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As life spans increased, neurodegenerative disorders that affect aging populations have also increased. Progressive neuronal loss in specific brain regions is the most common cause of neurodegenerative disease; however, key determinants mediating neuron loss are not fully understood. Using a model of mitochondrial membrane potential (ΔΨm) loss, we found only 25% cell loss in SH-SY5Y (SH) neuronal mono-cultures, but interestingly, 85% neuronal loss occurred when neurons were co-cultured with BV2 microglia. SH neurons overexpressing uncoupling protein 2 exhibited an increase in neuron–microglia interactions, which represent an early step in microglial phagocytosis of neurons. This result indicates that ΔΨm loss in SH neurons is an important contributor to recruitment of BV2 microglia. Notably, we show that ΔΨm loss in BV2 microglia plays a crucial role in microglial activation and phagocytosis of damaged SH neurons. Thus, our study demonstrates that ΔΨm loss in both neurons and microglia is a critical determinant of neuron loss. These findings also offer new insights into neuroimmunological and bioenergetical aspects of neurodegenerative disease.

This study tested the hypothesis that hydrophilic chemotypes of the medicinal vine Uncaria tomentosa (UT) would facilitate recovery of sensorineural functions following exposure to a damaging level of noise. The particular chemotypes investigated were carboxy alkyl esters (CAE) which are known to exhibit multifunctional cytoprotective properties that include: enhanced cellular DNA repair, antioxidation and anti-inflammation. Long-Evans rats were divided into four treatment groups: vehicle-control, noise-only, CAE-only and CAE+noise. The noise exposure was an 8kHz octave band of noise at 105dB SPL for 4h. Outer hair cell (OHC) function was measured with the cubic 2f(1)-f(2) distortion product otoacoustic emissions (DPOAE) at the start of the study (baseline) and at time-points that corresponded to 1day, 1week and 4weeks post-noise exposure to determine within-group effects. Compound action potentials to puretone stimuli were recorded from the VIIIth craniofacial nerve at 4weeks post-noise exposure to determine between-group effects. Additionally, cytocochleograms were constructed for each row of OHCs from each group. Noise exposure produced significant sensorineural impairments. However, CAE treatment facilitated almost complete recovery of OHC function and limited the magnitude of cell loss. The loss of neural sensitivity to puretone stimuli was inhibited with CAE treatment. Therefore, it appears that the multifunctional cytoprotective capacity of CAE from UT may generalize to otoprotection from acoustic over-exposure.

Kaplan, Suleyman/0000-0003-1477-5002; Ucok, Kagan/0000-0001-6404-4510 WOS: 000265673000019 PubMed: 19230827 The effects of electromagnetic fields (EMFs) emitted by mobile phones on humans hold special interest due to their use in close proximity to the brain. The current study investigated the number of pyramidal cells in the cornu ammonis (CA) of the 16-week-old female rat hippocampus following postnatal exposure to a 900 megahertz (MHz) EMF. In this study were three groups of 6 rats: control (Cont), sham exposed (Sham), and EMF exposed (EMF). EMF group rats were exposed to 900 MHz EMF (1 h/day for 28 days) in an exposure tube. Sham group was placed in the exposure tube but not exposed to EMF (1 h/day for 28 days). Cont group was not placed into the exposure tube nor were they exposed to EMF during the study period. In EMF group rats, the specific energy absorption rate (SAR) varied between 0.016 (whole body) and 2 W/kg (locally in the head). All of the rats were sacrificed at the end of the experiment and the number of pyramidal cells in the CA was estimated using the optical firactionator technique. Histopathological evaluations were made on sections of the CA region of the hippocampus. Results showed that postnatal EMF exposure caused a significant decrease of the pyramidal cell number in the CA of the EMF group (P < 0.05). Additionally, cell loss can be seen in the CA region of EMF group even at qualitative observation. These results may encourage researchers to evaluate the chronic effects of 900 MHz EMF on teenagers' brains. (C) 2009 Elsevier B.V. All rights reserved.

