Progress in characteristics and application of olfactory bulbectomy animal model / 药学学报

In rodents, bilateral olfactory bulbectomy (OBX) results in a series of changes in behaviors and neurobiology, similar to the clinical symptoms of depression in patients. These changes can be reversed by chronic but not acute treatment of antidepressants. Owing to the face, construct and predictive validities, the OBX model has been used to investigate the mechanisms of depression, screen for antidepressants, and reveal the mechanism of drug action. In addition, there are certain features in OBX animals resembling those of patients with Alzheimer's disease (AD), including the impaired learning and memory ability and the accumulation of amyloid-β protein (Aβ). In this review, we present the association between olfaction and depression or AD, the surgical procedure of OBX, the behavioral features of OBX animals, the abnormal changes in cortex and hippocampus, and the application of this model for studying depression and AD. These lines of information are important for the development of antidepressant and anti-dementia drugs using this model.

Surface modification of PGP for a neutrophil-nanoparticle co-vehicle to enhance the anti-depressant effect of baicalein

Exploiting cells as vehicles combined with nanoparticles combined with therapy has attracted increasing attention in the world recently. Red blood cells, leukocytes and stem cells have been used for tumor immunotherapy, tissue regeneration and inflammatory disorders, and it is known that neutrophils can accumulate in brain lesions in many brain diseases including depression. -Acetyl Pro-Gly-Pro (PGP) peptide shows high specific binding affinity to neutrophils through the CXCR2 receptor. In this study, PGP was used to modify baicalein-loaded solid lipid nanoparticles (PGP-SLNs) to facilitate binding to neutrophils . Brain-targeted delivery to the basolateral amygdala (BLA) was demonstrated by enhanced concentration of baicalein in the BLA. An enhanced anti-depressant effect was observed and The mechanism involved inhibition of apoptosis and a decrease in lactate dehydrogenase release. Behavioral evaluation carried out with rats demonstrated that anti-depression outcomes were achieved. The results indicate that PGP-SLNs decrease immobility time, increase swimming time and climbing time and attenuate locomotion in olfactory-bulbectomized (OB) rats. In conclusion, PGP modification is a strategy for targeting the brain with a cell-nanoparticle delivery system for depression therapy.

Antidepressant effects of standardized extract of Commiphora mukul Engl. in olfactory bulbectomized rats

The objective of this work was to evaluate the effects of standardized hydroalcholic extract of Commiphora mukul (HECM) in animal model of chronic stress medicated depression, namely olfactory bulbectomy (OBX) model in rats. Effects of 14-day (subacute) oral pretreatment of HECM (50, 100 and 200 mg/kg) were evaluated on depression and stress related parameters on OBX rats. Separate groups for sham control, OBX control and positive controls namely imipramine (20 mg/kg), fluoxetine (30 mg/kg) and desipramine (15 mg/kg) were also maintained. Behavioral and physiological parameters in open field and elevated plus maze were recorded. HECM showed dose-dependent reversal of OBX-induced physiological effects such as reduction of body weight, body temperature, heart rate and serum sodium concentration. HECM also showed reversal effects on OBX induced food intake increase and hyperactivity in open field and elevated plus maze paradigm. In conclusion, HECM demonstrated restorative effects in OBX induced depression model in rats probably due to stress reliving mechanisms.

Assessment of a major depression animal model for old man established with orchidectomized plus olfacto-ry bulbectomized rat / 中华行为医学与脑科学杂志

Objective To evaluate the effectiveness of a major depression animal model for old man es?tablished with orchidectomized(ORX) and subsequently olfactory bulbectomized(OBX) rat. Methods Healthy Sprague?Dawley male adult rats were randomly assigned to six groups with ten rats in each group:intact,sham?oper?ated,model,vehicle,fluoxetine plus testosterone propionate(Flu+TP) and amitriptyline plus testosterone propionate (Ami+TP) groups. ORX+OBX rat model was established. Therapy of Flu or Ami (10 mg/kg,i.p.) combined with TP(25 mg/kg,s.c.) was administered. Behavioral changes of rats in each group were detected. Results Open field test: The number of rat crossing lattices in model((124.50±14.25)lattices) or vehicle group( 118.70± 10.27) was significantly larger than those of intact(38.20±6.30),sham?operated(33.70±9.58),Flu+TP (34.00± 9.82) and Ami+TP group (35.20±12.54). The rearing number of model or vehicle group was also significantly larger than those of intact,sham?operated,Flu+TP and Ami+TP group.Statistical differences in the above corre?sponding comparisons of open field test existed (P<0.01). Forced swimming test: The immobility time of model ((131.70±32.44)s) or vehicle group ((135.10±34.01)s) was significantly longer than those of intact((66.60± 12.06)s),sham?operated((62.00±13.38)s),Flu+TP((59.60±8.89)s) and Ami+TP group ((64.80±10.78)s). There were statistical differences in the above corresponding comparisons (P<0.01). Morris water maze test: The escape latency of model((62.00±26.05)s) or vehicle group ((60.52±27.00)s) was significantly longer than those of intact((24.19±9.12)s),sham?operated((21.06±8.13)s),Flu+TP((22.88±8.01)s) and Ami+TP group ((27.04±10.11)s);while the time rat swimming in the quadrant originally put a platform of model or vehicle group was significantly shorter than those of intact,sham?operated,Flu+TP and Ami+TP group. There were statisti?cal differences in the above corresponding comparisons of Morris water maze test (P<0. 01, P<0. 05 ) . Conclusion The above data demonstrates that ORX+OBX rat model is both repeatability and reliability,and can be a major depression animal model of old man for future researches.

