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Effects of basic fibroblast growth factor on memory and learning performances in basal forebrain lesioned mice
931
El
P.m.281
insenoside
, increases ten
decoys syste Benishin,
Department
of Fhysiologv,
University
of Alberta,
C.G. Edmonton,
Alberta
T6G 2H7, Canada
With an ever increasing aging population, the occurrence of diseases associated with aging, such as senile dementia of the Alzheimer’s type (SBAT), and age associated memory impairment (AAMI), is becoming more prevalent. The clear cut understanding of the etiologies of these diseases, as well as effective treatments, have been the subject of numerous studies, but have remained elusive. Additionally, many of the drugs currently used clinically have associated undesirable side effects. Studies on autopsy specimens from patients suffering from SDAT and PAMI indicate that these diseases are associated with certain characteristic pathological changes. Notable of these changes is the degeneration of choline+ nerve tracts projecting from the medial forebrain complex to the cortex and hippocampus, which are believed to be involved in memory and learning processes. Treatments which may increase central cholinergic function are proposed to be effective in alleviating some of the symptoms of these aging diseases. Extracts of ginseng have long been used in Chinese traditional medicine for the alleviation of many of the ailments associated with aging. Recent studies have suggested that the saponin components (ginsenosides) of the roots of this plant may be useful in the improvement of memory and learning in several animal models (Sruto, 1985). The pu of the present study was to examine the effect of one ginsenoside (Rb,) on central cholinergic metabolism. Acetylcholine (ACh) release from hippocampal slices was measured using a perfusion protocol, and stimulating release with exposure to depolarizing concentrations of potassium. Results indicate that Rb, increases the depolarized release of ACh. This stimulation of release occurs even in the absence of extracellular Ca; however, release is not increased in the absence of depolarization. The increase in depolarized release is not associated with a simultaneous increase in 4’Ca uptake into nenie terminals, or in the concentration of inirazel’rular Ca. Acetylcholinesterase and choline acetyltransferase activity are also unaltered by Rbl. Analysis of the subcellular contents of central cholinergic nerve endings indicates that the increase in release is accompanied by an increase in the content of ACh, which may result from a dcisc-dqendent increase in the uptake of the synthetic precursor, choline. Kinetic analysis of the effects of Rb, on choline uptake indicates that the maximal velocity of transport is increased, but not the affinity of the carrier for choline. Quantitation of the carriers by hemicholinium-3 binding show that chronic administration of Rb, can increase the number of choline carriers. These results suggest that the ability of Rb, to reverse memory deficits in animal models of memory and learning may be related to an increase in central choline@ metabolism, and this substance may be useful in the treatment of some memory disorders.
Reference Saito, H., 1985. in Advances in Chinese Materials Res., eds. H.M. Chang, H.W. Yeung, W-W. Tso and A. Koo, p. 509.
I
P.tu.282
ces
Effects of basic fibroblwt growth factor on in basal forebrain le Ishihara, Department
of Chemical
Pharmacology.
A., Saito I-I. and Nishiyama,
Faculty of Pharmaceutical
Scimces,
N.
