Arnold E. Eggers

A serotonin hypothesis of schizophrenia

Chronic widespread stress-induced serotonergic overdrive in the cerebral cortex in schizophrenia, especially in the anterior cingulate cortex (ACC) and dorsolateral frontal lobe, is the basic cause of the disease. The concept of excessive serotonergic stimulation is supported by NMR spectroscopy; peripheral depletion of phospholipids, serotonergic 5-HT2A receptors being linked to phospholipase A2; positron emission tomography data with serotonergic ligands; and the fact that blockade of serotonergic 5-HT2A receptors by atypical neuroleptics slows down the course of the disease. Disruption of glutamate signalling by serotonergic overdrive leads to neuronal hypometabolism and ultimately synaptic atrophy and grey matter loss according to principles of brain plasticity. Normal dopamine input to an impaired ACC causes positive symptoms. Frontal lobe hibernation causes negative symptoms and cognitive impairment.

Autoradiographic and fluorescence antibody studies of the human host immune response to gliomas.

A THEORY of a two-stage immunological response to neoplasia has recently been proposed.’ The first stage is held to be mediated by lymphocytes which are specifically sensitized to tumor antigens and may destroy the tumor, thus aborting the disease, or which, in the case of tumors that become clinically apparent, may not be mobilized in sufficient quantities before the appearance of “enhancing antibodies” that coat the tumor and hide it from the lymphocytes. Because the CNS is an immunologically “privileged site”2 with no lymphatic drainage, it seemed possible that any two-stage response to gliomas might be slowed, with the result that the tumors might become clinically apparent after the appearance of specifically sensitized lymphocytes and before the appearance of enhancing antibodies. A report has appeared describing the autoradiographically detected stimulation of autologus lymphocytes by glioblastoma cells in tissue culture, where the tumor cells produced stimulation intermediate between that produced by phytohemagglutinin and that produced by autologus fibroblasts.3 This experimental system was further explored, and the results were correlated with fluorescence antibody findings.

Why do Alzheimer's disease and Parkinson's disease target the same neurons?

The puzzle is to explain how cerebral involvement in the sporadic forms of Alzheimers disease (AD) and Parkinsons disease (PD) can target the same population of vulnerable neurons. These neurons are poorly-myelinated projection neurons, lack of myelin being associated with high metabolic demand, high oxygen consumption, and high baseline oxidative stress. Yet the two diseases are clearly separable, with different intracellular markers, different risk factors, and different patterns of subcortical involvement. A theory is developed to show how two different pathophysiologies can preferentially affect the same neurons. In the case of AD, the hypothesis is as follows: the so-called vascular risk factors of AD, which include hypertension, diabetes, hyperlipidemia, and smoking, are all associated with increased systemic extracellular oxidative stress. High extracellular oxidative stress synergizes with high baseline intracellular oxidative stress to cause the disease. In the case of PD, mitochondrial failure associated with normal aging leads to diminished energy production and increased leakage of reactive oxygen species from mitochondria, a process which preferentially targets neurons with high baseline oxidative stress. In one case, the extra oxidative stress comes from outside the cell and, in the other case, it comes from inside the cell, i.e. from mitochondria. There is also evidence that neurofibrillary tangles are a protective mechanism against extracellular oxidative stress and that alpha-synuclein is a marker for mitochondrial failure. The basic pathophysiological difference is that AD is caused by oxidative stress alone, whereas PD is caused by oxidative stress plus failure of energy production.

Extending David Horrobin’s membrane phospholipid theory of schizophrenia: Overactivity of cytosolic phospholipase A2 in the brain is caused by overdrive of coupled serotonergic 5HT2A/2C receptors in response to stress

