Biomedical subjects

L Paljärvi

Publications and source records attributed to L Paljärvi.

At least 19 recordsLinked to original sources

PubMed1998

Beta-galactosidase gene transfer to human malignant glioma in vivo using replication-deficient retroviruses and adenoviruses.

Both retro- and adenovirus-mediated gene therapy have been suggested as a novel approach to the treatment of malignant brain tumors. However, little information is available about the gene transfer efficiency in human malignant glioma in vivo. We compared the feasibility and safety of retrovirus- and adenovirus-mediated beta-galactosidase gene transfer in human malignant glioma. Beta-galactosidase gene was transferred to 10 patients with malignant glioma via a catheter inserted into the tumor. The catheter was left in place until the tumor resection. To maximize gene transfer efficiency, gene transfer vectors (BAG retroviruses, titer, 6 x 10(5) CFU; and adenoviruses, titer from 3 x 10(8) to 3 x 10(10) PFU) were injected into the tumor via the catheter once a day for three consecutive days, followed by tumor resection 1-2 days later. Tumor was resected in such a way that the catheter was still in place inside the tumor, which permitted accurate histological analysis of the transduced tumors. X-Gal staining for beta-galactosidase activity was used to study gene transfer efficiency and distribution of the marker gene. Beta-galactosidase gene transfer was well tolerated with both vectors. Except for two patients with clear increases in serum adenovirus antibody titers, no adverse tissue responses or systemic complications were noticed in any of the patients. Gene transfer was successful in all patients. Gene transfer efficiency varied between <0.01 and 4% with retroviruses and between <0.01 and 11% with adenoviruses. However, the transgene activity was not evenly distributed in the tumors. Both glioma cells and endothelium in the tumor blood vessels were transduced with retro- and adenovirus vectors. In conclusion, the safety and feasibility of in vivo gene transfer to human malignant glioma was established with retro- and adenovirus vectors. Adenoviruses were more efficient than retroviruses in achieving in vivo gene transfer. Transduction of endothelial cells may have important consequences for the proposed treatment strategies and selection of treatment genes. The results justify clinical gene therapy trials for malignant glioma.

Adenoviridae↗

PubMed1998

Calretinin-immunoreactive terminals make synapses on calbindin D28k-immunoreactive neurons in the lateral nucleus of the human amygdala.

A double-labeling immunohistochemical procedure and correlated light and electron microscopy were used to examine if calretinin-immunoreactive terminals make synapses on calbindin D28k-positive cells. In the lateral nucleus of the human amygdala, calretinin terminals make symmetric-like synapses on the somata and proximal dendrites of calbindin D28k-labeled cells. Our data provide the first evidence that neurons which contain two different calcium-binding proteins form synaptic contacts with each other in the human amygdala.

Adult↗

PubMed1998

Remodeling of neuronal circuitries in human temporal lobe epilepsy: increased expression of highly polysialylated neural cell adhesion molecule in the hippocampus and the entorhinal cortex.

Neuronal loss and axonal sprouting are the most typical histopathological findings in the hippocampus of patients with drug-refractory temporal lobe epilepsy (TLE). It is under dispute, however, whether remodeling of neuronal circuits is a continuous process or whether it occurs only during epileptogenesis. Also, little is known about the plasticity outside of the hippocampus. We investigated the immunoreactivity of the highly polysialylated neural cell adhesion molecule (PSA-NCAM) in the surgically removed hippocampus and the entorhinal cortex of patients with drug-refractory TLE (n=25) and autopsy controls (n=7). Previous studies have shown that the expression of PSA-NCAM is associated with the induction of synaptic plasticity, neurite outgrowth, neuronal migration, and events requiring remodeling or repair of tissue. In patients with TLE, the optical density (OD) of punctate PSA-NCAM immunoreactivity was increased both in the inner and outer molecular layers of the dentate gyrus, compared with controls. The intensity of PSA-NCAM immunoreactivity in the inner molecular layer correlated with the duration of epilepsy, severity of hippocampal neuronal loss, density of mossy fiber sprouting, and astrogliosis. In TLE patients with only mild neuronal loss in the hippocampus, the density of infragranular immunopositive neurons was increased twofold compared with controls, whereas in TLE patients with severe neuronal loss, the infragranular PSA-NCAM-positive cells were not present. In the hilus, the somata and tortuous dendrites of some surviving neurons were intensely stained in TLE. PSA-NCAM immunoreactivity was also increased in CA1 and in layer II of the rostral entorhinal cortex, where immunopositive neurons were surrounded by PSA-NCAM-positive fibers and puncta. Our data provide evidence that synaptic reorganization is an active process in human drug-refractory TLE. Moreover, remodeling is not limited to the dentate gyrus, but also occurs in the CA1 subfield and the entorhinal cortex.

