Effect of prior treatment with thioglycolate on the incubation period of intraperitoneally injected scrapie

Injection of mice with thioglycolate 5 days prior to intraperitoneal injection of scrapie brain homogenate led to a statistically significant increase in scrapie incubation periods. This was seen with two different scrapie strains (ME7 and 139A), in different mouse strains (C57BL/6J and Compton White), and at several dilutions of the scrapie inoculum.     

Profound sex-specific effects on incubation times for transmission of bovine spongiform encephalopathy to mice

Four strains of mice were inoculated intracerebrally with a primary isolate of bovine spongiform encephalopathy (BSE) and the cloned mouse-adapted scrapie strain ME7. Clinical prion disease diagnosis was made at the appearance of three or more neurological symptoms and their persistence for 3 consecutive weeks and confirmed by neuropathological criteria. For BSE, incubation periods were profoundly different between the sexes in all four mouse strains, being longer in the females. In contrast, ME7 scrapie incubation times were similar between the sexes. Our results indicate that sex-specific processes are involved in the course of primary BSE transmission. Research into this phenomenon may provide clues to the prophylaxis of BSE and have possible implications for new variant Creutzfeldt-Jakob disease in humans.     

Competition between strains of scrapie depends on the blocking agent being infectious

Compton White mice (Sincs7) were injected twice intraperitoneally, first with the 22A strain of scrapie agent (in brain homogenates) and then, after 105 days, with the 22C strain. Incubation periods were calculated from the time of the first injection. The experiment was designed so that, with no interaction between strains, the second strain (22C) should have produced cases about 300-350 days after the first injection, depending on the dose of 22C. This was well before the limit of 470 days set by the mean incubation period minus 3 SD of 22A alone: a limit which was used to distinguish 22C from 22A clinical cases. In fact, 22A blocked 22C as shown by (i) the lengthening of 22C incubation periods, (ii) the reduced proportion of cases due to 22C, and (iii) the reduced effective titer of 22C. The blocking efficiency of 22A was not greatly reduced by physicochemical treatments that had little or no effect on its infectivity by the intraperitoneal route. However, treatment of 22A homogenates with 6 M urea virtually eliminated infectivity and also abolished blocking ability. It is concluded that competition depends on the infectivity of the scrapie strain used for blocking.     

Preclinical changes in weight of scrapie-infected mice as a function of scrapie agent-mouse strain combination

Several inbred strains of mice were injected with different scrapie agents and their total body weight was monitored throughout the incubation period. As a control, mice were injected with normal mouse brain homogenate. For most combinations of scrapie agent and mouse strain, weights during the preclinical phase were similar to or lower than the average weight of controls. For some combinations there was a significant increase in weight (compared to controls) during the latter part of the preclinical phase of disease. The effect was dependent on both agent and mouse strain, i.e., in some cases a mouse strain showed the increase with one scrapie agent but not another and some scrapie agents caused the increase in one inbred strain of mouse but not in another strain. The increase in weight was due to accumulations of fat rather than a generalized increase in weight of various organs. With one mouse strain (SJL), there was increased vacuolation seen in the hypothalamus of mice injected with scrapie agents that showed the increase in weight compared to the lesion intensity with an agent which did not cause the weight increase.     

CXCL1/CXCR2在羊瘙痒因子感染小鼠脑组织中的分布特征研究

目的 探究朊病毒感染小鼠脑组织CXC趋化因子配体1 (CXCL1)与CXC趋化因子受体2 (CXCR2)的分布特征。方法 通过免疫组织化学、免疫组织荧光双染实验明确羊瘙痒因子139A及ME7感染终末期小鼠脑组织中CXCL1/CXCR2的分布特征,确定CXCL1/CXCR2的靶细胞及与羊瘙痒因子样朊蛋白(PrPSc)沉积的关系。结果 通过全脑区免疫组化染色发现,CXCL1/CXCR2在羊瘙痒因子139A及ME7感染终末期小鼠脑组织中的含量明显升高,主要分布在海马、皮层、丘脑、小脑及延髓5个脑区。CXCL1与小胶质细胞和神经元细胞存在共定位,而CXCR2与神经元细胞存在共定位。在羊瘙痒因子139A及ME7感染终末期小鼠脑组织中CXCL1、CXCR2和PrP^Sc三者存在明显共定位。结论 CXCL1/CXCR2分布于朊病毒感染小鼠脑组织中朊病毒病理特征集中的脑区。     

