Design and Assessment of a Potent Sodium Channel Blocking Derivative of Mexiletine for Minimizing Experimental Neuropathic Pain in Several Rat Models

Weston, Robert M.; Subasinghe, Kamani; Staikopoulos, Vasiliki; Jarrott, Bevyn

doi:10.1007/s11064-009-0012-y

Cited by 7 publications

(14 citation statements)

References 30 publications

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“…The pharmacological goal, therefore: target the damaged-membrane’s Nav-CLS channels with lipophilic inhibitors that, at voltages near V rest , stabilize C R or C A conformations (see Figure 1). Strongly lipophilic antagonists that readily cross the blood–brain-barrier (e.g., Weston et al, 2009) would be ideal. While these may be relatively poorer inhibitors of slow I Na (see Lenkey et al, 2011) staunching the Nav-CLS leak in mildly damaged cells before they depolarize is the “first responder” goal.…”

Section: Rudimentary Simulations For Ramp Clamp – the Simplest Modelmentioning

confidence: 99%

Left-Shifted Nav Channels in Injured Bilayer: Primary Targets for Neuroprotective Nav Antagonists?

Morris¹,

Boucher²,

Joós³

2012

Front. Pharmacol.

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Mechanical, ischemic, and inflammatory injuries to voltage-gated sodium channel (Nav)-rich membranes of axon initial segments and nodes of Ranvier render Nav channels dangerously leaky. By what means? The behavior of recombinant Nav1.6 (Wang et al., 2009) leads us to postulate that, in neuropathologic conditions, structural degradation of axolemmal bilayer fosters chronically left-shifted Nav channel operation, resulting in ENa rundown. This “sick excitable cell Nav-leak” would encompass left-shifted fast- and slow-mode based persistent INa (i.e., Iwindow and slow-inactivating INa). Bilayer-damage-induced electrophysiological dysfunctions of native-Nav channels, and effects on inhibitors on those channels, should, we suggest, be studied in myelinated axons, exploiting INa(V,t) hysteresis data from sawtooth ramp clamp. We hypothesize that (like dihydropyridines for Ca channels), protective lipophilic Nav antagonists would partition more avidly into disorderly bilayers than into the well-packed bilayers characteristic of undamaged, healthy plasma membrane. Whereas inhibitors using aqueous routes would access all Navs equally, differential partitioning into “sick bilayer” would co-localize lipophilic antagonists with “sick-Nav channels,” allowing for more specific targeting of impaired cells. Molecular fine-tuning of Nav antagonists to favor more avid partitioning into damaged than into intact bilayers could reduce side effects. In potentially salvageable neurons of traumatic and/or ischemic penumbras, in inflammatory neuropathies, in muscular dystrophy, in myocytes of cardiac infarct borders, Nav-leak driven excitotoxicity overwhelms cellular repair mechanisms. Precision-tuning of a lipophilic Nav antagonist for greatest efficacy in mildly damaged membranes could render it suitable for the prolonged continuous administration needed to allow for the remodeling of the excitable membranes, and thus functional recovery.

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Section: Rudimentary Simulations For Ramp Clamp – the Simplest Modelmentioning

confidence: 99%

Left-Shifted Nav Channels in Injured Bilayer: Primary Targets for Neuroprotective Nav Antagonists?

Morris¹,

Boucher²,

Joós³

2012

Front. Pharmacol.

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“…VGSCs are predominantly distributed in small-diameter DRG neurons that mediate nociceptive transmission via primary Aδ-and C-fibers. We know that DRG neurons contribute to below-level neuropathic pain after rodent SCI because some articles report that systemic, not intrathecal, administration of sodium-channel blockers, such as ambroxol and mexiletine, attenuated mechanical allodynia and thermal hyperalgesia in rat hind paws [12,13].…”

Section: Peripheral Sensitization After Spinal Cord Injurymentioning

confidence: 99%

Neuronal Hyperexcitability: A Substrate for Central Neuropathic Pain After Spinal Cord Injury

Gwak

Hulsebosch

2011

Curr Pain Headache Rep

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Neuronal hyperexcitability produces enhanced pain transmission in the spinal dorsal horn after spinal cord injury (SCI). Spontaneous and evoked neuronal excitability normally are well controlled by neural circuits. However, SCI produces maladaptive synaptic circuits in the spinal dorsal horn that result in neuronal hyperexcitability. After SCI, activated primary afferent neurons produce enhanced release of glutamate, neuropeptides, adenosine triphosphate, and proinflammatory cytokines, which are known to be major components for pain transmission in the spinal dorsal horn. Enhanced neurochemical events contribute to neuronal hyperexcitability, and neuroanatomical changes also contribute to maladaptive synaptic circuits and neuronal hyperexcitability. These neurochemical and neuroanatomical changes produce enhanced cellular signaling cascades that ensure persistently enhanced pain transmission. This review describes altered neurochemical and neuroanatomical contributions on neuronal hyperexcitability in the spinal dorsal horn, which serve as substrates for central neuropathic pain after SCI.