Adult↗

PubMed1996

Apolipoprotein E (apoE) levels in brains from Alzheimer disease patients and controls.

We measured apolipoprotein E (apoE) level in neutral and acidic pH extracts of the frontal, temporal and cerebellar cortices from patients with definite Alzheimer's disease (AD) and controls, and analyzed the relationship among apoE levels, clinical and neuropathological findings, and apoE genotype. Our data showed that the levels varied in different brain regions being lowest in the frontal cortex and highest in the cerebellum in Ad brains. ApoE levels in neutral pH extracts from the frontal cortex from AD patients were significantly lower than those of controls, and correlated negatively with the number of neurofibrillary tangles. ApoE genotype was not associated with the levels of apoE. There was no correlation between apoE levels and amyloid load or synaptophysin-immunoreactivity in the brain. We conclude that apoE levels are not increased in AD brains. However, apoE levels vary in different brain regions, and local factors related to the synthesis and metabolism of apoE may be crucial in the pathogenesis of AD.

Aged↗

PubMed1996

Cerebrospinal fluid concentrations of soluble amyloid beta-protein and apolipoprotein E in patients with Alzheimer's disease: correlations with amyloid load in the brain.

OBJECTIVE: To compare soluble amyloid beta-protein and apolipoprotein E levels in cerebrospinal fluid (CSF) and brain extracts from patients with definite Alzheimer's disease. SETTING: University medical center. PATIENTS: Nineteen patients with definite Alzheimer's disease. MAIN OUTCOME MEASURES: Soluble amyloid beta-protein and apolipoprotein E levels in CSF, in neutral and low-pH brain extracts, and in formic acid-treated sections of the frontal, temporal, and cerebellar cortices, measured using enzyme-linked immunosorbent assay. RESULTS: Soluble amyloid beta-protein and apolipoprotein E levels in CSF were significantly lower in patients with congophilic angiopathy than in those without angiopathy. The levels did not correlate with the number of amyloid plaques in the neocortex. There was, however, a tendency toward an inverse correlation between the amount of amyloid beta-protein in the frontal cortex extracts and the soluble amyloid beta-protein level in CSF. CONCLUSION: Soluble amyloid beta-protein levels in CSF may reflect amyloid accumulation in brain blood vessels.

Aged↗

PubMed1996

Pseudoexfoliation syndrome with poorly dilating pupil: a light and electron microscopic study of the sphincter area.

BACKGROUND: The study was carried out to examine histological changes in the iris sphincter muscle and surrounding tissue in eyes with pseudoexfoliation syndrome (PXS). METHODS: Seventeen patients with PXS, 14 of them having capsular glaucoma, were enrolled into the study. Iris biopsies were obtained during extracapsular cataract extractions (ECCE) requiring sphincterotomies. Thirteen biopsy specimens underwent histological examination by light microscopy, and four were examined with the electron microscope. Three iris biopsies from cadaver eyes and one obtained during ECCE from a patient with a miotic pupil (no PXS) served as control specimens on light microscopy. Electron microscopic controls included three iris specimens from cadavers. RESULTS: In the light microscopic examination, blood vessel walls were stained with Congo Red in seven of the 13 PXS specimens. In three of these seven specimens the stromal tissue was extensively fibrotized, and in two specimens fibrosis was moderate. Distinct stromal fibrosis was also observed in one and moderate fibrosis in two PXS specimens negative for amyloid. The control specimens were not positive for Congo Red, but stromal tissue was moderately fibrotized in one specimen. Light microscopy did not reveal differences in muscle tissue between PXS and control specimens. Electron microscopically, however, the muscle tissue was fibrotic or disorganized in three PXS specimens and in one control specimen. Fibrils, similar to the fibrillar component of pseudoexfoliation material described in previous studies, were found in intimate association with the capillary basal lamina in all of the PXS specimens showing muscular fibrosis. CONCLUSIONS: These findings support the theory that PXS is associated with amyloid, and in some PXS eyes miosis is connected with degenerative changes both in the stromal tissue and in the muscular layer of the iris.

Adult↗

PubMed1996

Diagnostic accuracy of Alzheimer's disease: a neuropathological study.