University
of Tokyo,
Tokp-o113, Japan
The basal forebrain (BF) choline@ system has been demonstrated to play an important role in memory functiou. Experimental lesioning of this region causes severe deficits in many kinds of learning tasks (Miyamoto, 1985). Basic fibroblast growth factor (bFGF) is one of the mitogenic proteins which has been demonstrated to promote survival
and ne~~c grrwtb of ~zveral CNS neurons in vitro (Morisson, 1986) and to rescue medial septal neurons after f~rnb~a fornix transection (Barotte, 1989). In the current investigation, effects of bFGF on memory and learning performance ability and on choline ~~ety~r~sf~~~e (ChAT) activity were investigated in basal forebrain lesioned mice. Male Std-QdY mice (8 weeks old) were received bilateral BF 1es;ons by the delivery of radiofr~uency current (70 OC, 60 set). The coordinates of the electrode placements were; 0.8 mm posterior to bregma, f2.8 mm lateral to the sag&al suture and 4.3 mm below brain surface, with the incisor bar placed at 2.2 mm ventral to the horizontal plane. Human bFGF (CS23, given from Takeda Chemical Industries, Ltd., Osaka, Japan, 5 and 50 rig/l ~1 of 0.01% BSA containing PBS/side), were injected bilater~y in the lesioned area immediately after lesion. From 15 days after surgery, when the body weight of lesioned mice were recovered, they were submitted to step through and step down tasks for 10 days. In step through test, mean latency to entering the dark compartment was significantly shortened in lesioned group than that of sham-operated and intact control group on the first retention trial. Fifty ng/pl bFGF prolonged the step through latency (p < 0.05). Percentage of animals that did not enter the dark compartment. which significantly decreased in lesioned group, tended to increase in bFGF treated groups. bFGF also showed the tendency to elongate the average duration of memory retention, which was shortened in lesioned animals. The number of total errors during the 10 days retention trials was increased in lesioned group. bFGF tr~trn~t tended to improved this parameter. In step down test, BF lesion resulted in only slight memory impairments. bFGF treated groups also exhibited ameliorating effect in this test. Cortical ChAT activity was significantly decreased in lesioned group, on which bFGF treatment was ineffective. By the microscopic examination with hematoxylin-cosine staining, gliosis was seen in lesioned area. No distinct pa~olo~c~ difference between lesioned and bFGF treated groups was observed. Conclusion: bFGF, injected immediately after lesioning, partially improved the BF lesion-induced learning performance deficits without effecting on the cortical ChAT activity.
Barotte, C., et al.. 1989,Neurosci. Lett., 101, 197-202. Miyamoto, M., et al., 1985,Brain Res., 328,97-l@%. Morisson.RS., et al., 1986,Pm. Natl. Acad. Sci. USA, 78,7205-7209
I
P.tu.283
van de Kamg, XL., Wehner, J.M. and Collins, AC. Institute for Behavioral Genetics. University of Colora&
Boulder, CO. 80309, U.S.A.
Many, studies have investigated the effects of acute administration of nicotine on various aspects of learning and/or memory in laboratory animals. Some of these studies demonstrated facilitating effects of nicotine whereas others detected no effect, or even an impairment. Recent evidence suggests that spatial memory is critically regulated by cholinergic systems since chronic treatment with a cholinesterase ~bitor impaired the ability of C57BI../61bg mice tc learn the Morris water task
El
P.m.281
insenoside
, increases ten
decoys syste Benishin,
Department
of Fhysiologv,
University
of Alberta,
C.G. Edmonton,
Alberta
T6G 2H7, Canada
With an ever increasing aging population, the occurrence of diseases associated with aging, such as senile dementia of the Alzheimer’s type (SBAT), and age associated memory impairment (AAMI), is becoming more prevalent. The clear cut understanding of the etiologies of these diseases, as well as effective treatments, have been the subject of numerous studies, but have remained elusive. Additionally, many of the drugs currently used clinically have associated undesirable side effects. Studies on autopsy specimens from patients suffering from SDAT and PAMI indicate that these diseases are associated with certain characteristic pathological changes. Notable of these changes is the degeneration of choline+ nerve tracts projecting from the medial forebrain complex to the cortex and hippocampus, which are believed to be involved in memory and learning processes. Treatments which may increase central cholinergic function are proposed to be effective in alleviating some of the symptoms of these aging diseases. Extracts of ginseng have long been used in Chinese traditional medicine for the alleviation of many of the ailments associated with aging. Recent studies have suggested that the saponin components (ginsenosides) of the roots of this plant may be useful in the improvement of memory and learning in several animal models (Sruto, 1985). The pu of the present study was to examine the effect of one ginsenoside (Rb,) on central cholinergic metabolism. Acetylcholine (ACh) release from hippocampal slices was measured using a perfusion protocol, and stimulating release with exposure to depolarizing concentrations of potassium. Results indicate that Rb, increases the depolarized release of ACh. This stimulation of release occurs even in the absence of extracellular Ca; however, release is not increased in the absence of depolarization. The increase in depolarized release is not associated with a simultaneous increase in 4’Ca uptake into nenie terminals, or in the concentration of inirazel’rular Ca. Acetylcholinesterase and choline acetyltransferase activity are also unaltered by Rbl. Analysis of the subcellular contents of central cholinergic nerve endings indicates that the increase in release is accompanied by an increase in the content of ACh, which may result from a dcisc-dqendent increase in the uptake of the synthetic precursor, choline. Kinetic analysis of the effects of Rb, on choline uptake indicates that the maximal velocity of transport is increased, but not the affinity of the carrier for choline. Quantitation of the carriers by hemicholinium-3 binding show that chronic administration of Rb, can increase the number of choline carriers. These results suggest that the ability of Rb, to reverse memory deficits in animal models of memory and learning may be related to an increase in central choline@ metabolism, and this substance may be useful in the treatment of some memory disorders.
