixty patients of LMCA stroke were enrolled and randomized within 72 h into two groups of 30 patients each. The control group received standard medical care without any neuroprotective agents while the intervention group received standard medical care combined with oral citicoline with vinpocetine for 3 months with initial 1 week intravenous and edaravone and cerebrolysin injection, started within 72 h of onset of stroke. Patients were assessed on the basis of the National Institutes of Health Stroke Scale, Fugl-Meyer Assessment Score, Glasgow Coma Scale, and Mini-Mental Status Examination at admission, discharge, and after 90 days.
RESULTS
The intervention group showed significant and early improvements in motor as well as cognitive recovery.
CONCLUSION
Combination therapy for neuroprotection which is acting on two pathways of EDM can be useful in functional recovery after acute ischemic stroke.
... For example, it was demonstrated that PDE1 inhibitors induced the expression of genes related to neuronal plasticity, neurotrophic factors, as well as molecules with neuroprotective function. 49 Since PDE inhibitors have been already proposed as promising PD therapeutic compounds, 50 we decided to evaluate whether VIN could also be exerting its neuroprotective effect in PD models based on DJ-1 deficiency through a different mechanism of action, such as VGNC inhibition. These channels play a vital role in excitable cells (like cardiomyocytes and neurons) to generate and propagate action potentials. ...
Parkinson's disease (PD) is an incurable neurodegenerative disorder caused by the selective loss of dopaminergic neurons in the substantia nigra pars compacta. Current therapies are only symptomatic and are not able to stop or delay its progression. In order to search for new and more effective therapies, our group carried out a high-throughput screening assay, identifying several candidate compounds that are able to improve locomotor ability in DJ-1β mutant flies (a Drosophila model of familial PD) and reduce oxidative stress (OS)-induced lethality in DJ-1-deficient SH-SY5Y human cells. One of them was vincamine (VIN), a natural alkaloid obtained from the leaves of Vinca minor. Our results showed that VIN is able to suppress PD-related phenotypes in both Drosophila and human cell PD models. Specifically, VIN reduced OS levels in PD model flies. Besides, VIN diminished OS-induced lethality by decreasing apoptosis, increased mitochondrial viability, and reduced OS levels in DJ-1-deficient human cells. In addition, our results show that VIN might be exerting its beneficial role, at least partially, by the inhibition of voltage-gated sodium channels. Therefore, we propose that these channels might be a promising target in the search for new compounds to treat PD and that VIN represents a potential therapeutic treatment for the disease.
... We report a patient with pharmacoresistant epilepsy caused by a missense GABRG2 pathogenic variant c.254T>A p.(Ile85Lys) (NM_198903.2) that initially responded dramatically to vinpocetine add-on with resolution of interictal epileptic discharges, myoclonic absences and GTCS in accordance with the principle of precision medicine. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 PDE1 inhibitors have shown promising results for the regulation of vasoconstriction, vascular and cardiac structure remodelling and neurotransmission [9]. Vinpocetine has been studied as a potential treatment of neurological conditions, such as stroke [10], Parkinson's [11], Alzheimer's [12] and Huntington's diseases [13]. ...
Introduction
Pathogenic variants of the GABRG2 gene, encoding a GABAA receptor subunit, have been associated with various epileptic syndromes and drug‐resistant epilepsy. Vinpocetine has been previously reported efficacious in a patient harboring a GABRB3 pathogenic variant, encoding another GABAA receptor subunit.
Case presentation
We describe a patient with GABRG2‐related drug‐resistant epilepsy who improved after vinpocetine treatment. An 8‐year‐old boy with a family history of epilepsy was diagnosed with early onset absence epilepsy at 6 months of age and was treated unsuccessfully with sodium valproate and ethosuximide. At 6 years of age, he developed generalized tonic–clonic seizures and increasing absences despite lamotrigine add‐on as well as learning difficulties. Brain MRI was normal and video‐EEG telemetry showed multiple myoclonic absences. An epilepsy gene panel analysis showed a GABRG2 pathogenic variant, c.254 T > A p.(Ile85Lys) (NM_198903.2), inherited from the proband's father. Seizures were resistant to several medications. After treatment with vinpocetine add‐on, the patient showed a dramatic initial response, further reduction of seizures, and improvement of his cognitive functions.
Conclusion
This case illustrates that vinpocetine could be considered in drug‐resistant epilepsies related to GABRG2 in accordance with the principles of precision medicine.