This prospective study focused on the accuracy of diagnosis of Alzheimer's disease (AD). We recruited 100 dementia patients and 20 controls who underwent a systematic evaluation. The clinical diagnosis of probable AD or possible AD according to the NINCDS-ADRDA criteria was assigned in 69% of the patients, 21% had vascular dementia (VaD) (DSM-III-R) and 8% had mixed AD-VaD; only 2 patients (2%) had the Lewy body variant of AD (AD-LB). During a 3-year period 57 patients died, 53 of them (93%) being autopsied. Neuropathological examination according to the CERAD criteria showed definite AD in 27 out of 28 (96%) patients diagnosed as probable AD. In the possible AD group, the diagnostic accuracy was also high, 86% showed at least some degree of AD pathological alterations. The neocortical senile plaque scores correlated significantly with tangle scores in patients with AD pathology, and there was a significant negative correlation between age of onset and neocortical tangle scores. The concordance between the clinical diagnosis and pathological findings was clearly lower in VaD than in AD. In the clinical VaD group, 8 of 10 patients had at least some degree of AD changes together with vascular changes and only 2 of 10 patients had pure VaD. This study confirms the high accuracy of the NINCDS-ADRDA criteria for diagnosing AD. In contrast, uncertainty in the clinical diagnosis of VaD should be taken into account, for example, in drug trials with VaD patients.

Age of Onset↗

PubMed1996

The effects of weight loss on insulin sensitivity, skeletal muscle composition and capillary density in obese non-diabetic subjects.

OBJECTIVE: To investigate whether the improvement in insulin resistance by weight loss is associated with changes in skeletal muscle fiber composition or capillary density. DESIGN: Longitudinal, clinical intervention study of a 2.1 MJ diet daily for 3 weeks and 3.4 MJ diet daily for 9 weeks. SUBJECTS: Seven obese (age: 41-59 y, five men, BMI > 34 kg/m2) non-diabetic subjects. MEASUREMENTS: Insulin action was measured by the euglycaemic hyperinsulinaemic clamp before and after 3 and 12 weeks of the very low calorie diet. In addition, the skeletal muscle biopsies were taken before and after the 12 weeks. RESULTS: During the 12 weeks, the subjects lost about 16% of body weight. The weight loss was accompanied by a nearly two-fold increase in total body glucose disposal rate (GDR; baseline vs 12 weeks: 842 +/- 91 vs 1505 +/- 242 mu mol/m2/min; p < 0.05). Most marked improvement was observed in non-oxidative component of GDR, which increased 2.7-fold as compared to baseline (292 +/- 113 vs 788 +/- 231 mu mol/m2/min; p < 0.05). However, no significant change in proportion of type II fibers as well as in skeletal muscle capillary density occurred during the study. CONCLUSION: In obese non-diabetic subjects the improvement in insulin sensitivity induced by weight loss was not accompanied by marked changes in skeletal muscle fiber composition or capillary density. However, due to small number of subjects studied, the role of structural changes in the muscle fiber composition cannot be entirely ruled out.

Adult↗

PubMed1995

Distribution of parvalbumin-immunoreactive cells and fibers in the human amygdaloid complex.

The calcium-binding protein, parvalbumin, was localized immunohistochemically in the human amygdaloid complex. Neuronal cell bodies and fibers that are immunoreactive to parvalbumin were observed in most of the amygdaloid nuclei and cortical areas. Three types of immunoreactive aspiny neurons, ranging from small spherical cells (type 1) to large multipolar cells (type 2) and fusiform cells (type 3), were observed. The densities of the types of neurons that were parvalbumin-immunoreactive varied in the different regions of the amygdala. The highest densities of parvalbumin-immunoreactive neurons were observed in the lateral nucleus, in the magnocellular and intermediate divisions of the basal nucleus, in the magnocellular division of the accessory basal nucleus and in the amygdalohippocampal area. The regions containing the lowest density of parvalbumin-immunoreactive cells were the paralaminar nucleus, the parvicellular division of the basal nucleus, the central nucleus, the medial nucleus and the anterior cortical nucleus. In general, the distribution of immunoreactive fibers and terminals paralleled that of immunoreactive cells. Parvalbumin-immunoreactive varicose fibers formed basket-like plexi and cartridges around the unstained neurons, which suggests that parvalbumin is located in GABAergic basket cells and chandelier cells, respectively. The distribution of parvalbumin-immunoreactive profiles in the human amygdaloid complex was similar to, rather than different from that previously reported in the monkey amygdala (Pitkänen and Amaral [1993] J. Comp. Neurol. 331:14-36). This study provides baseline information about the organization of GABAergic inhibitory circuitries in the human amygdaloid complex.