Effect of albiflorin on behavior and hypothalamic-pituitary-adrenocortical axis in olfactory bulbectomized rats / 中国药理学与毒理学杂志

OBJECTIVE Toexploretheantidepressanteffectsofalbiflorinandtheinvolvementof hypothalamic-pituitary-adrenocortical (HPA) axis function in its antidepressant potency.METHODS Two weeks after the olfactory bulbectomized (OB)surgery,albiflorin (2.5 ,5.0 ,10.0 mg·kg -1 ,ig) and imipramine 5.0 mg·kg -1 (ig)were given to rats twice a day for 14 d.The open-field test was con-ducted to evaluate the move ment distance,move ment ti me and velocity of olfactory bulbecto mized rats and sham-operated rats.The serum levels of corticosterone(CORT)and adrenocorticotropic hormone (ACTH)in rats were measured by the enzyme linked immunosorbent assay.The expression levels of glucocorticoids receptor (GR)in the hippocampus of the rats were analyzed using Western blot proce-dures.RESULTS Comparedwithsham-operatedrats,movementdistance,movementtimeandveloci-ty of the OB rats were significantly increased (P<0.01 ).Albiflorin 1 0.0 mg·kg -1 significantly reduced the movement distance,movement time and velocity of OB rats (P<0.05)after being given for 7 d. The movement properties were significantly reduced by albiflorin 5.0 and 10.0 mg·kg -1 when given for 14 d (P<0.05).The OB rats demonstrated significantly increased levels of serum CORT and ACTH (P<0.01 )and decreased GR expression in the hippocampus (P<0.01 ).Albiflorin 2.5,5.0 and 10.0 mg·kg -1 significantly reduced the serum CORT and ACTH levels (P<0.05),while albiflorin 5.0 and10.0mg·kg-1increasedtheexpressionofhippocampalGR(P<0.05).CONCLUSION Albiflorin may have re markable behavioral antidepressant effects on olfactory rats and one of the related mecha-nis ms may be its regulation of the hyperactivity of HPA axis function.

Anti-depressant like activity of N-n-butyl-3-methoxyquinoxaline-2-carboxamide (6o) a 5-HT3 receptor antagonist.

The compound 6o (at 0.5, 1 and 2 mg/kg, ip) with optimum log P and pA2 value, was subjected to forced swim test (FST) and tail suspension test (TST). The compound 6o significantly reduced the duration of immobility in mice without affecting the base line locomotion in actophotometer. Moreover, 6o (2 mg/kg, ip), potentiated the 5-hydroxytryptophan (5-HTP)-induced head twitch responses in mice and at 1 and 2 mg/kg, ip antagonized the reserpine-induced hypothermia (RIH) in rats. In interaction studies with various standard drugs/ligands using FST, 6o (1 and 2 mg/kg, ip) potentiated the anti-depressant effect fluoxetine (5 mg/kg, ip) and reversed the depressant effect of parthenolide (1 mg/kg, ip) by reducing the duration of immobility. Furthermore, 6o (1 and 2 mg/kg, ip) potentiated the effect of bupropion (10 mg/kg, ip) in TST. The behavioural anomalies of the olfactory bulbectomised (OBX) rats were augmented by chronic 6o (1 and 2 mg/kg) treatment as observed from the modified open field test (parameters: ambulation, rearing, fecal pellet). The results suggest that compound 6o exhibited anti-depressant like effect in rodent models of depression.

Antidepressant and anxiolytic-like effects of 4n, a novel 5-HT3 receptor antagonist using behaviour based rodent models.