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“…It has now been established from electrophysiological and molecular biological techniques that Na v Chs play an important role in the molecular pathophysiology of DN (36). As it is known, high glucose stimulates increased kinases' activity through increased cAMP, which can increase Na v Chs trafficking and thus potentiate the sodium current (37).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the Effects of Novel Nafimidone Derivatives on Thermal Hypoalgesia in Mice with Diabetic Neuropathy

et al. 2013

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The worldwide diabetes epidemic has shown no signs of abatement. Its prevalence has more than doubled since 1980 (1). Diabetic neuropathy (DN) is the most common diabetic complication, afflicting over 50% of all diabetics. The possible biochemical pathomechanisms include oxidative stress, activation of the polyol pathway, increased advanced glycation end products (AGEs) and their receptors, impaired ionic homeostasis of cells and activation of protein kinases (PKC and PKA), and mitogen-activated protein kinases (MAPK), and inducible nitric oxide synthase (2-6).Understanding the biochemical mechanisms underlying diabetic neuropathic pain and sensory disorders requires preclinical studies in animal models. The streptozotocin (STZ)-induced diabetic rodent is the most commonly used animal model of diabetes (7,8). On the other hand, existing animal models of diabetic painful and insensate neuropathy, however, have serious limitations. Diabetic rats and mice have limited life span and rarely show evidence of overt neuropathy, such as demyelination, axonal degeneration, fiber loss, or axonal regeneration in their peripheral nerves. This makes diabetic rodents unsuitable for studying the contribution of these phenomena of DN to pain or to loss of sensory function (9). Nonetheless, despite these limitations, assessment of behavioral responses to external stimuli in diabetic rats and mice (i.e., thermal and mechanical hyper and hypoalgesia, tactile allodynia, as well as formalin-induced spontaneous nociceptive behavior) has led to identification of a number of mechanisms of loss of sensation and/or pain in diabetes (10).Decades of research elucidating the pathophysiology of diabetic neuropathy have failed, thus far, to produce a treatment that prevents or reverses its development and progression. Recently, however, numerous competing or parallel pathological pathways have begun to intersect and complement each other, illuminating potential pharmacologic targets. The current foci of diabetic neuropathy research are excessive activation of sodium channels and corrupted molecular mechanisms of cellular pathways of related kinases (11).Voltage-gated sodium channels (Na v Chs) are a necessary component of normal sensation, emotions, thoughts and movements and are of particular interest as target for neuro- ABSTRACTObjective: Diabetic neuropathy (DN) is a common complication in Diabetes Mellitus. The streptozotocin-induced diabetic rodent is the most commonly used animal model of diabetes and increased sodium channel expression and activity were revealed in this model. At this study, we evaluated the effect of three different nafimidone derivatives which have possible anticonvulsant activity on disorders of thermal pain sensation in diabetic mice.Study Design: Randomized animal experiment.Material and Methods: Mice were divided randomly into five groups (5 mice per group): Control, Diabetes, Dibetes+C1, Diabetes+C2, Diabetes+C3. We used hot and cold plate, and tail-immersion tests for assessment of thermal nociceptive response...

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Design and Assessment of a Potent Sodium Channel Blocking Derivative of Mexiletine for Minimizing Experimental Neuropathic Pain in Several Rat Models

Cited by 7 publications

References 30 publications

Left-Shifted Nav Channels in Injured Bilayer: Primary Targets for Neuroprotective Nav Antagonists?

Left-Shifted Nav Channels in Injured Bilayer: Primary Targets for Neuroprotective Nav Antagonists?

Neuronal Hyperexcitability: A Substrate for Central Neuropathic Pain After Spinal Cord Injury

Evaluation of the Effects of Novel Nafimidone Derivatives on Thermal Hypoalgesia in Mice with Diabetic Neuropathy

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