Adult↗

PubMed1995

A severe loss of choline acetyltransferase in the frontal cortex of Alzheimer patients carrying apolipoprotein epsilon 4 allele.

We measured the activities of choline acetyltransferase (ChAT) in the post mortem frontal cortex in 32 Alzheimer's disease (AD) patients with different apolipoprotein E (apoE) genotypes. The ChAT values were significantly lower for the AD patients with 2 epsilon 4 alleles than for those with 0 epsilon 4 (ANOVA, P < 0.05). The ChAT activities of AD patients carrying 2 or 1 epsilon 4 alleles and those without the epsilon 4 allele also differed significantly: 16.3 +/- 15.2 versus 30.5 +/- 20.6 pmol/mg protein per min, ANOVA, P < 0.05. However, the AD patients carrying the epsilon 4 allele were significantly younger than those with 0 epsilon 4 allele. The study indicates that AD patients carrying the epsilon 4 allele have a more severe cholinergic deficit than the AD patients without the epsilon 4 allele.

Aged↗

PubMed1995

Loss of synaptophysin-like immunoreactivity in the hippocampal formation is an early phenomenon in Alzheimer's disease.

We studied a synatophysin-like immunoreactivity in the hippocampal formation of patients with definite Alzheimer's disease, multi-infarct dementia, patients with no evidence of clinical dementia with neuropathological findings fulfilling the criteria of possible Alzheimer's disease, and age-matched nondemented controls. Possible Alzheimer's disease cases were of special interest because they were considered to represent early Alzheimer's disease. We also studied the spatial relationship of synaptophysin-like immunopositivity with amyloid-beta-protein immunopositive senile plaques and anti-paired helical filament immunopositive degenerating neurons locally as well as considering the intrinsic circuits in the hippocampal formation. The synaptophysin-like immunoreactivity was decreased in the hippocampus and the entorhinal cortex in patients with definite and possible Alzheimer's disease but not in multi-infarct dementia patients compared to controls. Equal loss of synapses in possible and definite Alzheimer's disease patients supports the hypothesis that synaptic loss is an early phenomenon in Alzheimer's disease. Unchanged synaptophysin-like immunopositivity in patients with multi-infarct dementia suggests that the loss of synapses is centrally involved in the pathogenesis of Alzheimer's disease and not dementia per se. There was no spatial correlation between loss of synapses and amyloid-beta-protein positive senile plaques. Moreover, we could not find a strict spatial relationship between senile plaques and degenerating neurons. Our results do not support the amyloid cascade hypothesis of Alzheimer's disease that local accumulation of amyloid-beta-protein leads to the loss of synapses.

Aged↗

PubMed1995

Relation of coronary atherosclerosis and apolipoprotein E genotypes in Alzheimer patients.

BACKGROUND AND PURPOSE: Apolipoprotein E (apoE) epsilon 4 allele has been associated with a high risk for coronary heart disease. Increased frequency of the epsilon 4 allele has also been reported in patients with late-onset familial and sporadic Alzheimer's disease (AD). The aim of this study was to investigate the degree of coronary and cerebral atherosclerosis in a neuropathologically verified series of AD patients with different apoE genotypes. In addition, we studied the relationship between the degree of coronary and cerebral atherosclerosis and the extent of beta-amyloid (A beta) accumulation. METHODS: We studied 38 subjects (32 patients with definite AD and 6 age-matched control subjects) for whom postmortem autopsy delay was less than 8 hours. ApoE genotypes were identified through Hha I digestion of the polymerase chain reaction-amplified samples. We used A beta immunohistochemistry to detect diffuse and neuritic plaques as well as cerebrovascular amyloid. The degree of coronary and cerebral atherosclerosis was rated as none, mild, moderate, or severe. RESULTS: The apoE genotypes of the AD patients were epsilon 4/4 2, epsilon 3/4 19, epsilon 3/3 9, and epsilon 3/2 2. We found more severe atherosclerosis of the coronary vessels among AD patients with the apoE epsilon 4 allele compared with those AD patients without the epsilon 4 allele (chi 2 = 4.1, df = 1, P < .05). The extent of cerebral atherosclerosis did not differ among AD subgroups with and without the epsilon 4 allele. The degree of coronary or cerebral atherosclerosis was not related to the amount of amyloid accumulation in the frontal and temporal cortices or in the hippocampal structures. CONCLUSIONS: This study confirms the association of apoE epsilon 4 allele with coronary atherosclerosis in AD patients.

