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Nimodipine in otolaryngology: from past evidence to clinical perspectives.

Monzani D, Genovese E, Pini LA, Di Berardino F, Alicandri Ciufelli M, Galeazzi GM, Presutti L - Acta Otorhinolaryngol Ital (2015)

Bottom Line: In hair cells of both cochlea and labyrinth, calcium cytoplasmic influx is the first physiological process that activates complex intracellular enzymatic reactions resulting in neurotransmitter release.Nimodipine, a highly lipophilic 1-4 dihydropyridine that easily crosses the brain-blood barrier, is generally used to reduce the severity of neurological deficits resulting from vasospasm in patients with subarachnoid haemorrhage.Moreover, due to its selective blocking activity on L-channel calcium currents, nimodipine is also suggested to be an effective countermeasure for cochlear and vestibular dysfunctions known as channelopathies.

View Article: PubMed Central - PubMed

Affiliation: Unità Operativa Complessa di Otorinolaringoiatria. Azienda Ospedaliero-Universitaria Policlinico di Modena, Italy;

ABSTRACT
As L-type voltage-gated calcium channels (VGCCs) control Ca(2+) influx and depolarisation of cardiac and vascular smooth muscle, they represent a specific therapeutic target for calcium channel blockers (CCBs), which are approved and widely used to treat hypertension, myocardial ischaemia and arrhythmias. L-type currents also play a role in calcium entry in the sensory cells of the inner ear. In hair cells of both cochlea and labyrinth, calcium cytoplasmic influx is the first physiological process that activates complex intracellular enzymatic reactions resulting in neurotransmitter release. Excessive calcium ion entry into sensory cells, as a consequence of L-VGCCs malfunction is responsible for over-activation of phospholipase A2 and C, protein kinase II and C, nitric oxide synthase and both endonucleases and depolymerases, which can cause membrane damage and cellular death if the cytoplasmic buffering capacity is overcome. Nimodipine, a highly lipophilic 1-4 dihydropyridine that easily crosses the brain-blood barrier, is generally used to reduce the severity of neurological deficits resulting from vasospasm in patients with subarachnoid haemorrhage. Moreover, due to its selective blocking activity on L-channel calcium currents, nimodipine is also suggested to be an effective countermeasure for cochlear and vestibular dysfunctions known as channelopathies. Indeed, experimental data in amphibians and mammalians indicate that nimodipine has a stronger efficacy than other CCBs (aminopyridine, nifedipine) on voltage-dependent whole-cell currents within hair cells at rest and it is the only agent that is also effective during their mechanically induced depolarisation. In humans, the efficacy of nimodipine is documented in the medical management of peripheral vestibular vertigo, sensorineural hearing loss and tinnitus, even in a pathology as complex as Ménière's disease. Nimodipine is also considered useful in the prophylaxis of damage to the facial and cochlear nerves caused by ablative surgery of cerebellopontine tumours; it has been recently hypothesised to accelerate functional recovery of recurrent nerve lesions during thyroid cancer surgery. Further trials with adequate study design are needed to test the efficacy of nimodipine in the treatment of vertigo due to cerebrovascular disease and vestibular migraine.

No MeSH data available.


Related in: MedlinePlus

A) Calcium channel structure comprising the α1, α2δ, β, and, γ subunits. The α1 subunit, represented here with its 4-fold monomeric structure, is responsible for many of the functional characteristics of these channels, including the pore voltagedependent gating and dihydropyridine binding. The α2 is the extracellular glycosylated subunit that interacts with the α1 subunit. The δ subunit has a single transmembrane region with a short intracellular portion that serves to anchor the protein in the plasma membrane. The β subunit is the only Ca2+ channel subunit that is entirely cytoplasmic. The γ1 subunit is a glycoprotein that, for the most part, is not required to regulate the channel complex. B) The α1 subunit forms the Ca2+ selective pore, which contains voltage-sensing apparatus and drug/toxin-binding sites. This subunit contains 4 homologous domains (labelled I–IV), each containing 6 transmembrane helices (S1–S6).
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Figure 1: A) Calcium channel structure comprising the α1, α2δ, β, and, γ subunits. The α1 subunit, represented here with its 4-fold monomeric structure, is responsible for many of the functional characteristics of these channels, including the pore voltagedependent gating and dihydropyridine binding. The α2 is the extracellular glycosylated subunit that interacts with the α1 subunit. The δ subunit has a single transmembrane region with a short intracellular portion that serves to anchor the protein in the plasma membrane. The β subunit is the only Ca2+ channel subunit that is entirely cytoplasmic. The γ1 subunit is a glycoprotein that, for the most part, is not required to regulate the channel complex. B) The α1 subunit forms the Ca2+ selective pore, which contains voltage-sensing apparatus and drug/toxin-binding sites. This subunit contains 4 homologous domains (labelled I–IV), each containing 6 transmembrane helices (S1–S6).

Mentions: Malfunction of VGCCs can lead to an excess of intracellular calcium that over-activates enzymes such as nucleases 20 and phospholipases 21 causing DNA injury and breakdown of phospholipids, respectively, which in turn irreversibly damage the membrane causing cellular death. VGCCs are complex proteins composed of distinct subunits (α1, α2δ, β1-4, and γ) (Fig. 1). The α1 subunit with a mass of 190 to 250 kDa is the largest. It represents the primary subunit that forms the ion conducting pore necessary for channel functioning, determines most of the channel voltage-dependent opening and closing behaviours and contains the drug/toxin-binding sites. It is encoded by at least 10 different genes in mammals. It consists of four homologous (I-IV) domains containing six transmembrane α-helices each (S1-S6) 22. The other subunits only exert an auxiliary modulation of the pharmacological and electrophysiological properties of VGCCs 23.