David Horrobins membrane phospholipid theory of schizophrenia has held up well over time because his therapeutic prediction that dietary supplementation with eicosapentaenoic acid (EPA) would have a therapeutic effect has been partially verified and undergoes continued testing. In the final version of his theory, he hypothesized that there was hyperactivity of phosphoslipase A(2) (PLA(2)) or a related enzyme but did not explain how the hyperactivity came about. It is known that serotonergic 5HT(2A/2C) receptors are coupled to PLA(2), which hydrolyzes both arachidonic acid (AA) and EPA from diacylglycerides at the sn-2 position. In this paper, Horrobins theory is combined with a previously published theory of chronic stress in which it was hypothesized that a disinhibited dorsal raphe nucleus, the principal nucleus of the serotonergic system, can organize the neuropathology of diseases such as migraine, hypertension, and the metabolic syndrome. The new or combined theory is that schizophrenia is a disease of chronic stress in which a disinhibited DRN causes widespread serotonergic overdrive in the cerebral cortex. This in turn causes overdrive of cPLA(2) and both central and peripheral depletion of AA and EPA. Because EPA is present in smaller amounts, it falls below threshold for maintaining an intracellular balance between AA-derived and EPA-derived second messenger cascades, which leads to abnormal patterns of neuronal firing. There are two causes of neuronal dysfunction: the disinhibited DRN and EPA depletion. Schizophrenia is statistically associated with metabolic syndrome, hypertension, and migraine because they form a cluster of diseases with similar pathophysiology. The theory provides an explanation for both the central and peripheral phospholipid abnormalities in schizophrenia. It also explains the role of stress in schizophrenia, elevated serum PLA(2) activity in schizophrenia, the relationship between untreated schizophrenia and metabolic syndrome, and the therapeutic rationale for EPA.

Neurological theory of hypertension.

Review of the older literature on the relationship between migraine and hypertension, written in the era before either condition could be treated, discloses a high rate of co-morbidity. A neurological theory of essential hypertension is proposed in which the two diseases are brought together into one entity. It is hypothesized that abnormally functioning serotonergic pacemaker cells in the dorsal raphe nucleus, as part of a chronic stress response, inappropriately activate and inhibit parts of the central and autonomic nervous systems, so as to cause the two conditions. This theory builds on a previously published neural theory of migraine.

Autologous adjuvant linked fibroblasts induce anti-glioma immunity: implications for development of a glioma vaccine

SummaryObjectives: Adjuvant-linked vaccines have been shown to induce anti-tumor immunity in patients with a variety of solid tumors. In this study we describe anin vitro model of active immunotherapy using autologous fibroblasts as immunogen. Correlative results from glioma patients immunized with autologous fibroblasts are also described. Methods: Peripheral blood lymphocytes (PBLs) from normal subjects were immunizedin vitro against autologous skin fibroblasts coupled to the adjuvant muramyl dipeptide. The lymphocytes developed cell-mediated cytotoxicity that was measured with a short-term chromium release assay. Results ofin vitro experiments were compared to data derived from glioma patients immunized with subcutaneous injection of an autologous adjuvantlinked fibroblast vaccine. Glioma target cells and fibroblast immunogens were derived from early passage primary tissue culture. Results: A comparison of autologous vs. homologous immunogen indicated that major histocompatibility complex matching was required at the sensitization stage of immunity (17.2±3.4% specific lysis vs. 0.4±3.1%,P<0.01). Pre-treatment of fibroblast immunogen cells with interferon gamma (IFN-γ) was found to significantly increase immunity (42.2±10.0%,P<0.01), as did IFN-γ pre-treatment of tumor target cells (35.8±9.0%,P<0.01). The positive effect of IFN-γ was diminished by treatment of cells with IFN-α. Thesein vitro results correlated well within vivo data derived from glioma patients immunized with an autologous adjuvant-linked fibroblast vaccine. PBLs from patients developed direct cell-mediated cytotoxicity against autologous tumor cells. Lysis of tumor targets afterin vivo immunization increased over a three-week interval (from 1.2 ± 3.0% to 21.0 ± 3.4%,P < 0.01) while lysis of a non-MHC matched control cell line remained essentially unchanged. Conclusions: Specific lysis of glioma targetsin vitro was achieved afterin vivo sensitization with autologous adjuvant-linked fibroblasts. Collectively, the data indicate that biochemically modified autologous cells can stimulate anti-glioma immunity in humans. The degree of specific immunity seen in our patients compares favorably with other published series using glioma cells as an antigenic source. Accordingly, fibroblasts may represent a practical alternative to glioma cells for vaccine construction.

An explanation of why schizophrenia begins with excitotoxic damage to the hippocampus

A recent paper by Schobel et al. provides evidence that schizophrenia begins with excitotoxic damage in the hippocampus, primarily in the CA1 subfield. MRI measurement of cerebral blood volume (CBV) was taken to be a marker of basal metabolism. High baseline CBV in the CA1 subfield of subjects at high risk for schizophrenia predicted progression to psychosis and the development of hippocampal atrophy. A mouse model of ketamine excitotoxicity reproduced the human imaging study, i.e. hypermetabolism in CA1 led to atrophy. The authors do not explain the pathophysiology of selective excitotoxicity in the hippocampus. A recently published serotonin theory of schizophrenia provides a hypothetical explanation for these findings. The serotonin theory predicts that schizophrenia begins with stress-induced overdrive of serotonergic pacemaker cells in the dorsal raphe nucleus. The overdrive is passed via the entorhinal cortex to the hippocampus, where it causes excitotoxicity. Passage through the entorhinal cortex converts a serotonergic signal into a glutamate signal, glutamate being the neurotransmitter of exicitotoxicity. The remitting-relapsing pattern of schizophrenia is explained by a balance between excitotoxicity in the hippocampus and repopulation by neurogenesis in the subgranular zone. Injury is balanced by healing.