... In the last decade, phosphodiesterase (PDE) inhibitors have been of great interest because central nervous system signaling pathways can be influenced by increasing cAMP and/or cGMP. Therefore, PDE inhibitors may have neuroprotective properties and can improve neuronal plasticity in various neurodegenerative diseases [50]. Phosphodiesterase-4 (PDE4) enzymes may be one of the potential therapeutic targets, especially in people with AD who do not have an amyloid burden [51]. ...
Dementia, most often associated with neurodegenerative diseases, affects millions of people worldwide, predominantly the elderly. Unfortunately, no treatment is still available. Therefore, there is an urgent need to address this situation. This review presents the state of the art of drug discovery and developments in targeting dementia. Several approaches are discussed, such as drug repurposing, the use of small molecules, and phosphodiesterase inhibitors. Furthermore, the review also provides insights into clinical trials of these molecules. Emphasis has been placed on small molecules and multi-target-directed ligands, as well as disease-modifying therapies. Finally, attention is drawn to the possibilities of applications of nanotechnology in managing dementia.
... Increasing cAMP levels through PDE4 inhibition suppresses the immune response and increases remyelination [10]. Thus, clinical trials are underway investigating the efficacy of PDE4 inhibitors in MS [11]. Compounds that affect phosphodiesterase enzymes are under investigation for treating multiple sclerosis; even rolipram (a selective phosphodiesterase-4 inhibitor) reached clinical trials, but it failed due to its effect on the blood-brain barrier, which is also essential for MS physiopathology [12]. ...
... The effect of PDE inhibitors has been widely studied in several PD models. For example, it was demonstrated that PDE1 inhibitors induced the expression of genes related to neuronal plasticity, neurotrophic factors as well as molecules with neuroprotective function (Medina, 2011). Indeed, PDE inhibitors have been proposed as promising PD therapeutic compounds (Nthenge-Ngumbau & Mohanakumar, 2018). ...
Parkinson's disease (PD) is an incurable neurodegenerative disorder caused by the selective loss of dopaminergic neurons in the substantia nigra pars compacta . Current therapies are only symptomatic, and are not able to stop or delay its progression. In order to search new and more effective therapies, our group carried out a high-throughput screening assay, identifying several candidate compounds able to suppress motor defects in DJ-1β mutant flies (a Drosophila model of familial PD) and to reduce oxidative stress (OS)-induced lethality in DJ-1 -deficient SH-SY5Y human cells. One of them was vincamine (VIN), a natural alkaloid obtained from the leaves of Vinca minor. Our results showed that VIN is able to suppress PD-related phenotypes in both Drosophila and human cell PD models. Specifically, VIN reduced OS levels in PD model flies. Besides, VIN diminished OS-induced lethality by decreasing apoptosis, increased mitochondrial viability and reduced OS levels in DJ-1 -deficient human cells. In addition, we have demonstrated that VIN is able to exert its beneficial role, at least partially, by the inhibition of voltage-gated Na ⁺ channels. Therefore, we propose that these channels might be a promising target in the search for new compounds to treat PD, and that VIN constitutes a potential therapeutic treatment for the disease.
... Beneficial effects have been also showed when using PDE-Is acting on both cGMP and cAMP degradation. Different studies have reported a significant improvement of neuronal plasticity and long-term memory in healthy and AD animal models treated with selective PDE1-Is and PDE2-Is [78,[152][153][154]. PDE2 has been considered a good candidate for AD treatment since it is highly expressed in the limbic nervous system, and its inhibition was found to rescue learning and memory performance, decrease neuroinflammation and apoptosis, and boost the PKA-and PKG-dependent pathways in mice injected with Aβ or transgenic models of AD [88,154]. ...
The nitric oxide (NO)/cGMP pathway has been extensively studied for its pivotal role in synaptic plasticity and memory processes, resulting in an increase of cAMP response element-binding (CREB) phosphorylation, and consequent synthesis of plasticity-related proteins. The NO/cGMP/CREB signaling is downregulated during aging and neurodegenerative disorders and is affected by Amyloid-β peptide (Aβ) and tau protein, whose increase and deposition is considered the key pathogenic event of Alzheimer's disease (AD). On the other hand, in physiological conditions, the crosstalk between the NO/cGMP/PKG/CREB pathway and Aβ ensures long-term potentiation and memory formation.
This review summarizes the current knowledge on the interaction between the NO/cGMP/PKG/CREB pathway and Aβ in the healthy and diseased brain, offering a new perspective to shed light on AD pathophysiology. We will focus on the synaptic mechanisms underlying Aβ physiological interplay with cGMP pathway and how this balance is corrupted in AD, as high levels of Aβ interfere with NO production and cGMP molecular signaling leading to cognitive impairment.
