Long-term effects of cytokine treatment on cognitive behavioral recovery and neuronal regeneration in soman-poisoned mice.

Increasing numbers of reports have substantiated to date, a beneficial influence of cytokine treatment on neurogenesis processes in damaged rodent brains. Most of these investigations further revealed that cytokine treatment induces either partial or full recovery of cognitive behavior impaired by cerebral lesions. Hence, we investigated the effects of a cytokine treatment on neuronal regeneration and cognitive behavior in mice subjected to nerve agent exposure. Subcutaneous injection of a mixture of 40 µg/kg fibroblast growth factor-2 (FGF-2) and epidermal growth factor (EGF) was administered daily over 8 days to soman-poisoned mice (1.2 LD50 soman). Memory performances (T-maze and Morris water maze) and emotional behavior (elevated plus maze; auditory and contextual response in a fear conditioning task) were assessed on post-soman days 30 and 90. Brains were collected on post-soman days 9, 30 and 90 so as to perform NeuN-immunohistochemistry in the hippocampus and amygdala (neuronal regeneration quantification). Following soman-induced brain lesions, a spontaneous neuronal regeneration occurred in both the hippocampus and amygdala. Cytokine treatment enhanced neuronal regeneration in the hippocampus however not in the amygdala. Soman poisoning fostered altogether memory impairments as well as anxiety or fear-like behavioral disturbances in mice. A spontaneous recovery of standard emotional behavior occurred overtime. Such a recovery displayed significantly enhanced speed under cytokine treatment. Unfortunately, no memory performance recovery was evidenced in soman-intoxicated mice whether treated or not with cytokines.

Long-term behavioral consequences of soman poisoning in mice.

We investigated the long-term (up to 90 days) consequences of soman intoxication in mice on weight, motor performances (grip strength, rotarod) and mnemonic cognitive processes (T-maze, Morris water maze test). First, a relative weight loss of 20%, measured 3 days after intoxication, was evidenced as a threshold beyond which neuropathological damage was observed in the hippocampus. Animals were then distributed into either low weight loss (LWL) or high weight loss (HWL) groups according to the relative 20% weight loss threshold. Compared to controls, both groups of poisoned mice quickly exhibited a decrease in their motor performance subsequent to an acute soman toxicity phase. Then, total motor recovery occurred for the LWL group. Comparatively, HWL mice showed only transient recovery prior to a second decrease phase due to soman-induced delayed toxicity. One month after intoxication, mnemonic cognitive performances of the LWL group were similar to controls while the HWL group did not exhibit any learning skill. Three months after poisoning, compared to controls, the LWL group showed similar mnemonic performances in the maze test but a mild deficit in the Morris water maze task. At the same time, learning skills slightly recovered in the HWL group. Mnemonic cognitive data are discussed in relation to the neuropathology, neurogenesis and sprouting occurring in the hippocampus of soman-intoxicated animals.

Review of the value of huperzine as pretreatment of organophosphate poisoning.

Today, organophosphate (OP) nerve agents are still considered as potential threats in both military or terrorism situations. OP agents are potent irreversible inhibitors of central and peripheral acetylcholinesterases. Pretreatment of OP poisoning relies on the subchronic administration of the reversible acetylcholinesterase (AChE) inhibitor pyridostigmine (PYR). Since PYR does not penetrate into the brain, it does not afford protection against seizures and subsequent neuropathology induced by an OP agent such as soman. Comparatively, huperzine (HUP) is a reversible AChE inhibitor that crosses the blood-brain barrier. HUP is presently approved for human use or is in course of clinical trials for the treatment of Alzheimer's disease or myasthenia gravis. HUP is also used as supplementary drug in the USA for correction of memory impairment. Besides, HUP has also been successfully tested for pretreatment of OP poisoning. This review summarizes the therapeutical value of HUP in this field. Moreover, the modes of action of HUP underlying its efficacy against OP agents are described. Efficacy appears mainly related to both the selectivity of HUP for red cell AChE which preserves scavenger capacity of plasma butyrylcholinesterases for OP agents and to the protection conferred by HUP on cerebral AChE. Finally, recent data, showing that HUP seems to be devoid of deleterious effects in healthy subjects, are also presented. Globally, this review reinforces the therapeutical value of HUP for the optimal pretreatment of OP poisoning.

Effects of chronic administration of huperzine A on memory in guinea pigs.

Effects of subchronic administration of huperzine A, a cholinesterase inhibitor, on spatial memory were studied in guinea pig. Spatial memory was appreciated by the Morris water maze test. At a dose of 0.25 microgram/h, inhibiting 36% of blood AChE and 14-20% of central AChE, no effect on spatial learning was found. At a dose of 1 microgram/h, inhibiting 20% of blood AChE and 14-20% of central AChE, no memory impairment was found, on the other hand, a memory enhancing effect, limited to the first day was shown. It thus appears that subchronic administration of huperzine A did not induce deleterious effects on spatial memory.