A new theory of essential hypertension based on analysis of the association between a polymorphism of the α2-adrenoceptor at the 10q24-q26 locus and hypertension in African-Americans.

Some key historical observations about essential hypertension (HTN) are reviewed, analyzed logically, and used to construct a new theory of hypertension. The historical observations are as follows: Lockette reported a statistical association between HTN in African-Americans and the 6.3-kb allele of a restriction fragment-length polymorphism of the gene for the α2-adrenoceptor, which is found on platelets. Individuals carrying at least one copy of the 6.3-kb allele had increased in vitro epinephrine-induced platelet aggregation. Systemic or blood-wide platelet activation (SPA) induced by epinephrine has been shown to be an in vivo feature of HTN, and serotonin and thromboxane A2, two vasoconstrictors released by activated platelets, synergize in vitro with angiotensin II. Esler showed that there is increased noradrenergic drive in the heart and kidney in HTN, although renin levels are usually normal. Mulvanys group showed that small arteries controlling vascular resistance undergo remodeling in HTN. Putting together these observations leads to the following theory. Essential HTN is a disease in which the brainstem set point for blood pressure (BP) is reset, which causes the autonomic nervous system to release increased norepinephrine in the heart and kidney and increased epinephrine from the adrenal medulla. Epinephrine release causes SPA. In the first stage of the disease, when renin is high, serotonin and thromboxane A2 released by activated platelets synergize with high angiotensin II to raise BP. Rising BP causes vascular remodeling, a structural attempt at autoregulation of blood flow which maintains normal flow artery-by-artery but has the side-effect of increasing total peripheral resistance (TPR), even beyond that caused by high renin. The presence of ever rising TPR and, therefore, ever rising BP, gradually overcomes the effect of noradrenergic drive in the kidney and leads to suppression of renin release by the juxtaglomerular apparatus. Renin levels fall pari passu with rising TPR caused by vascular remodeling. In the second stage of the disease, when renin has fallen back to normal (or low), increased TPR caused by vascular remodeling persists as a factor raising BP.

A gedanken experiment to find a neuroanatomical model for post-traumatic stress disorder.

Post-traumatic stress disorder is a persistent stress syndrome in which abnormal brain physiology persists long after cessation of the acute psychological event that causes it. Normal physiological homeostasis depends on equilibria. The basic unit of equilibrium is the negative feedback loop (NFL) and the simplest way to disrupt homeostasis would be to break an NFL. The resulting model requires two nuclei in the brain reciprocally-connected in an NFL, one of which, in response to the perception of overwhelming threats or demands, generates rapid pacemaker firing which leads to excitotoxic cell death in the other. The injured nucleus must also be able to undergo neurogenesis, which would explain clinical recovery. The relevant site of neurogenesis is the hippocampus, which is reciprocally connected with the dorsal raphe nucleus (DRN), a serotonergic pacemaker nucleus which has been shown to light up on PET scan (i.e. undergo burst firing) in response to stress. The model postulates that the DRN delivers an excitotoxic blow to the hippocampus. Then, via a second pathway, it promotes neurogenesis. The model incorporates potential sites of action for several psychoactive drugs, including anti-depressants and lithium, which promote neurogenesis; and valproate and atypical anti-psychotics, which block excitotoxicity. The theory has the advantage of being formulated in terms of how the brain actually works, i.e. through the interaction between pacemakers and processed sensory input from the outside world. It also directs pharmacological thinking to the role played by pacemakers and pacemaker currents.

Induction of anti-idiotypic antibodies to a myeloma protein linked covalently to muramyl dipeptide

BALB/c mice immunized with the MOPC-315 myeloma protein linked covalently to the adjuvant muramyl dipeptide developed antibodies against the MOPC protein. The anti-idiotypic nature of the antibodies was demonstrated by the ability of N epsilon-2,4-dinitrophenyl-l-lysine, a known MOPC-315 ligand, to block antibody binding. Immunized mice developed protection against in vivo challenge with MOPC-315 tumor cells. No anti-tumor cell-mediated cytotoxicity could be demonstrated in immunized and challenged mice.