Antitumor activity of lipopolysaccharide in tumor-bearing mice pretreated with BCG

The antitumor activity of lipopolysaccharide (LPS) was investigated in BCG-treated mice. C3H/He mice and CDF1 mice were injected with BCG and then were inoculated with syngeneic mouse hepatoma MH134 and mastocytoma P815 respectively. Hemorrhagic necrosis and retarded growth of tumor were observed after an intravenous (i.v.) injection of LPS, when tumor cells had been inoculated subcutaneously (s.c.). However an intraperitoneal (i.p.) injection of BCG plus LPS did not increase the mean survival time of mice that had been inoculated with tumor cells i.p. Sera from mice that had been treated with BCG plus LPS i.v. were cytotoxic for cultured tumor cells. These results seemed to indicate that growth-inhibitory effects of LPS on tumors inoculated s.c. were mediated by a humoral factor.     

羊瘙痒因子139A感染引起小鼠脑组织中的1-ACT表达增加

目的 探究1-ACT在羊瘙痒因子139A感染小鼠脑组织中的变化情况。方法 利用蛋白免疫印迹、免疫组织化学、间接免疫荧光及荧光共聚焦方法分析羊瘙痒因子139A感染小鼠脑组织中1-ACT表达的变化和分布特点。结果 蛋白免疫印迹方法显示在羊瘙痒因子139A感染小鼠终末期脑组织中1-ACT的含量较正常对照小鼠明显上调且随着潜伏期的延长而逐渐增加;免疫组织化学方法发现1-ACT主要分布于羊瘙痒因子139A感染小鼠的皮层、丘脑和小脑区域;间接免疫荧光实验显示羊瘙痒因子139A感染终末期小鼠脑组织中补体成分C3含量明显增加,同时荧光共聚焦实验表明1-ACT与补体成分C3存在明显的共定位现象。结论 羊瘙痒因子139A感染终末期小鼠脑组织中1-ACT含量明显增加。     

Disappearance of scrapie virus from tissues of the mouse

Examination of newborn mice, inoculated intraperitoneally with high doses of scrapie virus, revealed that the virus could not be reisolated from their tissues after about 1 week following inoculation, until almost 1 year later. The inoculum was rapidly removed and was not detectable, although the animals became latently infected. Homogenization of whole inoculated newborn animals showed that only about 3% of virus could be recovered by the 2nd day postinoculation (p.i.). During the first 6 days p.i. the half-life of titratable scrapie was about 15 h. A further study of the rate of disappearance of clarified scrapie virus from blood after intravenous inoculation showed an even more rapid disappearance, with a half-life of 5.16 min. Prior treatment of the recipient mice with either carbon black or silica to block the reticuloendothelial system (RES) did not affect the rate of disappearance. It was concluded that the mouse possesses a very efficient means of scrapie virus removal from the blood which is not dependent upon an active RES. However, after 1 h the rate of disappearance changed dramatically; the residual virus level was very stable, with no significant drop during the next 21 h. This finding was compatible with the possibility that two forms of scrapie virus, with different removal rates, coexisted in the inoculum. Silica treatment caused a shortened scrapie incubation period.     

Morphine antinociception in different strains of mice: relationship of supraspinal-spinal multiplicative interaction to tolerance

In the rat and mouse when morphine is coadministered intracerebroventricularly (i.c.v.) in the brain and intrathecally (i.t.) in the spinal cord, a multiplicative (synergistic) interaction occurs for the antinociceptive response. In the male Swiss Cox mouse, with the development of a high degree of systemic tolerance to morphine, this multiplicative interaction decreases (becomes additive), whereas no change occurs in the ED50 for the i.c.v. or i.t. site itself. The purpose of the present study was to extend these findings in one mouse strain to other strains in order to determine how generally applicable such findings are to the phenomenon of tolerance to morphine. Eight different strains of outbred mice were used in the antinociceptive tail-flick test to quantify the multiplicative interaction of simultaneous administration (i.c.v. and i.t.) in relation to the amount of tolerance developed to morphine administered systemically (s.c.). Even though the control ED50 values for s.c. morphine were similar among strains, the amounts of tolerance developed by 3 days of implantation of a morphine pellet were very different (2-18-fold). A relationship was found between the degree of tolerance developed to s.c. morphine and changes in the multiplicative interaction (as reflected by changes in the i.c.v. plus i.t. morphine ED50 values). In control animals, a multiplicative i.c.v.-i.t. interaction was produced in six of the eight strains, whereas an additive interaction was shown in the remaining two strains. With 3 days of morphine pellet implantation, in three strains which developed a large amount of tolerance to s.c. morphine (7-18-fold), the multiplicative interaction decreased to an additive interaction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metaphit, a proposed phencyclidine receptor acylator: disruption of mouse motor behavior and absence of PCP antagonist activity

