Hyperexcitability, neuronal

Sodium channel blockers including local anesthetic, anticonvulsant and antiarrhythmic drugs exhibit voltage- and frequency-dependent blockade which makes them useful drugs for blocking hyperexcitable neurons... 

The common mechanism of voltage- and frequency-dependent block of sodium channels gives rise to a preferred block of hyperexcitable neurons within pain pathways and comparatively less interference with normal physiological sensory and motor function. In clinical studies, adverse effects are usually reported as mild or moderate however, there are also rare, but life-threatening incidents associated with the central nervous and cardiovascular systems. 

Increased stimulations from the cerebral neurons or lack of inhibition in the spinal cord or at the skeletal muscles cause hyperexcitable neurons, resulting in increased muscle tone and spasticity. 

Drew LJ, Harris J, Milins PJ, Kendall DA, Chapman V (2000) Activation of spinal cannabinoid 1 receptors inhibits C-fibre driven hyperexcitable neuronal responses and increases [35S]GTPgammaS binding in the dorsal horn of the spinal cord of noninflamed and inflamed rats. Eur J Neurosci 12 2079-2086... 

Synchronization of hyperexcitable neurons is dependent on ionic currents that flow through sodium, potassium, and calcium channels. Alterations in ion channels are seen in both animal models and surgically resected human tissue (Lombardo et al., 1996 Beck et al., 1997 Vreugdenhil et al., 1998 Straub et al., 2000). 

Ligand based design and synthesis of imidazolidine-2,4-dione analogs for their use as inhibitors of hyperexcited neuronal voltage-gated sodium channels... 

Isaacs syndrome (an acquired neuromyotonia) is caused by autoantibodies directed against 4-aminopyr-idine or a-dendrotoxin-sensitive K+ channels (Kvl.l and Kvl.6) in motor and sensory neurons. The syndromes include muscle twitching during rest, cramps during muscle contraction, impaired muscle relaxation, and muscle weakness due to hyperexcitability of peripheral motor nerves. 

Centrally mediated hyperalgesia involves the hyperexcitability of second-order sensory neurons in the dorsal horn of the spinal cord. In the case of severe or persistent tissue injury, C fibers fire action potentials... 

Mechanisms that may contribute to synchronous hyperexcitability include Alterations of ion channels in neuronal membranes... 

Pharmacology The primary site of action of hydantoins appears to be the motor cortex, where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, hydantoins tend to stabilize the threshold against hyperexcitability. 

In epilepsy certain neurons and/or groups of neurons become hyperexcitable and begin firing bursts of action potentials that propagate in a synchronous manner to other brain structures (and in the case of generalized seizures, to practically all areas of the brain). These may be the result of abnormalities in neuronal membrane stability or in the connections among neurons. It is known that the epileptic bursts consist of sodium-dependent action potentials and a calcium-dependent depolarizing potential. 

Mectianism of Action An anticonvulsant that blocks sodium channels, resulting in stabilization of hyperexcited neural membranes, inhibition of repef if ive neuronal firing, and diminishing synapfic impulses. Therapeutic Effect Prevenfs seizures. Pharmacokinetics Complefely absorbed from GI tract and extensively metabolized in the liver to active metabolite. Protein binding 40%. Primarily excreted in urine. Half-life 2 hr metabolite, 6-10 hr. 

Mechanism of Action An anticonvulsant agent that stabilizes neuronal membranes in motor cortex, and decreases abnormal ventricular automaticity. Therapeutic Effect Limits spread of seizure activity Stabilizes threshold against hyperexcitability. Decreases post-tetanic potentiation and repetitive discharge. Shortens refractory period, QT interval, and action potential duration. 

It is a keto analog of carbamazepine. It produces blockade of voltage sensitive sodium channels, leading to stabilisation of hyperexcited neural membranes, inhibition of repetitive neuronal firing and diminution of propagation of synaptic impulses. 

Metabolites that are less reactive than suicide inhibitors may impact more distant enzymes, within the same cell, adjacent cells, or even in other tissues and organs, far removed from the original site of primary metabolism. For example, organopho-sphates (OPs), an ingredient in many pesticides, are metabolized by hepatic CYPs to intermediates, which, when transported to the nervous system, inhibit esterases that are critical for neural function. Acetylcholinesterase (AChE) catalyzes the hydrolysis of the ester bond in the neurotransmitter, acetylcholine, allowing choline to be recycled by the presynaptic neurons. If AChE is not effectively hydrolyzed by AChE in this manner, it builds up in the synapse and causes hyperexcitation of the postsynaptic receptors. The metabolites of certain insecticides, such as the phos-phorothionates (e.g., parathion and malathion) inhibit AChE-mediated hydrolysis. Phosphorothionates contain a sulfur atom that is double-bonded to the central phosphorus. However, in a CYP-catalyzed desulfuration reaction, the S atom is... 

Stabilizes the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient, possibly by promoting sodium efflux from neurons... 

Let me emphasize that these findings clearly demonstrate that the brain can generate its own information, independent of any external inputs, simply by changing the excitability of certain of its component neurons. In this case, the pontine neurons that become hyperexcitable almost certainly include the cholinergic elements of the PPT, and there is abundant evidence indicating that the PGO waves can be experimentally induced... 

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