Nimodipine in otolaryngology: from past evidence to clinical perspectives.

Monzani D, Genovese E, Pini LA, Di Berardino F, Alicandri Ciufelli M, Galeazzi GM, Presutti L - Acta Otorhinolaryngol Ital (2015)

A) Calcium channel structure comprising the α1, α2δ, β, and, γ subunits. The α1 subunit, represented here with its 4-fold monomeric structure, is responsible for many of the functional characteristics of these channels, including the pore voltagedependent gating and dihydropyridine binding. The α2 is the extracellular glycosylated subunit that interacts with the α1 subunit. The δ subunit has a single transmembrane region with a short intracellular portion that serves to anchor the protein in the plasma membrane. The β subunit is the only Ca2+ channel subunit that is entirely cytoplasmic. The γ1 subunit is a glycoprotein that, for the most part, is not required to regulate the channel complex. B) The α1 subunit forms the Ca2+ selective pore, which contains voltage-sensing apparatus and drug/toxin-binding sites. This subunit contains 4 homologous domains (labelled I–IV), each containing 6 transmembrane helices (S1–S6).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4510937&req=5

Figure 1: A) Calcium channel structure comprising the α1, α2δ, β, and, γ subunits. The α1 subunit, represented here with its 4-fold monomeric structure, is responsible for many of the functional characteristics of these channels, including the pore voltagedependent gating and dihydropyridine binding. The α2 is the extracellular glycosylated subunit that interacts with the α1 subunit. The δ subunit has a single transmembrane region with a short intracellular portion that serves to anchor the protein in the plasma membrane. The β subunit is the only Ca2+ channel subunit that is entirely cytoplasmic. The γ1 subunit is a glycoprotein that, for the most part, is not required to regulate the channel complex. B) The α1 subunit forms the Ca2+ selective pore, which contains voltage-sensing apparatus and drug/toxin-binding sites. This subunit contains 4 homologous domains (labelled I–IV), each containing 6 transmembrane helices (S1–S6).
Mentions: Malfunction of VGCCs can lead to an excess of intracellular calcium that over-activates enzymes such as nucleases 20 and phospholipases 21 causing DNA injury and breakdown of phospholipids, respectively, which in turn irreversibly damage the membrane causing cellular death. VGCCs are complex proteins composed of distinct subunits (α1, α2δ, β1-4, and γ) (Fig. 1). The α1 subunit with a mass of 190 to 250 kDa is the largest. It represents the primary subunit that forms the ion conducting pore necessary for channel functioning, determines most of the channel voltage-dependent opening and closing behaviours and contains the drug/toxin-binding sites. It is encoded by at least 10 different genes in mammals. It consists of four homologous (I-IV) domains containing six transmembrane α-helices each (S1-S6) 22. The other subunits only exert an auxiliary modulation of the pharmacological and electrophysiological properties of VGCCs 23.

Bottom Line: In hair cells of both cochlea and labyrinth, calcium cytoplasmic influx is the first physiological process that activates complex intracellular enzymatic reactions resulting in neurotransmitter release.Nimodipine, a highly lipophilic 1-4 dihydropyridine that easily crosses the brain-blood barrier, is generally used to reduce the severity of neurological deficits resulting from vasospasm in patients with subarachnoid haemorrhage.Moreover, due to its selective blocking activity on L-channel calcium currents, nimodipine is also suggested to be an effective countermeasure for cochlear and vestibular dysfunctions known as channelopathies.

View Article: PubMed Central - PubMed

Affiliation: Unità Operativa Complessa di Otorinolaringoiatria. Azienda Ospedaliero-Universitaria Policlinico di Modena, Italy;

ABSTRACT
As L-type voltage-gated calcium channels (VGCCs) control Ca(2+) influx and depolarisation of cardiac and vascular smooth muscle, they represent a specific therapeutic target for calcium channel blockers (CCBs), which are approved and widely used to treat hypertension, myocardial ischaemia and arrhythmias. L-type currents also play a role in calcium entry in the sensory cells of the inner ear. In hair cells of both cochlea and labyrinth, calcium cytoplasmic influx is the first physiological process that activates complex intracellular enzymatic reactions resulting in neurotransmitter release. Excessive calcium ion entry into sensory cells, as a consequence of L-VGCCs malfunction is responsible for over-activation of phospholipase A2 and C, protein kinase II and C, nitric oxide synthase and both endonucleases and depolymerases, which can cause membrane damage and cellular death if the cytoplasmic buffering capacity is overcome. Nimodipine, a highly lipophilic 1-4 dihydropyridine that easily crosses the brain-blood barrier, is generally used to reduce the severity of neurological deficits resulting from vasospasm in patients with subarachnoid haemorrhage. Moreover, due to its selective blocking activity on L-channel calcium currents, nimodipine is also suggested to be an effective countermeasure for cochlear and vestibular dysfunctions known as channelopathies. Indeed, experimental data in amphibians and mammalians indicate that nimodipine has a stronger efficacy than other CCBs (aminopyridine, nifedipine) on voltage-dependent whole-cell currents within hair cells at rest and it is the only agent that is also effective during their mechanically induced depolarisation. In humans, the efficacy of nimodipine is documented in the medical management of peripheral vestibular vertigo, sensorineural hearing loss and tinnitus, even in a pathology as complex as Ménière's disease. Nimodipine is also considered useful in the prophylaxis of damage to the facial and cochlear nerves caused by ablative surgery of cerebellopontine tumours; it has been recently hypothesised to accelerate functional recovery of recurrent nerve lesions during thyroid cancer surgery. Further trials with adequate study design are needed to test the efficacy of nimodipine in the treatment of vertigo due to cerebrovascular disease and vestibular migraine.

No MeSH data available.


Related in: MedlinePlus