Equivalent antiinflammatory doses of steroids including betamethasone, methylprednisolone and dexamethasone were administered in the neonatal period in a rat model. In situ cell death in hippocampus quantified by Terminal Deoxynucleated Transferase Nick-End Labeling and on ratio of brain to body weight was investigated. Apoptotic index (AI) was significantly higher in methylprednisolone, and high dose dexamethasone groups than the other groups. AI in "Cornu ammonis 1" (CA1) and "Cornu ammonis 3" (CA3) subregions of high dose dexamethasone group was the highest among the five groups tested. AI in CA3 subregions of methylprednisolone group was also significantly higher than the control, betamethasone and low dose dexamethasone groups. AI in CA1 subregion were not different among control, betamethasone, methylprednisolone and low dose dexamethasone groups. In addition, high dose dexamethasone resulted significant decrease in the ratio of brain weight to body weight in comparison to all other groups tested. In conclusion, betamethasone and low dose dexamethasone may be better alternative treatments among agents tested in this study for chronic lung disease (CLD). © 2008.

Binge-like neonatal exposure to ethanol (EtOH) in rats, during the period of brain development comparable to that of the human third trimester, produces significant, dose-dependent Purkinje cell loss in the cerebellum and deficits in eyeblink classical conditioning. There are currently no published reports of whether neuronal loss in the cerebellar deep nuclei also results from binge-like neonatal exposure to EtOH and what the functional consequences of any cell loss might be. Since eyeblink conditioning requires cerebellar deep nuclear cells for normal learning to occur, we examined the effects of binge-like neonatal EtOH exposure on the total number of deep nuclear cells and eyeblink conditioning in adult rats. Group Ethanol (n=11) received EtOH doses of 5.25 g/kg/day on postnatal days 4-9, producing average peak blood alcohol concentrations of 363 mg/dl. Group Sham Intubated (n=11) underwent acute intragastric intubation on postnatal days 4-9 but did not receive any EtOH infusions. Group Unintubated Control (n=10) did not receive any intubations. When rats were at least 3 months old, they received either paired eyeblink conditioning or unpaired training. Following training, estimates of the total number of cerebellar deep nuclear cells were obtained using the optical fractionator, an unbiased stereological counting procedure. Rats in Group Ethanol had approximately 50% fewer deep nuclear cells compared to rats in Groups Sham Intubated and Unintubated Control, which did not differ. For 21 rats that received paired eyeblink conditioning, a highly significant correlation (+0.80) was found between the number of deep nuclear cells and learning rate in eyeblink conditioning.

[3H]Nisoxetine ([3H]NIS) was used to measure uptake sites for norepinephrine (NE) in the locus coeruleus (LC) of humans. Regression analysis demonstrated an inverse correlation between age and the binding of [3H]NIS to NE uptake sites in the LC (r = -0.6; P less than 0.01). Since considerable cell loss has been reported to occur with age in the human LC, the decreased binding of [3H]NIS probably reflects loss of LC cells rather than a down-regulation of these sites.

Quin2-acetoxymethylester (quin2/AM) (50 microM), administered directly to the motoneuronal pool of the frog spinal cord, could be loaded into the motoneuron as well as the other cells in the lumbar region. Depolarizing responses of the ventral root to L-glutamate in the quin2-loaded side persisted even after prolonged exposure to A23187 (2.0 microM), while the responses in the unloaded side were markedly reduced. Histologically confirmed neuronal cell loss from the motoneuronal pool induced by A23187 (2.0 microM) or by a high concentration of L-glutamate (10 mM) was prevented by pretreatment with quin2/AM. A23187- and L-glutamate-induced histological and functional damage in neuronal cells and the protective effects of quin2 on them provide further evidence for cell death due to Ca2+ overloading.

The histochemical, biochemical and behavioural consequences of MPTP administration in C-57 black mice was assessed 0.5 h, 24 h and 7 days after the last injection of this drug administered daily for 10 days during a 12 day period (30 mg/kg/injection or vehicle). A slight but significant impairment of open field performance was observed at 0.5 h after the last injection of MPTP while a facilitation of locomotory behaviour was observed only in the 24 h post-injection group. Striatal dopamine levels were reduced to 14, 18 and 27% of control levels in the 0.5 h, 24 h and 7 day post-MPTP treated groups, respectively. Histochemical assessment was in agreement with the biochemical assay results in that all MPTP treated animals showed severe depletion of striatal terminal fields. Other terminal fields were occasionally affected by MPTP treatment and only rarely was any change in the fluorescence or morphology of nigral cell bodies seen. Accumulation of amines in the degenerating amine-containing axons which traverse the lateral hypothalamus was not seen in any of the MPTP treated animals. These results indicate that, in the C-57 black mouse, MPTP causes a depletion of striatal dopamine without causing nigral cell loss or axon swelling as is observed with other experimental treatments such as 6-hydroxydopamine. Consistent with this is the behavioural data, indicating that severe deficits in motor function which are associated with nigrostriatal cell loss were not seen. We conclude that the inability of MPTP to produce motor function impairment in various species is related to its failure to produce true degenerative changes in nigrostriatal neurons which include amine accumulation in the degenerating axons and cell loss in the substantia nigral complex.