Reference Saito, H., 1985. in Advances in Chinese Materials Res., eds. H.M. Chang, H.W. Yeung, W-W. Tso and A. Koo, p. 509.
I
P.tu.282
ces
Effects of basic fibroblwt growth factor on in basal forebrain le Ishihara, Department
of Chemical
Pharmacology.
A., Saito I-I. and Nishiyama,
Faculty of Pharmaceutical
Scimces,
N.
University
of Tokyo,
Tokp-o113, Japan
The basal forebrain (BF) choline@ system has been demonstrated to play an important role in memory functiou. Experimental lesioning of this region causes severe deficits in many kinds of learning tasks (Miyamoto, 1985). Basic fibroblast growth factor (bFGF) is one of the mitogenic proteins which has been demonstrated to promote survival
and ne~~c grrwtb of ~zveral CNS neurons in vitro (Morisson, 1986) and to rescue medial septal neurons after f~rnb~a fornix transection (Barotte, 1989). In the current investigation, effects of bFGF on memory and learning performance ability and on choline ~~ety~r~sf~~~e (ChAT) activity were investigated in basal forebrain lesioned mice. Male Std-QdY mice (8 weeks old) were received bilateral BF 1es;ons by the delivery of radiofr~uency current (70 OC, 60 set). The coordinates of the electrode placements were; 0.8 mm posterior to bregma, f2.8 mm lateral to the sag&al suture and 4.3 mm below brain surface, with the incisor bar placed at 2.2 mm ventral to the horizontal plane. Human bFGF (CS23, given from Takeda Chemical Industries, Ltd., Osaka, Japan, 5 and 50 rig/l ~1 of 0.01% BSA containing PBS/side), were injected bilater~y in the lesioned area immediately after lesion. From 15 days after surgery, when the body weight of lesioned mice were recovered, they were submitted to step through and step down tasks for 10 days. In step through test, mean latency to entering the dark compartment was significantly shortened in lesioned group than that of sham-operated and intact control group on the first retention trial. Fifty ng/pl bFGF prolonged the step through latency (p < 0.05). Percentage of animals that did not enter the dark compartment. which significantly decreased in lesioned group, tended to increase in bFGF treated groups. bFGF also showed the tendency to elongate the average duration of memory retention, which was shortened in lesioned animals. The number of total errors during the 10 days retention trials was increased in lesioned group. bFGF tr~trn~t tended to improved this parameter. In step down test, BF lesion resulted in only slight memory impairments. bFGF treated groups also exhibited ameliorating effect in this test. Cortical ChAT activity was significantly decreased in lesioned group, on which bFGF treatment was ineffective. By the microscopic examination with hematoxylin-cosine staining, gliosis was seen in lesioned area. No distinct pa~olo~c~ difference between lesioned and bFGF treated groups was observed. Conclusion: bFGF, injected immediately after lesioning, partially improved the BF lesion-induced learning performance deficits without effecting on the cortical ChAT activity.
Barotte, C., et al.. 1989,Neurosci. Lett., 101, 197-202. Miyamoto, M., et al., 1985,Brain Res., 328,97-l@%. Morisson.RS., et al., 1986,Pm. Natl. Acad. Sci. USA, 78,7205-7209
I
P.tu.283
van de Kamg, XL., Wehner, J.M. and Collins, AC. Institute for Behavioral Genetics. University of Colora&
Boulder, CO. 80309, U.S.A.
Many, studies have investigated the effects of acute administration of nicotine on various aspects of learning and/or memory in laboratory animals. Some of these studies demonstrated facilitating effects of nicotine whereas others detected no effect, or even an impairment. Recent evidence suggests that spatial memory is critically regulated by cholinergic systems since chronic treatment with a cholinesterase ~bitor impaired the ability of C57BI../61bg mice tc learn the Morris water task