The present study was designed to investigate the putative antidepressant and anxiolytic-like effects of N-n-Butylquinoxalin-2-carboxamide (4n), a novel 5-HT3 receptor antagonist, with an optimal log P (2.01) and pA2 value (7.3) greater than ondansetron (6.9) using rodent behavioural models of depression and anxiety. Acute treatment of 4n (1-4 mg/kg, ip) in mice produced antidepressant-like effect in forced swim test (FST) without affecting the baseline locomotion in actophotometer test in mice. 4n (2-4 mg/kg, ip) treatment also potentiated the 5-hydroxytryptophan (5-HTP) induced head twitch response in mice. Further, 4n (1-4 mg/kg, ip) treatment antagonized reserpine induced hypothermia in rats. Chronic treatment (14 days) with 4n (1-4 mg/kg) and paroxetine (10 mg/kg) significantly attenuated the behavioural anomalies induced by bilateral olfactory bulbectomy in rats in modified open field paradigm. An anxiogenic-like behaviour was induced by light alone as the stimulus using light-dark aversion test. 4n (2-4 mg/kg, ip) treatment significantly increased no. of transitions between dark and lit area and the time spent in the lit area. In conclusion, these preliminary investigations confirm that 4n exhibited antidepressant and anxiolytic-like effects in rodent models of depression and anxiety.

Effect of newly synthesized 1,2,4-triazino5,6-bindole-3-thione derivatives on olfactory bulbectomy induced depression in rats

<p><b>OBJECTIVE</b>To study the derivatives of 1,2,4-triazino[5,6-b]indole-3-thione for antidepressant activity in olfactory bulbectomized (OBX) rats. Out of various derivatives tested for acute tail suspension test, the two derivatives showing prominent action were selected for bilateral olfactory bulbectomy model of chronic depression in rats.</p><p><b>METHODS</b>The sub acute effects of 14-day oral pretreatment of two derivatives labeled as 3a (70 mg/kg) and 3r (70 mg/kg), imipramine (20 mg/kg), fluoxetine (30 mg/kg) and moclobemide (15 mg/kg) were evaluated on bilateral bulbectomy induced rise in body weight, hyperphagia, hyperactivity, and on sexual dysfunction. The serum sodium concentration, body temperature, and heart rate were also recorded.</p><p><b>RESULTS</b>The derivatives 3a and 3r showed reversal of drop in body weight, reversed OBX induced hyperactivity, normalized body temperature, heart rate, and serum sodium concentration. In elevated maze test, moclobemide, 3a, 3r treatment significantly reduced time spent in open arm as compared to OBX rats. 3a and 3r also improved sexual behavior parameters.</p><p><b>CONCLUSIONS</b>The present study shows promising antidepressant action and provides a proof of concept for the chronic treatment of 3a, 3r to treat depression.</p>

MRI Structure and Histological Change of Rat after Memantine Intake in Olfactory Bulbectomised Depression Model / 대한정신약물학회지

OBJECTIVE: The validity of olfactory bulbectomized rat as an animal depression model and the possibilities of the NMDA antagonist as an antidepressant would be evaluated by demonstrating structural alterations in their brain MRIs and histological findings of hippocampus. METHODS: Those 8-week old male Sprague-Dawley rats received either an olfactory bulbectomy or sham operation and volume changes at ventricles and caudate nucleus in their brain MRI were acquired at preoperation and postoperation. Those olfactory bulbectomized rats received either memantine, an uncompetitive NMDA antagonist, or normal saline, a placebo, and their brain structural changes in MRI were acquired. At preoperation, postoperation, and postmedication each one of the rats with sham-operation, with memantine, and with placebo was sacrificed to acquire histological impressions. RESULTS: 1) Comparison of the volume changes between preoperation and postoperation showed statistical significance; the volumes of the left and right lateral ventricles (p=0.007, p=0.008) and the third ventricle (p=0.003) increased significantly but the volumes of left and right caudate nucleus decreased (p=0.014, p=0.032), compared to that of the controls. 2) After 6-weeks of memantine administrations, the OB rats revealed more definite recovery in brain MRIs statistically than the controls: the volumes of left and right ventricles and left and right caudate nucleus (p=0.004, p=0.03 ; p=0.04, p=0.05). 3) The hippocampus histological findings of the olfactory bulbectomy showed frequently eosinophilic cytoplasm and hyperchromatic nucleus with shrinkage in CA3. After memantine intake, the hippocampus histological findings returned to nearly normal and showed mixtures of normal cell and abnormal neuron cell. CONCLUSION: The OB models would be valid as an animal model of depression and alterations in their brain MRI images after administrations of NMDA antagonist could be an indicator of antidepressant effects.