Aged↗

PubMed1994

beta-Amyloid protein immunoreactivity in skin is not a reliable marker of Alzheimer's disease. An autopsy-controlled study.

OBJECTIVES: As a possible diagnostic marker for Alzheimer's disease (AD), we investigated beta-amyloid protein (beta/A4) immunoreactivity in skin. Furthermore, we studied the presence of beta-amyloid precursor protein 695 immunoreactivity in skin. DESIGN: Lifetime skin biopsy specimens were stained for beta/A4 and beta-amyloid precursor protein 695. The follow-up period was 12 months. We determined the correlation between beta/A4 immunoreactivity in skin and brain in patients with a neuropathologic diagnosis. SETTING: All patients with dementia were hospitalized; most of them had moderate to severe dementia. Aged nondemented controls were residents of a nursing home. The Down's syndrome (DS) group included both hospitalized and ambulatory patients. Young nondemented controls were medical students or staff members who volunteered for the study. PATIENTS AND OTHER PARTICIPANTS: The study included a total of 111 subjects. Thirty-five patients had probable AD, nine had possible AD, 15 had multi-infarct dementia, one had idiopathic Parkinson's disease, and one had Parkinson's disease and possible AD. There were also 19 elderly nondemented controls, 23 patients with DS, and eight young nondemented controls. MAIN OUTCOME MEASURES: Immunohistochemical detection of beta/A4 in skin and correlation to the diagnosis of AD. RESULTS: Immunopositivity for beta/A4 antibody was present in and around the endothelium of dermal blood vessels in a proportion of patients with AD and multi-infarct dementia as well as elderly controls. The patients with sporadic AD displayed beta/A4 immunoreactivity significantly more frequently than did patients with familial AD, patients with multi-infarct dementia, and controls. The beta/A4 immunopositivity in skin was rare in the patients with DS and not present in young controls. Instead, 48% of patients with DS but none of other groups had beta-amyloid precursor protein 695 immunoreactivity in skin. Only four (31%) of 13 patients with neuropathologically confirmed AD had shown endothelial beta/A4 immunopositivity in skin biopsy specimens while alive. CONCLUSION: Our results do not support beta/A4 as a diagnostic marker for AD.

Aged↗

PubMed1994

Running training alters fiber type composition in spinal muscles.

The issue of whether exercise can induce changes in muscle fiber types has been long debated. Knowledge about the alterations in spinal muscle fiber types is scarce. In this study, the alterations initiated by long-distance running on spinal muscle fiber type distribution was studied. Ten young dogs were run on a treadmill for 55 weeks, 5 days a week, and ten dogs from the same litters served as controls. The daily running distance was gradually increased to 40 km and maintained at that level for the final 15 weeks. Histological sections were prepared from the cervical, thoracic, and lumbar multifidus muscles and the medial and lateral heads of triceps brachii and analyzed for the fiber type composition and cross-sectional area of fibers. In the lumbar multifidus, the numerical percentage of the muscle fibers with low oxidative capacity (type II) increased significantly in the running group. However, in the thoracic and cervical spine multifidus, the response to running resembled more of the significant shift from type II to type I fibers (with high oxidative capacity), which was also observed in the triceps brachii muscle. In these muscles, the quantitative image analysis of nicotinamide adenine dinucleotide tetrazolium reductase (NADH-TR) reaction also demonstrated a shift towards a higher oxidative capacity within the type II fibers. The results show that training can induce changes in fiber type composition not only in limb muscles but also in the stabilizing spinal muscles.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Late onset foot-drop muscular dystrophy with rimmed vacuoles.

We studied a family with late-onset (fifth or sixth decade) or asymptomatic hereditary myopathy of the anterior tibial muscle. The occurrence of the disease in two successive generations pointed out an autosomal dominant pattern of inheritance. The initial symptom was uni- or bilateral foot drop resembling peroneal paresis. Surprisingly many of the diagnosed patients were asymptomatic and considered themselves healthy whether there was any foot drop or not. The anterior tibial muscles were atrophic in patients with foot drop but the long toe extensors were usually and the short ones were always spared. Apparently the toe extensors could relieve the foot drop symptom. As shown by computed tomography there was often an early uni- or bilateral involvement of the semimembranosus muscle in males. The proband showed also a late involvement of the femoral biceps and the minor gluteal muscles. The muscles of the upper extremity were spared. The anterior tibial muscles had a characteristic myopathic alteration with rimmed vacuoles in histopathological study. This picture was most evident in latent cases without atrophy of the anterior tibial muscle, but with distinctly abnormal EMG of that muscle. Non-affected muscles showed only slight non-specific histopathological changes. We suggest that this disease is a new mild variety of autosomal dominant distal myopathy with rimmed vacuoles.