Metaphit, a derivative of phencyclidine (PCP) differing by the meta substitution of an isothiocyanate group on the phenyl ring, was given into the lateral cerebral ventricle of mice alone and as a pretreatment to the subsequent i.p. injection of PCP and pentobarbital. Drug effects on motor performance as an index of neurologic impairment were quantified using the mouse platform test. The ED50 of metaphit to disrupt mouse platform behavior 5 min after i.c.v. administration was 0.48 mumol. An isobolographic analysis indicated that metaphit interacted additively with PCP and pentobarbital. Animals that recovered 24 or 48 hr after a large dose (1 mumol i.c.v.) of metaphit or phenylisothiocyanate, a nonspecific acylating control substance, were then given PCP (18.3 mumol/kg i.p.) or pentobarbital (76.7 mumol/kg i.p.). Both agents enhanced PCP-induced failure of mice to climb to the top of the platform. Metaphit also enhanced pentobarbital-induced failure of mice to climb to the top of the platform. No evidence was obtained that metaphit antagonized the behavioral effects of PCP in mice.     

A comparative study of monoaminergic involvement in the antinociceptive action of E-2078, morphine and U-50,488E.

E-2078 ([N-methyl-Tyr1, N-alpha-methyl-Arg7, D-Leu8]dynorphin A(1-8) ethylamide) is a systemically active dynorphin analog. We examined monoaminergic involvement in the antinociceptive action of E-2078 compared with morphine and U-50,488E (trans-3,4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)- benzene-acetamide monohydrochloride). The antinociceptive effect of these drugs was determined using the mouse tail-flick test after depletion of norepinephrine or 5-HT by pretreatment with various neurotoxins. Reserpine (i.p.) depleted both norepinephrine and 5-HT. Selective degeneration of noradrenergic nerves was induced by N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4, i.p.) or intrathecal (i.t.) 6-hydroxydopamine (6-OHDA), whereas 5-HT was depleted by p-chlorophenylalanine (PCPA, i.p.) or 5,7-dihydroxytryptamine (5,7-DHT, i.t.). The antinociceptive action of E-2078 administered s.c. was significantly attenuated in mice treated with reserpine, DSP-4, 6-OHDA, PCPA or 5,7-DHT compared with that in non-neurotoxin animals. Antinociception induced by intracerebroventricular (i.c.v.) and i.t. injection of E-2078 was reversed by reserpine, DSP-4 or PCPA. The antinociceptive action of morphine (s.c.) was attenuated by reserpine, DSP-4, 6-OHDA and PCPA, but not by 5,7-DHT. Antinociception produced by i.c.v. morphine was antagonized by reserpine, DSP-4 and PCPA. In contrast, morphine given i.t. was not affected by these neurotoxins. U-50,488E (s.c.)-induced antinociception was attenuated by reserpine, DSP-4, 6-OHDA, PCPA and 5,7-DHT. Intracerebroventricular U-50,488E was antagonized by reserpine, DSP-4 and PCPA, whereas i.t. U-50,488E was reversed only by reserpine and PCPA(ABSTRACT TRUNCATED AT 250 WORDS)     

Intrinsic B cell defects in NZB and NZW mice contribute to systemic lupus erythematosus in (NZB x NZW)F1 mice

