Experimental neurology
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Experimental neurology · Jul 2000
Lentiviral vectors as a gene delivery system in the mouse midbrain: cellular and behavioral improvements in a 6-OHDA model of Parkinson's disease using GDNF.
Local delivery of therapeutic molecules represents one of the limiting factors for the treatment of neurodegenerative disorders. In vivo gene transfer using viral vectors constitutes a powerful strategy to overcome this limitation. The aim of the present study was to validate the lentiviral vector as a gene delivery system in the mouse midbrain in the perspective of screening biotherapeutic molecules in mouse models of Parkinson's disease. ⋯ Apomorphine-induced rotation was significantly decreased in the GDNF-injected group compared to control animals. Moreover, GDNF efficiently protected 69.5% of the tyrosine hydroxylase-positive cells in the substantia nigra against 6-hydroxydopamine-induced toxicity compared to 33.1% with control mutated GDNF. These data indicate that lentiviral vectors constitute a powerful gene delivery system for the screening of therapeutic molecules in mouse models of Parkinson's disease.
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Experimental neurology · Jun 2000
A behavioral test paradigm to measure the aversive quality of inflammatory and neuropathic pain in rats.
The present experiment assessed the aversive quality of neuropathic and inflammatory pain in rats. Compared to sham-treated animals, L5 ligated (neuropathic) and complete Freund's adjuvant (inflammatory)-treated animals displayed an initial period of escape followed by avoidance of a preferred location of the test chamber that was associated with mechanical stimulation of the hyperalgesic paw. The onset of the avoidance behavior occurred during the first 10-15 min of behavioral testing and was maximal at 30 min. It is concluded that animals find mechanical stimulation of the hyperalgesic paw aversive and that this behavioral test paradigm is an additional method that may be used to assess nociception in rat neuropathic and inflammatory models.
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Experimental neurology · May 2000
In situ produced 7-chlorokynurenate provides protection against quinolinate- and malonate-induced neurotoxicity in the rat striatum.
Excitotoxic mechanisms may play a critical role in the pathophysiology of several neurological and psychiatric diseases. Excitatory amino acid receptor antagonists are therefore of great therapeutic interest, but untoward side effects often prevent their clinical use. Targeting the glycine coagonist site of the (NMDA) receptor may bypass these shortcomings. ⋯ In control striata, the treatment gave rise to 170 +/- 25 pmol 7-Cl-KYNA/mg protein, approximately six times less than an infusion of 27 nmol exogenous 7-Cl-KYNA, indicating greatly superior efficacy of the focally produced antagonist. Notably, the conversion of 4-Cl-KYN to 7-Cl-KYNA increased by 82% in the presence of QUIN. 4-Cl-KYN was also metabolized to 4-chloro-3-hydroxyanthranilate, an established, powerful inhibitor of QUIN synthesis. This unique pharmacological profile and the fact that the prodrug, unlike 7-Cl-KYNA, readily penetrates the blood-brain barrier suggest that 4-Cl-KYN may be exceptionally useful as an anti-excitotoxic agent.
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Experimental neurology · May 2000
Development of a mouse model of neuropathic pain following photochemically induced ischemia in the sciatic nerve.
A mouse model of neuropathic pain was developed by a photochemically induced ischemic nerve injury in normal male C57/BL6 mice. The ischemia was induced by unilateral irradiation of the sciatic nerve with an argon ion laser after intravenous administration of a photosensitizing dye, erythrosin B. The nerve injury resulted in a significant decrease in withdrawal threshold of the hindpaws to mechanical stimulation with von Frey hairs, as well as increased responsiveness to cold and heat stimulation. ⋯ Moreover, the nerve injury is associated with the development of abnormal pain-related behaviors. Both the behavioral and the morphological changes are correlated with the duration of irradiation. These results establish a mouse model of partial nerve injury with neuropathic pain-like behaviors which may be useful in studies using genetically modified mice.
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Experimental neurology · May 2000
Persistent neuroprotection with prolonged postischemic hypothermia in adult rats subjected to transient middle cerebral artery occlusion.
Postischemic hypothermia provides long-lasting neuroprotection against global cerebral ischemia in adult rats and gerbils. Studies indicate that hypothermia must be prolonged (e.g., 24 h) to indefatigably salvage hippocampal CA1 neurons. Delayed hypothermia also reduces focal ischemic injury. ⋯ Delayed hypothermia treatment significantly reduced cortical injury to 10% +/- 10 SD (P < 0.001) while striatal injury was marginally reduced to 79% loss +/- 17 SD (P < 0.05). Delayed hypothermia of only 34 degrees C provided long-lasting cortical and striatal protection in adult rats subjected to a severe MCAo insult. These results strongly support the clinical assessment of hypothermia in acute stroke.