MPP+-Lesioned Mice: an Experimental Model of Motor, Emotional, Memory/Learning, and Striatal Neurochemical Dysfunctions.

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces motor and nonmotor dysfunctions resembling Parkinson's disease (PD); however, studies investigating the effects of 1-methyl-4-phenylpyridinium (MPP+), an active oxidative product of MPTP, are scarce. This study investigated the behavioral and striatal neurochemical changes (related to oxidative damage, glial markers, and neurotrophic factors) 24 h after intracerebroventricular administration of MPP+ (1.8-18 µg/mouse) in C57BL6 mice. MPP+ administration at high dose (18 µg/mouse) altered motor parameters, since it increased the latency to leave the first quadrant and reduced crossing, rearing, and grooming responses in the open-field test and decreased rotarod latency time. MPP+ administration at low dose (1.8 µg/mouse) caused specific nonmotor dysfunctions as it produced a depressive-like effect in the forced swim test and tail suspension test, loss of motivational and self-care behavior in the splash test, anxiety-like effect in the elevated plus maze test, and short-term memory deficit in the step-down inhibitory avoidance task, without altering ambulation. MPP+ at doses of 1.8-18 µg/mouse increased tyrosine hydroxylase (TH) immunocontent and at 18 µg/mouse increased α-synuclein and decreased parkin immunocontent. The astrocytic calcium-binding protein S100B and glial fibrillary acidic protein (GFAP)/S100B ratio was decreased following MPP+ administration (18 µg/mouse). At this highest dose, MPP+ increased the ionized calcium-binding adapter molecule 1 (Iba-1) immunocontent, suggesting microglial activation. Also, MPP+ at a dose of 18 µg/mouse increased thiobarbituric acid reactive substances (TBARS) and glutathione (GSH) levels and increased glutathione peroxidase (GPx) and hemeoxygenase-1 (HO-1) immunocontent, suggesting a significant role for oxidative stress in the MPP+-induced striatal damage. MPP+ (18 µg/mouse) also increased striatal fibroblast growth factor 2 (FGF-2) and brain-derived neurotrophic factor (BDNF) levels. Moreover, MPP+ decreased tropomyosin receptor kinase B (TrkB) immunocontent. Finally, MPP+ (1.8-18 µg/mouse) increased serum corticosterone levels and did not alter acetylcholinesterase (AChE) activity in the striatum but increased it in cerebral cortex and hippocampus. Collectively, these results indicate that MPP+ administration at low doses may be used as a model of emotional and memory/learning behavioral deficit related to PD and that MPP+ administration at high dose could be useful for analysis of striatal dysfunctions associated with motor deficits in PD.

Antinociceptive effects of (1→3),(1→6)-linked ß-glucan isolated from Pleurotus pulmonarius in models of acute and neuropathic pain in mice: evidence for a role for glutamatergic receptors and cytokine pathways.

UNLABELLED: The present study evaluated the antinociceptive effect of (1→3),(1→6)-linked ß-glucan (GL) isolated from Pleurotus pulmonarius (Fr.) Quel. in mice and its possible mechanism of action. Intraperitoneal administration of GL inhibited glutamate-induced licking with an ID(50) of 0.34 mg/kg and inhibition of 96% ± 3%. The treatment of animals with GL (1 mg/kg i.p.) inhibited nociception induced by intrathecal injection of N-methyl-D-aspartic acid, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, kainate and interleukin -1ß in 67% ± 13%, 89% ± 11%, 74% ± 9%, and 75% ± 7%, respectively, but not the nociceptive response induced by (±)-1-aminocyclopentane-trans-1,3-dicarboxylic acid, substance P, and tumor necrosis factor-α. Moreover, GL (30 mg/kg i.p.) also reduced mechanical allodynia caused by partial sciatic nerve ligation for 2 hours, with inhibition of 47% ± 10% observed 0.5 hours after treatment. When given chronically (twice a day) over 7 days, GL reversed the mechanical allodynia caused by partial sciatic nerve ligation (inhibition of 45% ± 13% to 60% ± 8%). Interestingly, GL did not affect the locomotor activity of mice in an open field test with doses that produce antinociceptive effects. Our findings show that GL inhibits acute and neuropathic pain in mice through mechanisms that involve the inhibition of ionotropic glutamate receptors and the interleukin -1ß pathway. PERSPECTIVE: This article presents the antinociceptive activity of GL in acute and neuropathic pain with participation of ionotropic glutamate receptors and pro-inflammatory cytokines (interleukin-1ß). After further experiments, this compound may represent a new pharmacological agent for the treatment of clinical pain.

Evidence for a role of 5-HT(1A) receptor on antinociceptive action from Geissospermum vellosii.

ETHNOPHARMACOLOGICAL RELEVANCE: Geissospermum vellosii is a tree widely found throughout the Amazonic forest and frequently used by the native population for painful disorders. AIM OF THE STUDY: The present study examined the antinociceptive effects of Geissospermum vellosii in behavioral models of nociception. MATERIALS, METHODS AND RESULTS: Oral administration of crude extract of Geissospermum vellosii or its dichloromethane fraction (1-100 mg/kg) inhibited formalin-induced inflammatory nociception and acetic acid-induced visceral nociception. The antinociceptive effect of Geissospermum vellosii was unrelated with motor dysfunctions. Furthermore, the alkaloid 12-metoxy-1-methyl-aspidospermidine (0.001-1 mg/kg), isolated from the dichloromethane fraction, also produced antinociception. The antinociception caused by the dichloromethane fraction was significantly attenuated by pre-treatment of mice with p-chlorophenylalanine methyl ester (PCPA, an inhibitor of serotonin synthesis, 100 mg/kg once a day for 4 consecutive days) and WAY-100635 (a 5-HT(1A) receptor antagonist, 0.3 mg/kg). In contrast, dichloromethane fraction antinociception was not affected by pre-treatment of animals with ketanserin (a 5-HT(2) receptor antagonist, 0.3 mg/kg) or ondansetron (a 5-HT(3) receptor antagonist, 0.5 mg/kg). CONCLUSIONS: Together, these results indicate that Geissospermum vellosii produces antinociception through an interaction with 5-HT(1A) receptors. Furthermore, the alkaloid 12-metoxy-1-methyl-aspidospermidine contributes to the antinociceptive properties reported for Geissospermum vellosii.