Inhibition of neuronal Ca2+ influx by gabapentin and pregabalin in the human neocortex

Fink, Klaus; Dooley, David; Meder, Wolfgang P.; Suman‐Chauhan, N.; Duffy, Sandra; Clusmann, Hans; Göthert, M.

doi:10.1016/s0028-3908(01)00172-1

Cited by 447 publications

(246 citation statements)

References 25 publications

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“…For example, voltagedependent Ca 2ϩ and NMDA channel activities decrease on actin depolymerization (Johnson and Byerly 1993;Rosenmund and Westbrook 1993;Akopian et al, 2006). Conversely, primary hippocampal neurons cultured from mice lacking gelsolin exhibit enhanced Ca 2ϩ influx after exposure to glutamate (Furukawa et al, 1997 influx and neurotransmitter release because they retain the machinery for the uptake, storage, and exocytosis of neurotransmitters (Fink et al, 2002a;Baldwin et al, 2003). Ca 2ϩ release from intrasyn- ] i increase (Mulkey and Zucker, 1991).…”

Section: Discussionmentioning

confidence: 99%

Impact of Actin Filament Stabilization on Adult Hippocampal and Olfactory Bulb Neurogenesis

Kronenberg¹,

Gertz²,

Baldinger³

et al. 2010

J. Neurosci.

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Rearrangement of the actin cytoskeleton is essential for dynamic cellular processes. Decreased actin turnover and rigidity of cytoskeletal structures have been associated with aging and cell death. Gelsolin is a Ca 2ϩ -activated actin-severing protein that is widely expressed throughout the adult mammalian brain. Here, we used gelsolin-deficient (Gsn Ϫ/Ϫ ) mice as a model system for actin filament stabilization. In Gsn Ϫ/Ϫ mice, emigration of newly generated cells from the subventricular zone into the olfactory bulb was slowed. In vitro, gelsolin deficiency did not affect proliferation or neuronal differentiation of adult neural progenitors cells (NPCs) but resulted in retarded migration. Surprisingly, hippocampal neurogenesis was robustly induced by gelsolin deficiency. The ability of NPCs to intrinsically sense excitatory activity and thereby implement coupling between network activity and neurogenesis has recently been established. Depolarization-induced [Ca 2ϩ ] i increases and exocytotic neurotransmitter release were enhanced in Gsn Ϫ/Ϫ synaptosomes. Importantly, treatment of Gsn Ϫ/Ϫ synaptosomes with mycotoxin cytochalasin D, which, like gelsolin, produces actin disassembly, decreased enhanced Ca 2ϩ influx and subsequent exocytotic norepinephrine release to wild-type levels. Similarly, depolarization-induced glutamate release from Gsn Ϫ/Ϫ brain slices was increased. Furthermore, increased hippocampal neurogenesis in Gsn Ϫ/Ϫ mice was associated with a special microenvironment characterized by enhanced density of perfused vessels, increased regional cerebral blood flow, and increased endothelial nitric oxide synthase (NOS-III) expression in hippocampus. Together, reduced filamentous actin turnover in presynaptic terminals causes increased Ca 2ϩ influx and, subsequently, elevated exocytotic neurotransmitter release acting on neural progenitors. Increased neurogenesis in Gsn Ϫ/Ϫ hippocampus is associated with a special vascular niche for neurogenesis.

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Section: Discussionmentioning

confidence: 99%

Impact of Actin Filament Stabilization on Adult Hippocampal and Olfactory Bulb Neurogenesis

Kronenberg¹,

Gertz²,

Baldinger³

et al. 2010

J. Neurosci.

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“…GBP exerts effects on the extrinsic properties of neurons (i.e., on different neurotransmitter systems at the presynaptic and the postsynaptic site), as well as on the intrinsic properties (e.g., on voltage-dependent ionic channels) (for review, see (5,6). GBP binds to the ␣ 2 ␦ subunit of voltage-gated calcium channels and may thereby induce an inhibition of calcium currents (7)(8)(9)(10)(11)(12), but see 13). Recently GBP also was suggested to act as a K ATP channel agonist (14).…”

mentioning

confidence: 99%

Gabapentin Increases the Hyperpolarization‐activated Cation Current I_h in Rat CA1 Pyramidal Cells