We have previously shown that long-term in vitro proliferating fetal liver pre-B cell lines derived from autoimmune-prone (NZB x NZW)F1 (BW) mice, but not normal (B6 x DBA2)F1 mice, can differentiate in severe combined immunodeficient (SCID) mice to produce elevated levels of serum immunoglobulin (Ig) M and IgG, and high titers of antinuclear antibodies The contribution of parental NZB and NZW strains to B cell abnormalities of BW hybrid mice was investigated here by preparing pre- B cells and transferring them into immunodeficient SCID- and RAG-2- targeted mice. We show that transfer of NZB pre-B cells led to a marked IgM hypergammaglobulinemia and to the production of limited amounts of IgG2a. On the other hand, the transfer of NZW pre-B cell lines led to moderately elevated IgM levels and marked hypergammaglobulinemia of IgG2a. High IgM and low IgG anti-DNA titers are found in the recipients of NZB pre-B cells, whereas those receiving NZW pre-B cells contained lower levels of IgM and high titers of IgG anti-DNA. In marked contrast, essentially identical titers of antibodies directed against a non-self-antigen, DNP, are found in all group of pre-B cell recipients. Thus, B-lineage cells of both NZB and NZW parental strains manifest abnormalities associated with the development of this lupus-like disease. Therefore, the present study strongly suggests a complex inheritance of B cell abnormalities in autoimmune-prone (NZB x NZW)F1 mice and emphasizes the critical importance of intrinsic B cell defects in the development of murine systemic lupus erythematosus.     

Absence of autoantibodies against neurofilament proteins in the sera of scrapie infected mice

Autoantibodies against neurofilament proteins were not detected in any of the sera from the following scrapie infected mice: 19 mice infected with scrapie agent 139A in pre-clinical stage, 32 histologically confirmed scrapie mice and other 12 clinical scrapie mice infected with various strains. The test sera were assayed against acetone-fixed central neuron cultures from fetal mice by indirect immunofluorescence and immunoperoxidase techniques. The negative result suggests that autoantibodies against neurofilament proteins do not play a role in the pathogenesis of scrapie.     

核转录因子-B(p65)在羊瘙痒因子139A感染小鼠脑组织中变化的研究

目的 研究NF-B（p65）在羊瘙痒因子139A感染小鼠脑组织中的变化。方法 通过蛋白质免疫印迹法及免疫组织化学的方法检测p65在139A感染的脑组织均浆中的含量变化。利用免疫荧光方法检测p65在神经元及胶质细胞中的分布情况。结果 在139A感染终末期小鼠脑组织均浆中，p65含量下降，差异有统计学意义。对感染不同时间点的动态分析结果显示，p65含量呈先升高随后逐渐降低趋势。免疫组织化学显示，139A感染终末期小鼠大脑皮层p65含量明显下降。免疫组织荧光显示在正常和139A感染终末期小鼠脑组织中，p65与神经元细胞存在共定位现象。结论 NF-B（p65）在小鼠中枢神经系统中主要分布于神经元细胞，在139A感染的小鼠终末期脑组织中，p65总量明显下降，提示在139A感染的小鼠脑组织中，NF-B（p65）出现了变化，在疾病进程中发挥一定作用。     

Plasma and pulmonary pharmacokinetics of bleomycin in murine strains that are sensitive and resistant to bleomycin-induced pulmonary fibrosis

Previous studies have shown that C57Bl/6N mice are sensitive and BALB/c mice are resistant to the pulmonary fibrotic effects of bleomycin (BLM). We assessed the plasma elimination and pulmonary content of BLM in C57Bl/6N and BALB/c mice treated with a single dose of [3H]BLM (80 mg/kg i.v.) to determine whether these murine strains show corresponding differences in BLM pharmacokinetics and pulmonary disposition after systemic administration of the drug. Serial blood samples were obtained from each animal and lungs were collected after pulmonary lavage or vascular perfusion with saline. Administration of BLM (80 mg/kg i.v.) produced significant elevations in lung hydroxyproline (35%) in C57Bl/6N but not in BALB/c mice. In contrast, BALB/c mice were more sensitive to pulmonary fibrosis induced with cyclophosphamide (200 mg/kg i.p.) compared to C57Bl/6N mice, indicating that strain sensitivity to pulmonary fibrosis is drug specific in these mice. BLM showed first order plasma elimination kinetics over 30 min in both strains with a shorter half-life in the sensitive strain (9.6 +/- 0.3 min in C57Bl/6N vs. 12.7 +/- 1.9 min in BALB/c). Plasma elimination deviated from first order kinetics after 30 min in both strains and plasma levels of BLM were up to 2-fold higher in the resistant strain over a 3-hr time course. Radioactivity in saline-perfused lungs was also significantly higher (1.5-2-fold) in BALB/c mice for least 1 hr after BLM injection. A similar fraction of the total lung radioactivity (approximately 80%) was recovered from both strains by pulmonary lavage, suggesting that BLM enters the alveolar spaces relatively freely in each strain.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antiviral Activity of BL-3849A, a Low-Molecular-Weight Oral Interferon Inducer