Adult↗

PubMed1993

Brain methionine- and leucine-enkephalin receptors in patients with dementia.

Brain [3H]Met- and [3H]Leu-enkephalin binding was studied in patients with Alzheimer's disease (AD) and vascular dementia (VD), and in age-matched controls. Brain areas investigated were the internal and external globus pallidus, amygdala, hippocampus and temporal cortex. In AD, the binding of both enkephalins decreased in all brain areas examined, except in the external globus pallidus for both enkephalins and in the internal globus pallidus for leucine-enkephalin. Scatchard analysis of amygdaloid samples showed a decrease in the number of receptors (Bmax) without any change in their affinity (Kd). In patients with VD, no significant changes in enkephalin binding were seen. Thus, in AD, enkephalin binding (mainly reflecting delta opioid receptor subtype) is decreased, especially in limbic areas.

Aged↗

PubMed1993

Malaoxon-induced neurotoxicity in old rats: alterations in cerebral inositol lipid signalling, brain tissue calcium levels and early neuronal injury.

Effects of malaoxon (MO) on brain regional inositol, inositol monophosphate and calcium levels, as well as on early neuronal injury, were studied in old (18 months) male rats. In old rats, a dose of 8.7 mg/kg of MO caused convulsions similar to those reported earlier in parallel experiments with young male (10 weeks) rats using a dose of 39.2 mg/kg. In the convulsing old male rats, MO caused a transient decrease of cerebral inositol 1 h post MO in the piriform cortex and thalamus, whereas more persistent decreases of inositol occurred in the frontal cortex and the cerebellum. In the non-convulsing rats, a decrease of inositol was only seen in the cerebellum. Cerebral inositol-1-phosphate (Ins1P) increased in all brain regions of convulsing rats, whereas Ins1P did not change in the non-convulsing rats. Brain Ca2+ increased post MO in convulsing and non-convulsing rats in the frontal cortex, caudate and thalamus; in the piriform cortex and hippocampus increases of Ca2+ were only seen in the convulsing rats. Inositol-4-phosphate (Ins4P) remained stable in all MO-exposed rats. MO-induced early neuronal injury occurred only in the convulsing rats and was most severe in the cortex, hippocampus and the subcortical structures. Qualitatively the effects of MO in the old and young rats were, however, similar and, therefore, probably due to cholinergic brain stimulation and subsequent increase in inositol lipid signalling. These results suggest that old rats are likely to be more sensitive than the young rats to the neurotoxic effects of MO.

Animals↗

PubMed1993

Sustained effects of pilocarpine-induced convulsions on brain inositol and inositol monophosphate levels and brain morphology in young and old male rats.

Cerebral inositol and inositol monophosphates, products of phosphoinositide (PI) turnover, and neuronal injury were studied in young (10 weeks) and old (24 months) male Wistar rats after pilocarpine-induced convulsions. The goal was to explore the association between short-term cholinergic convulsions, brain PI signaling, and changes in the brain morphology in the young and the old rats. Pilocarpine caused convulsions in young rats at a dose of 300 mg/kg, whereas a dose of 175 mg/kg was required to obtain the same effect in old rats. A dose of 5 mg/kg of diazepam was used to terminate the convulsions 2 hr after their initiation; the rats were then examined on Day 5 postpilocarpine. Inositol and inositol monophosphate levels were similar in both the young and the old control rats. Pilocarpine-induced convulsions decreased cerebral inositol and increased inositol-1-phosphate in both the young and the old rats. Inositol-4-phosphate was stable in the young rats but increased in the frontal cortex and the hippocampus in the old rats. Delayed neuronal death also occurred in the convulsing rats, i.e., a variable proportion of neurons appeared shrunken with eosinophilic cytoplasm and pyknotic nuclei. The hippocampus was the most severely affected brain area. These results show that old rats are more sensitive than young ones to short-term pilocarpine convulsions, associated with sustained PI turnover, and brain injury. Mechanisms in addition to cholinergic ones are likely to be involved in the prolonged cerebral effects of cholinergic convulsions in rats.

Aging↗