Finally, we will discuss results from preclinical and clinical studies proposing the increase of cGMP signaling as a therapeutic strategy in the treatment of AD.
... Further nimodipine which is being tested pre-clinically and clinically for the treatment of AD, can possibly follow the both pathway; PDE1 inhibition and amelioration of intracellular Ca 2+ dysregulation [88]. Thus all these signify the importance of targeting the both pathways simultaneously to improve the CREB phosphorylation A detailed note on the PKA-CREB pathway and PDEI will be presented later in this review. ...
Despite large investments by industry and governments, no disease-modifying medications for the treatment of patients with Alzheimer's disease (AD) have been found. The failures of various clinical trials indicate the need for a more in-depth understanding of the pathophysiology of AD and for innovative therapeutic strategies for its treatment. Here, we review the rational for targeting IP3 signaling, cytosolic calcium dysregulation, phosphodiesterases (PDEs), and secondary messengers like cGMP and cAMP, as well as their correlations with the pathophysiology of AD. Various drugs targeting these signaling cascades are still in pre-clinical and clinical trials which support the ideas presented in this article. Further, we describe different molecular mechanisms and medications currently being used in various pre-clinical and clinical trials involving IP3/Ca⁺² signaling. We also highlight various isoforms, as well as the functions and pharmacology of the PDEs broadly expressed in different parts of the brain and attempt to unravel the potential benefits of PDE inhibitors for use as novel medications to alleviate the pathogenesis of AD.
... Cyclic nucleotide phosphodiesterases (PDE) is a family comprised of 11 enzymes from PDE1 to PDE11, responsible for degradation of cyclic nucleotides viz., cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) (Francis et al., 2011). PDE1 is present heterogeneously in several brain areas (frontal cortex, striatum, cerebellum and hippocampus) (Yan et al., 1994;Medina, 2011). PDE inhibition is known to induce phosphorylation and activation of CREB, an important downstream component of the cAMP/pCREB pathway. ...
... PDE1 inhibitors prevent the hydrolysis of cAMP/ cGMP and thereby increase the activity of dependent protein kinases (protein kinase A and protein kinase C). This results in phosphorylation and activation of CREB (Medina, 2011;Wu et al., 2018). Radio-labeled assay of vinpocetine has revealed CNS entry and binding with PDE1 enzymes with a heterogeneous distribution upon oral administration, suggesting the drug easily crosses the blood brain barrier and is accumulated in the brain upon oral administration (Gulyás et al., 2002). ...
Hyperserotonemia, during the early developmental phase, generates behavioral and biochemical phenotypes associated with autism spectrum disorder (ASD) in rats. Phosphodiesterase‑1 (PDE1) inhibitors are known to provide benefits in various brain conditions. We investigated the role of a selective PDE1 inhibitor, vinpocetine on ASD‑related behavioral phenotypes (social behavioral deficits, repetitive behavior, anxiety, and hyperlocomotion) in a developmental hyperserotonemia (DHS) rat model. Also, effects on biochemical markers related with neuronal function brain derived neurotrophic factor (BDNF) and phosphorylated cAMP response element binding protein (pCREB), inflammation interleukins (IL‑6 and IL‑10) and tumor necrosis factor-alpha (TNF‑α), and oxidative stress (TBARS and GSH) were studied in important brain areas (frontal cortex, cerebellum, hippocampus, and striatum). Administration of 5‑methoxytryptamine (5‑MT) to rats prenatally (gestational day 12) and in early developmental stages postnatal day (PND 0 - PND 20), resulted in impaired behavior and brain biochemistry. Administration of vinpocetine daily (10 and 20 mg/kg) to 5‑MT rats from PND 21 to PND 48 resulted in an improvement of behavioral deficits. Also, vinpocetine administration significantly increased the levels of BDNF, ratio of pCREB/ CREB, IL‑10, and GSH, and significantly decreased TNF‑α, IL‑6, and TBARS levels in different brain areas. Finally, our correlation analysis indicated that behavioral outcomes were significantly associated with the biochemical outcome. Vinpocetine, a selective PDE1 inhibitor, rectified important behavioral phenotypes related with ASD, possibly by improving markers of neuronal function, brain inflammation, and brain oxidative stress. Thus, PDE1 could be a potential target for pharmacological interventions and furthering our understanding of ASD pathogenesis.