Oral administration of BL-3849A to adult mice resulted in peak serum interferon titers of 4,000 units from 15 to 30 h after administration, with detectable levels persisting until 48 h. After intraperitoneal (i.p.) inoculation, peak serum interferon titers of 1,000 to 3,000 units were noted between 9 and 18 h. Multiple injections of the inducer by either route resulted in a marked decrease in the interferon response with each successive dose. In mice infected intranasally with the Rochester mouse virus strain of encephalomyocarditis virus, oral treatment with BL-3849A reduced mortality when initiated either 18 h before or 1 h after infection. In contrast, administration of drug by the i.p. route decreased mortality only if begun before infection. In mice inoculated i.p. with encephalomyocarditis virus, treatment by both the oral and the i.p. route decreased the mortality whether initiated 18 h before or 1 h after infection. Treatment by the oral, but not the i.p., route reduced mortality of mice inoculated i.p. with Semliki forest virus or Herpesvirus hominis type 2. BL-3849A appeared to be as effective as tilorone hydrochloride, but less effective than polyriboinosinic-polyribocytidylic acid, in the treatment of these viral infections of mice.     

Potential of Novel Antimicrobial Peptide P3 from Bovine Erythrocytes and Its Analogs To Disrupt Bacterial Membranes In Vitro and Display Activity against Drug-Resistant Bacteria in a Mouse Model

With the emergence of many antibiotic-resistant strains worldwide, antimicrobial peptides (AMPs) are being evaluated as promising alternatives to conventional antibiotics. P3, a novel hemoglobin peptide derived from bovine erythrocytes, exhibited modest antimicrobial activity in vitro. We evaluated the antimicrobial activities of P3 and an analog, JH-3, both in vitro and in vivo. The MICs of P3 and JH-3 ranged from 3.125 μg/ml to 50 μg/ml when a wide spectrum of bacteria was tested, including multidrug-resistant strains. P3 killed bacteria within 30 min by disrupting the bacterial cytoplasmic membrane and disturbing the intracellular calcium balance. Circular dichroism (CD) spectrometry showed that P3 assumed an α-helical conformation in bacterial lipid membranes, which was indispensable for antimicrobial activity. Importantly, the 50% lethal dose (LD₅₀) of JH-3 was 180 mg/kg of mouse body weight after intraperitoneal (i.p.) injection, and no death was observed at any dose up to 240 mg/kg body weight following subcutaneous (s.c.) injection. Furthermore, JH-3 significantly decreased the bacterial count and rescued infected mice in a model of mouse bacteremia. In conclusion, P3 and an analog exhibited potent antimicrobial activities and relatively low toxicities in a mouse model, indicating that they may be useful for treating infections caused by drug-resistant bacteria.     