The present experiments investigate the effects of neonatal lesions upon projection patterns of the uncrossed retinotectal pathway in albino rats. The results indicate that enlargement of the terminal field from one eye can be induced either by a contralateral optic tract lesion or by removal of the opposite eye at birth. The extent of the enlargement is more prominent in the latter case. If an optic tract lesion is accompanied by eye enucleation on the side ipsilateral to the tract lesion, the uncrossed retinotectal projection from the remaining eye will undergo further enlargement. However, optic fiber counts show that such an enlargement of the terminal field is not due to a significant increase in the number of uncrossed optic axons which contribute to the enlarged projection, but rather to an increased terminal arbor of individual axons (as shown by results from fiber counts). While a severe ganglion cell loss was observed in the retina contralateral to a tract lesion, a substantial population of cells persists in the ganglion cell layer and the number of cells appears much higher than the number of uncrossed optic axons arising from the same eye. The implications of these findings are discussed in relation to results reported in previous studies.

Evidence of a postnatal loss of cerebral cells has been presented, based on counts of the activity of cerebral DNA following labeling with [3H]thymidine on embryonic day 14. In otherwise untreated rats, the loss was about 15 percent of the labeled cells between postnatal days 3 and 15. There was no further loss of activity thereafter. Littermates given corticosterone at day 3 showed little additional loss of labeled cells. Ganglioside NANA (N-acetylneuraminic acid) was reduced in proportion to the reduction in cerebral weight in the corticosterone treated rats. Sulfatide was reduced more, so that the concentration was 11 percent below that of the controls; It is concluded that the deficit in DNA after postnatal corticosterone treatment must be due primarily to an irreversible suppression of DNA synthesis, involving mainly glia. The reduction in gangliosides may represent a deficit in the growth of neuronal processes, leading to a reduction in the amount of neuropil, and perhaps contributing to a decrease in the number or size of myelinated axons.

The effects of damage of the striatum and globus pallidus of one side on the size of cells in the pars reticulata and pars compacta of the substantia nigra on both sides and in the contralateral globus pallidus have been examined. Cellular cross-sectional areas have been compared with those for neurons in the same nuclei in normal age and sex matched littermate control animals. One week after removal of the left striatum and globus pallidus and overlying cortex, the cells in the ipsilateral pars compacta are significantly shrunken (15%). This decrease in size gets progressively more marked with longer survival times reaching 50% 112 days after operation, the longest survival time examined. The shrinkage is accompanied by marked cell loss. Neurons in the contralateral pars compacta show an initial significant hypertrophy of their cell bodies (20%) in the first week after the operation, and later show a shrinkage of 20% to 35 days. The degree of this contralateral shrinkage gradually declines to 12% at 112 days. The changes in the pars compacta are accompanied by a significant enlargement (33%) of the cells in the pars reticulata of the substantia nigra on the side of the damage. This hypertrophy is present by 35 days after operation and persists at least until 112 days. Similar hypertrophy occurs in the ipsilateral globus pallidus in the one case where this could be examined. There are no significant changes in the contralateral pars reticulata, but there is significant enlargement (23%) of the neurons in the contralateral globus pallidus.

Following lesions of the pyramidal tract in hamsters, retrograde changes were studied in the sensorimotor cortex and in the pyramidal tract axons proximal to the lesion, at survival times ranging from 2 weeks to 14 months. Severe cell shrinkage occurred in layer 5 pyramidal neurons as early as 2 weeks, but there was no cell loss among these neurons even with long survival times. Use of the Fink-Heimer method for degenerating axons revealed that the pyramidal tract proximal to the lesion had undergone a retrograde axon degeneration which, in some respects, resembled anterograde degeneration. The retrograde axon degeneration began at the lesion site and advanced slowly rostralwards with time involving increasingly greater numbers of fibers. However, even at the longest survival times the degeneration fell off markedly at pontine levels. The results indicate that this process represents a true retrograde fiber degeneration (as opposed to an indirect Wallerian degeneration) which appears to reach a point of equilibrium such that a partially shrunken pyramidal cell is maintaining a partially degenerated axon.