Surges¹,

Freiman

Feuerstein³

2003

Epilepsia

115

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Summary:Purpose: Gabapentin (GBP) is a commonly used drug in the treatment of partial seizures, but its mode of action is still unclear. The genesis of seizures in temporal lobe epilepsy is thought to be crucially influenced by intrinsic membrane properties. Because the I h substantially contributes to the intrinsic membrane properties of neurons, the effects of GBP on the I h were investigated in CA1 pyramidal cells of rat hippocampus.Methods: CA1 pyramidal cells in hippocampal slices were examined by using the whole-cell patch-clamp technique.Results: GBP increased the I h amplitude in a concentrationdependent manner mainly by increasing the conductance, without significant changes in the activation properties or in the time course of I h . The effects ranged from ∼20% at 50 M, ∼25% at 75 M, to ∼35% at 100 M GBP (at -110 mV). In the presence of intracellular cyclic adenosine monophosphate (cAMP), the effects of GBP on I h were similar to those obtained in the absence of cAMP.Conclusions: These results suggest that GBP increases the I h through a cAMP-independent mechanism. Because the applied GBP concentrations were in a clinically relevant range, the observed effect may contribute to the anticonvulsant action of GBP in partial seizures and may represent a new concept of how this anticonvulsant drug works.

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“…Similar to gabapentin, pregabalin was developed as a treatment for epileptic seizures, but it has evolved to include other indications, such as neuropathic pain [50,51]. Their mechanisms of action require the binding to the high affinity α2-delta subunit protein of the voltagegated Ca 2+ channels [52], thereby reducing release of excitatory neurotransmitters in the central nervous system [53]. To our knowledge, there has only been one retrospective case study that has examined the effects of pregabalin on spasticity [54].…”

Section: Pregabalinmentioning

confidence: 99%

Latest Approaches for the Treatment of Spasticity and Autonomic Dysreflexia in Chronic Spinal Cord Injury

Rabchevsky

Kitzman

2011

Neurotherapeutics

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Summary: Two of the most prevalent secondary complications following spinal cord injury (SCI), besides loss of function and/ or sensation below the level of injury, are uncontrolled muscle spasticity and hypertensive autonomic dysreflexia. Despite the desires of the SCI community, there have been few advances in the treatment and/or management of these fundamental impediments to the quality of life associated with chronic SCI. Therefore, the purpose of this review is to focus on current drug treatment strategies that alleviate symptoms of spasticity and autonomic dysfunction. Subsequently, looking ahead, we discuss whether individuals suffering from autonomic dysreflexia and/or muscle spasms can take certain compounds that specifically and rapidly block the neurotransmission of pain into the injured spinal cord to get rapid relief for both aberrant reflexes for which painful stimuli below the level of SCI are common precipitants.

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Inhibition of neuronal Ca2+ influx by gabapentin and pregabalin in the human neocortex

Cited by 447 publications

References 25 publications

Impact of Actin Filament Stabilization on Adult Hippocampal and Olfactory Bulb Neurogenesis

Impact of Actin Filament Stabilization on Adult Hippocampal and Olfactory Bulb Neurogenesis

Gabapentin Increases the Hyperpolarization‐activated Cation Current I_h in Rat CA1 Pyramidal Cells

Latest Approaches for the Treatment of Spasticity and Autonomic Dysreflexia in Chronic Spinal Cord Injury

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Inhibition of neuronal Ca2+ influx by gabapentin and pregabalin in the human neocortex

Cited by 447 publications

References 25 publications

Impact of Actin Filament Stabilization on Adult Hippocampal and Olfactory Bulb Neurogenesis

Impact of Actin Filament Stabilization on Adult Hippocampal and Olfactory Bulb Neurogenesis

Gabapentin Increases the Hyperpolarization‐activated Cation Current Ih in Rat CA1 Pyramidal Cells

Latest Approaches for the Treatment of Spasticity and Autonomic Dysreflexia in Chronic Spinal Cord Injury

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Gabapentin Increases the Hyperpolarization‐activated Cation Current I_h in Rat CA1 Pyramidal Cells