STUDIES IN RODENT POLIOMYELITIS : I. FURTHER EXPERIMENTS WITH THE MURINE STRAIN OF SK POLIOMYELITIS VIRUS

1. SK murine virus maintained over more than 200 serial mouse passages increased in virulence for mice from an initial intracerebral titer of about 1:1 million to a maximum titer of not less than 1:1 billion dilution activity. 2. Following intracerebral injection with murine virus of remote mouse passages, 5 of 13 rhesus monkeys developed a characteristic encephalitic syndrome. Repeated intravenous injection of massive doses of virus caused localized flaccid paralysis in 2 of 14 monkeys. 3. Intracerebral injection of graded doses of murine virus into mice of different age groups caused fatal paralysis in young and old animals alike. Infection with small doses of virus by peripheral routes, while uniformly fatal to young mice, was followed by survival of almost half of the old mice. 4. The incubation period of the disease in young mice infected intracerebrally with a standard dose of murine virus, when studied throughout the period of 1 year, was found considerably lengthened during the summer months. 5. Cross neutralization tests furnished no evidence for any serological relationship between SK murine virus and lymphocytic choriomeningitis virus. Theiler''s virus was found to be neutralizable by antimurine horse serum and, to a lesser extent, by concentrated antipoliomyelitis horse serum; however, such inactivation, in both cases, was distinctly inferior to that occurring with SK murine virus. On the other hand, no neutralization whatsoever was obtained between SK murine virus and normal adult mouse serum, whereas the same serum completely neutralized Theiler''s virus. Mice surviving infection with Theiler''s virus, though acquiring immunity to this virus, remained fully susceptible to reinfection with SK murine virus. 6. Neutralization tests with SK murine virus against poliomyelitis-convalescent monkey sera gave irregular results, but neutralization of murine virus occurred regularly with a hyperimmune antipoliomyelitis horse serum. Hyperimmune antimurine horse and rabbit sera, on the other hand, failed to inactivate three strains of monkey poliomyelitis virus (SK, RMV, Aycock) by intracerebral tests in monkeys. The same sera inactivated murine virus in mice by intraperitoneal, but not by intracerebral injection of virus-serum mixtures. 7. The identity of SK murine virus and its relation to other rodent strains of poliomyelitis virus is discussed on the basis of the available data.     

Prevention of bacterial infection and LPS-induced lethality by interleukin-1 alpha in mice

In order to make clear the characteristic biological properties of IL-1 alpha, its protective capabilities on bacteria-induced and LPS-induced lethality were compared with other BRMs in BALB/c mice. Pretreatment with IL-1 alpha (i.p., s.c.) or OK-432 (i.p.), could protect mice from the lethality of a K. pneumoniae infection (i.p.), and pretreatment with IL-1 alpha or TNF alpha could protect mice from LPS (i.p.) lethality. IL-1 alpha could protect mice from both bacteria- and LPS-induced lethality. There was no difference in serum corticosterone levels after the LPS injection between the IL-1 alpha pretreated and untreated groups. However, a more rapid clearance of LPS from the serum and a stronger LPS-neutralizing activity in serum were observed with the LAL assay in IL-1 alpha pretreated mice than in untreated mice. The enhanced LPS-clearance was suggested to be partly responsible for the increased protection against LPS-lethality. IL-1 alpha was indicated to be a unique BRM and to become a useful tool for the prevention of life-threatening bacterial infections and subsequent endotoxin shock.     

Effect of glatiramer acetate on short‐term memory impairment induced by lipopolysaccharide in male mice

Glatiramer acetate (GA) demonstrates neuroprotective, neurogenesis, and anti‐inflammatory properties. This study examines the probable protective effect of acute GA on lipopolysaccharide (LPS)‐induced memory impairment in male mice and further explores which routes of administration [subcutaneous (s.c.) or intracerebroventricular (i.c.v.)] exert optimum effect. Memory performance was evaluated in two‐trial recognition Y‐maze and passive‐avoidance tasks evaluating special recognition memory and fear memory, respectively. Memory impairment was induced by LPS [100 μg/kg, intraperitoneally (i.p.)], 4 h before training. In Y‐maze, GA (10, 2.5, 0.625, 0.153, and 0.03 mg/kg, s.c.; 250 μg/mouse; i.c.v.) was administered 10 min following LPS, and special memory was assayed in Y‐maze apparatus. In passive avoidance, LPS (100, 250 μg/kg; i.p.) was injected 4 h before receiving foot shock, and GA (10, 2.5; s.c.) or (250 μg/mouse; i.c.v.) was administered 4 h before the shock. Following 24 h, the fear memory was evaluated. Memory impaired significantly following LPS (100, 250 μg/kg; i.p.) in Y‐maze and passive‐avoidance tasks, P < 0.001 and P < 0.05, respectively. The data revealed that GA (250 μg/mouse, i.c.v.) and GA (10, 2.5 mg/kg; s.c.) in Y‐maze reversed memory impairment (LPS 100 μg/kg, i.p.) (P < 0.01). In passive‐avoidance task, GA (2.5, 10 mg/kg; s.c.) reversed LPS‐induced impairment and the mice showed significantly longer latency times during the retention trial (P < 0.01). GA improved memory impairment both centrally and systemically. It improved spatial recognition memory increasing the average time in the novel arm and improved fear memory increasing latency time. GA administration improved memory impairment profoundly through both systemic and central routs.