Postinjury scopolamine administration in experimental traumatic brain injury

The effects of Rivastigmine, a novel centrally-acting anticholinesterase agent, were evaluated on cerebral edema, neurological and motor deficits, and impairment of spatial memory induced in mice by closed-head injury (CHI). Severe injury was induced in the left hemisphere of mice under ether anesthesia. Rivastigmine (1 or 2 mg/kg) or saline (10 ml/kg) was injected SC 5 min later. Rivastigmine (2 mg/kg) reduced cerebral edema by at least 50% (p < 0.01), 24 h after CHI and accelerated the recovery of motor function 7 and 14 days after CHI. Control mice (n = 24), previously trained to find the goal platform in a Morris water maze failed to recall or relearn its position for at least 11 days post-injury. Those given a single injection of Rivastigmine (2 mg/kg) regained their pre-test latencies by the third day after CHI. The neuroprotective effects of Rivastigmine on brain edema, neurological and motor function, and performance in the Morris water maze were completely antagonized by simultaneous SC injection of either scopolamine (0.5 mg/kg) or mecamylamine (2.5 mg/kg). The antagonists alone had no significant effect on any of these parameters. These data show that the reduction by Rivastigmine of the immediate and long-term sequelae of brain injury are mediated by increased cholinergic activity at both muscarinic and nicotinic receptors.

Section: Mwm)supporting

confidence: 92%

Section: Mwm)mentioning

confidence: 93%

Rivastigmine, a Brain-Selective Acetylcholinesterase Inhibitor, Ameliorates Cognitive and Motor Deficits Induced by Closed-Head Injury in the Mouse

Chen¹,

Shohami²,

Constantini³

et al. 1998

“…Previous studies have postulated that changes in brain choline acetyltransferase (ChAT) activity and/or alterations in the density of muscarinic cholinergic receptors may be involved in TBI-induced cognitive decline. In support of this hypothesis, muscarinic receptor antagonists administered acutely following TBI have been shown to attenuate some of the biochemical and behavioral deficits that ensue Saija et al, 1988;Robinson et al, 1990;Lyeth et al, 1992;Jenkins et al, 1999). The chronic or delayed phase of TBI has also been shown to cause alterations in the functional properties of CNS cholinergic neurons.…”

Section: Discussionmentioning

confidence: 86%

Traumatic Brain Injury Reduces Hippocampal α7 Nicotinic Cholinergic Receptor Binding

Verbois¹,

Sullivan²,

Pauly³

2000

Changes in the expression of central nervous system (CNS) neurotransmitter receptors may contribute to behavioral and physiological deficits that occur following traumatic brain injury (TBI). Studies investigating the neurochemical basis for the protracted cognitive dysfunction that follows TBI have focused in part on cholinergic mechanisms. The present study compared the effects of mild and moderate cortical contusion injury (CCI) on the density of cholinergic receptor subtypes, NMDA-type glutamate receptors, and calcium channel expression. Quantitative autoradiography was used to determine the effects of CCI on receptor expression, 48 h following injury. The most robust and consistent change in receptor binding was in the density of alpha7 nicotinic receptors as determined by alpha-[125I]-bungarotoxin (BTX) binding. Bilateral deficits in BTX binding were present following both mild and moderate levels of injury. In contrast, changes in the density of alpha3/alpha4 nAChr's, muscarinic AChr's, NMDA-type glutamate receptors, and L-type calcium channel expression were more regionally restricted and lower in magnitude, as compared to changes in BTX binding. The high calcium permeability of the alpha7 nAChr may be related to the extensive decrease in BTX binding that occurs following TBI.

“…Administration of the anticholinergic scopolamine was observed to effectively attenuate both the transient (Lyeth et al, 1988a) and long-term motor deficits observed following experimental brain injury in the rat (Lyeth et al, 1988b). However, subsequent studies revealed that scopolamine was only effective within a very short therapeutic window (15 min postinjury) and was ineffective if treatment was delayed to 30 or 60 min postinjury (Lyeth et al, 1992). Other studies employing scopolamine reported that administration of this anticholinergic attenuated trauma-induced alterations in central ACh turnover, suggesting that the drug was improving motor function by blocking cholinergic neuronal activation as well as through a postsynaptic blockade of muscarinic receptors (Saija et al, 1988).…”

Section: Anticholinergics and Cholinomimeticsmentioning

confidence: 90%

Novel Pharmacologic Strategies in the Treatment of Experimental Traumatic Brain Injury: 1998

McIntosh¹,

Juhler²,

Wieloch³

1998

290

143

The mechanisms underlying secondary or delayed cell death following traumatic brain injury are poorly understood. Recent evidence from experimental models suggests that widespread neuronal loss is progressive and continues in selectively vulnerable brain regions for months to years after the initial insult. The mechanisms underlying delayed cell death are believed to result, in part, from the release or activation of endogenous "autodestructive" pathways induced by the traumatic injury. The development of sophisticated neurochemical, histopathological and molecular techniques to study animal models of TBI have enabled researchers to begin to explore the cellular and genomic pathways that mediate cell damage and death. This new knowledge has stimulated the development of novel therapeutic agents designed to modify gene expression, synthesis, release, receptor or functional activity of these pathological factors with subsequent attenuation of cellular damage and improvement in behavioral function. This article represents a compendium of recent studies suggesting that modification of post-traumatic neurochemical and cellular events with targeted pharmacotherapy can promote functional recovery following traumatic injury to the central nervous system.