Summary Two weeks of binocular lid suture in adult cats caused selective cell loss nn lamina A1 of the lateral geniculate nucleus. The loss was manifested as a shift in the latency distribution of LGN cell responses to optic chiasm shock. Proportionately fewer LGN cells with slowly conducting retinal afferents (X-cell range) were in evidence following binocular suture. This change was observed only in lamina A1 while laminae A and C retained normal latency distributions. These observations confirm and extend recent reports of the susceptibility of adult cat visual system to environmental modification.

The posterior lateral hypothalamic area has been suggested as a possible site of action for the reinforcing effects of opiates on the basis of the finding that rats would lever-press for direct microinjections of opiates into this region. The present study reports the effects of kainic acid-induced lateral hypothalamic cell loss on the intravenous self-administration of heroin. Kainic acid injection resulted in marked cellular depletion yet failed to alter heroin self-administration.

We have compared the effects of electrolytic and kainic acid lesions of the pontine gigantocellular tegmental field (FTG) upon paradoxical sleep (PS). Following bilateral electrolytic destruction of the ventrolateral part of the FTG, there was an almost total suppression of PS which lasted at least for 5 weeks. Muscular atonia was absent and ponto-geniculo-occipital (PGO) activity was reduced by 80% in the few remaining episodes of PS. Contrary to to these effects, total neuronal cell loss of the FTG induced by bilateral kainic acid injection was not followed by a significant quantitative and qualitative alteration of PS. These results indicate that the neurons located within the FTG are not critical for the generation of both phasic and tonic components of PS. Elimination of this state of sleep after electrolytic destruction of the ventrolateral pontine reticular formation can be explained by interruption of fibers connecting the region of the locus coeruleus complex and the bulbar reticular formation.

The axons of dentate granule cells (mossy fibers) have been reported to appear in the regio superior (CA1) of the rat hippocampal formation following destruction of the pyramidal cells in the regio inferior (CA3). We undertook the present experiments to confirm this finding and to determine the requirements for this dramatic neuronal rearrangement. We found that extensive (> 80%) loss of CA3 cells, as well as the presence of surviving CA1 neurons within a narrow period of development (postnatal days 3–5) is necessary, however apparently not sufficient, for the appearance of CA1 mossy fibers. That the absence of normal target cells during a restricted period of mossy fiber development will lead to their association with novel targets suggests that much of the specificity of this developing connection depends on the presence of normal targets during a critical period.

Summary Histological changes are described in the brain of a patient in whom a hemicerebellactomy had been performed 14 years before death. There is cell and fibre loss, partial or total, in nuclei known to have direct connections with the cerebellum. In some nuclei the sequel to cell loss is marked fibrillary gliosis. In other nuclei the cells have disappeared without trace. The degeneration of these tracts with a direct connection with the cerebellum has also led to degeneration of other tracts in synaptic relationship with them. This transneuronal degeneration has occurred in the corticopontine tracts and in the central tegmental tract, in the former definitely, and in the latter probably, retrogradely. It is probable that transneuronal degeneration has also occurred in other tracts. The extent of the degeneration and, in particular, the occurrence of overt transneuronal degeneration, suggest that the examination of material after a very long term of survival might be of value in experimental work concerned with mapping neuroanatomical networks.

The effects of unilateral intercostal nerve transection have been studied in adult rats neonatally treated with capsaicin. Two rats were treated with capsaicin-free vehicle and served as controls. It is shown that capsaicin treatment leads to a dorsal root ganglion cell loss of about 43%, and about a 72% loss of unmyelinated dorsal root fibers. Myelinated dorsal root fibers remain unaffected. The cell size spectrum shows a 27% increase in median cell area in the capsaicin-treated rats, indicating a loss of preferentially smaller cells. A subsequent peripheral nerve transection resulted in a further cell loss of about 30% with no major change in cell size spectrum. The peripheral nerve transection also somewhat further reduces both the number of unmyelinated and myelinated dorsal root axons. The data indicate that neurons which die after a prripheral nerve transection belong to both the groups of cells, which are capsaicin-sensitive and capsaicin-resistant.

The sites of calcium accumulation were studied by 45Ca autoradiography during kainic acid (KA)-induced limbic seizure in rats. Two hours after KA injection into unilateral amygdala, calcium accumulated in CA3 of the hippocampus, lateral septal nucleus and thalamic reticular nucleus on KA-injected side. Those sites coincided with the sites where neuronal cell damage appeared 4 h after KA injection. These results suggested that regional calcium accumulation might be responsible for neuronal cell loss induced by seizures.