Biomedical subjects

Suzanne Evans

Publications and source records attributed to Suzanne Evans.

3 recordsLinked to original sources

PubMed2006

Dynamic changes in CA1 dendritic spines associated with ischemic tolerance.

Hippocampal CA1 neurons are particularly vulnerable to 5-10 min durations of global ischemia. These cells can develop tolerance to ischemia through prior exposure to brief episodes of ischemia (ischemic preconditioning, IP). Dendritic spines are implicated in various forms of neuroplasticity including memory and recovery of function. Here we characterized the changes in hippocampal CA1 dendritic spines during the development of ischemic tolerance and the subsequent postischemic recovery period. Gerbils received 5 min, bilateral carotid artery occlusions preceded by two 1.5 min occlusions each of which were 24 h apart (tolerance groups). Spine densities were calculated from CA1 apical and basilar dendrites in tolerant animals that survived 3 (IP3), 10 (IP10) or 30 (IP30) days as well as sham-operated animals and those that received only the two preconditioning episodes (PO). Habituation to a novel open-field was assessed 3, 7, 10 and 30 days after ischemia to gauge CA1 functional integrity. Dendritic spines were quantified from Golgi-Cox stained sections of the CA1 subfield. IP10, IP30 and PO animals had significantly higher CA1 basilar and apical spine densities than all other groups. Tolerant animals initially displayed open-field habituation impairments at a time when spine densities were reduced. Behavioral impairments gradually subsided over time in coincidence with an increase in CA1 spine densities. These findings suggest that dendritic spines may play a role in recovery of function associated with ischemic tolerance and stroke.

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PubMed2003

Long-term effects of clomethiazole in a model of global ischemia.

The failure of neuroprotective drugs in clinical trials has raised questions about the predictive value of animal models. To address this issue we reexamined the efficacy of clomethiazole using functional and histological outcome measures in combination with long-term survival times. Gerbils were exposed to 5 min of global ischemia and received 400 mg/ml clomethiazole (via osmotic minipump) plus a bolus injection (60 mg/kg) 30 min after ischemia. Brain temperature was maintained at approximately 36.5 degrees C during ischemia and for the first 30 min after ischemia, and was monitored in all groups for 24 h. Subgroups of clomethiazole-treated gerbils had their temperatures regulated in the normothermic range while in other animals temperature was not controlled. Open-field habituation tests were conducted 5, 10, 30, and 60 days after occlusion. CA1 cell counts and CA1 slice recordings were done at the conclusion of behavioral testing. Clomethiazole significantly attenuated CA1 cell loss at 10-, 30-, and 60-day survival. A modest reduction in habituation deficits was evident only on Day 10 (P < 0.05). Similarly, field potential amplitude was not maintained in the rostral CA1 region. Clomethiazole produced mild hypothermia that developed over several hours. Based on short-term CA1 cell counts, clomethiazole provided significant histological protection with limited functional preservation. Neuroprotection disappeared when longer survival times (60 day) were employed and temperature confounds eliminated. These data demonstrate the necessity of utilizing more clinically relevant survival times and carefully monitoring/regulating postischemic temperature when assessing potential neuroprotective compounds.

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PubMed2003

Treatment of dementia with neurotransmission modulation.

The prevalence of dementia is growing in developed countries where elderly patients are increasing in numbers. Neurotransmission modulation is one approach to the treatment of dementia. Cholinergic precursors, anticholinesterases, nicotine receptor agonists and muscarinic M(2) receptor antagonists are agents that enhance cholinergic neurotransmission and that depend on having some intact cholinergic innervation to be effective in the treatment of dementia. The cholinergic precursor choline alfoscerate may be emerging as a potential useful drug in the treatment of dementia, with few adverse effects. Of the anticholinesterases, donepezil, in addition to having a similar efficacy to tacrine in mild-to-moderate Alzheimer's disease (AD), appears to have major advantages; its use is associated with lower drop-out rates in clinical trials, a lower incidence of cholinergic-like side effects and no liver toxicity. Rivastigmine is efficacious in the treatment in dementia with Lewy bodies, a condition in which the other anticholinesterases have not been tested extensively to date. Galantamine is an anticholinesterase and also acts as an allosteric potentiating modulator at nicotinic receptors to increase the release of acetylcholine. Pooled data from clinical trials of patients with mild-to-moderate AD suggest that the benefits and safety profile of galantamine are similar to those of the anticholinesterases. Selective nicotine receptor agonists are being developed that enhance cognitive performance without influencing autonomic and skeletal muscle function, but these have not yet entered clinical trial for dementia. Unlike the cholinergic enhancers, the M(1) receptor agonists do not depend upon intact cholinergic nerves but on intact M(1) receptors for their action, which are mainly preserved in AD and dementia with Lewy bodies. The M(1) receptor-selective agonists developed to date have shown limited efficacy in clinical trials and have a high incidence of side effects. A major recent advancement in the treatment of dementia is memantine, a non-competitive antagonist at NMDA receptors. Memantine is beneficial in the treatment of severe and moderate-to-severe AD and may also be of some benefit in the treatment of mild-to-moderate vascular dementia. Drugs that modulate 5-HT, somatostatin and noradrenergic neurotransmission are also being considered for the treatment of dementia.

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