A study conducted by Hyman et al. (1995) has shown that psychostimulants and dopamine stimulate the rat striatum, further activating gene expression and the reward system in the rat brain. Thus, psychostimulants such as amphetamine and cocaine were found to be involved in the expression of c-fos mRNA and other immediate early genes (IEGs), but blocked by dopamine receptor antagonists (i.e., antipsychotic drugs). For example, the activation of the IEG gene prodynorphin (involved in the encoding of endogenous opioid dynorphin peptides) was found to stimulate D1 receptors in the striatum (Hyman et al. 1995) as a result of psychostimulants. Therefore, it is possible that these genes are connected to schizophrenia. Antipsychotic drugs counteract the stimulatory effects of IEGs by actively binding to dopamine receptors, resulting in decreased dopamine activity and an eventual recovery in psychosis sufferers. Consequently, it is possible that inhibition of these genes could reduce the likelihood of developing this disorder.

Dopamine build-up may be caused by a faulty gene that codes for the enzyme Dopamine-b-hydroxylase, which converts dopamine to norepinephrine. Angst (1956) showed that blocking this enzyme with the drug disulfiram results in psychosis indistinguishable from schizophrenia in alcoholics who overdosed on disulfiram. According to Stein and Wise (1971), some of the dopamine was autoxidized to 6-hydroxydopamine and caused degeneration of peripheral sympathetic nerve terminals that resulted in a marked and long-lasting depletion of norepinephrine. Evidence supporting 6-hydroxydopamine as a neural degenerative agent of noradrenergic nerve endings comes from the isolation and identification of an odorous substance (known as trans-3-methyl-2-hexenoic acid, a metabolic product of 6-hydroxydopamine) found in the sweat of schizophrenics. Phenethylamine derivatives with the same 2,4,5- substitution pattern as 6-hydroxydopamine were found to have high hallucinogenic activity in humans.

New atypical neuroleptic drugs such as Clozapine (dibenzodiazepine derivative) have a relatively weak binding to D1 and D2 dopamine receptors, as compared to traditional neuroleptic drugs. The drug also has a potent binding affinity for serotonin receptors 5-HT_1A and 5-HT₂ (Jann 1991), so serotonin may be involved in schizophrenia. This is because serotonin and dopamine have the same ethylamine side chain, and this side chain makes their respective receptors active. Therefore, dopamine receptors may not be able to distinguish between serotonin and dopamine; as a result, serotonin may in fact stimulate dopamine receptors. Bourson et al. (1995) found that the newly cloned 5-HT₆ receptors were mediated through changes in cholinergic neurotransmission. This study used antisense oligonucleotides to study whether or not the receptor was expressed in rat brains and to study the resulting physiological affects. Treatment with antisense oligonucleotides and scrambled oligonucleotides produced a toxic response in some rats that was found to be dose dependent. The toxic response was due to the inhibition of RNA translation into the receptor protein and not the oligonuleotide. The toxic response of the antisense oligonulceotides may have resulted in increased cholinergic neurotransmission, indicating that 5-HT₆ receptors may control the levels of cholinergic neurotransmission.

Biosynthesis of Tyrosine

Chorismate is the precursor of aromatic amino acids like tyrosine, phenylalanine, and tryptophan; its production is through the shikimic acid pathway. The first reaction in the shikimic acid pathway is between erythrose 4- phosphate and phosphoenolpyruvate; thus, high levels of these compounds will favour chorismate production. A diet low in Mg²⁺ may retard pyruvate kinase, preventing the dephosphorylation of phosphoenolpyruvate in the final step of glycolysis and favouring chorismate production (Matthews and Von Holde 1996).

More tyrosine may be produced in vivo by the conversion of phenylalanine to tryrosine, a reaction catalyzed by phenylalanine hydroxylase. An overactive phenylalanine hydroxylase could be responsible for excessive biosynthesis of tyrosine, whereas a deficiency of this enzyme is responsible for phenylketonuria (PKU). If phenylalanine hydroxylase is overactive, then you might expect to find an imbalance between the cofactor H₄-biopterin and H₂-biopterin, favouring the latter. The rate at which dihydropteridine reductase converts H₂-biopterin to H₄-biopterin may be slightly less than the phenylalanine hydroxylase conversion of H₄-biopterin to H₂-biopterin. A diet high in iron may further stimulate phenylalanine hydroxylase by acting as a co-factor, favouring tyrosine production (Letendre 1975).

The Role of Phenylacetic Acid in the Biosynthesis of Tyrosine and 6-Hydroxydopamine

Studies have revealed that phenylacetic acid is one of the by-products of dopamine catabolism. A high concentration of phenylacetic acid in the cerebrospinal fluid and other bodily fluids of schizophrenics is to be expected, because of its role as:

1. A possible bio-indicator of tyrosine biosynthesis and/or intake.

2. An alternative source of 6-hydroxydopamine (2,4,5-trihydroxyphenethylamine).

However, phenylacetic acid (free) was found to be 21.2 ng/ml for controls, 12.8 ng/ml for schizophrenics on neuroleptic drugs, and 10.8 ng/ml for schizophrenics off neuroleptic drugs (Hafner et al. 1987). If cerebrospinal fluid is taken leading up to and during a psychotic episode, the concentration of phenylacetic acid may be higher than normal. According to Olivera et al. (1994), catabolism of phenylacetic acid and 4-hydroxphenylacetic acid in Pseudomonas putida U occurs in two unrelated pathways. Phenylacetic acid is involved in the biosynthesis of phenylacetyl CoA, which goes into the citric acid cycle. If this reaction occurs in humans and requires the same co-factor, Mg²⁺, phenylacetyl CoA will not be biosynthesised according to this reaction in the schizophrenic. Catabolism of phenylacetic acid via one pathway will give succinic acid, while taking the other pathway will give acetoacetic acid and fumaric acid. The work of Takeda and Sugiyama (1993), on the metabolism of biogenic monoamines in Tetrahymena pyriformis, indicates the formation of hydroxyphenylacetic acid-4 from tyrosine-4. If a similar pathway occurs in humans, then hydroxphenylacetic acid may indicate tyrosine biosynthesis and/or intake. The formation of phenylacetic acid may in turn be formed by the selective dehydroxylation of hydroxyphenylacetic acid. An alternative source of 2,4,5-trihydroxyphenethylamine (6-hydroxydopamine) may be found from a yet-to-be discovered pathway involving 2,4,5- trihydroxyphenylacetaldehyde. Thus, phenylacetic acid may be involved in the eventual biosynthesis of 6-hydroxydopamine. The reasoning behind this possibility is the following:

1. If phenylacetic acid is catabolized in humans, as is the case in Pseudomonas putida U, then it will lead to the formation of 3,4-dihydroxyphenylacetic acid, instead of leading to the eventual biosynthesis of succinic acid. Evidence indicates that, in humans, the breakdown of dopamine by the enzyme (Monoamine oxidase) results in the formation of homovanillic acid (the end product of dopamine catabolism). However, the intermediate product of this reaction is 3,4-dihydroxyphenylacetic acid (Summers et al. 1979). It seems likely that monoamine oxidase plays a vital role in phenylacetic acid formation. Such a process possibly found in humans may occur differently. Therefore, in humans, this process may involve 4,5 -dihydroxyphenylacetic acid being hydroxylated to 2,4,5-trihydroxyphenylacetic acid, which is converted to an aldehyde to form 2,4,5-trihydroxyphenylacetaldehyde; finally, the aldehyde 2,4,5-trihydroxyphenylacetaldehyde is converted to 6 -hydroxydopamine by reductive amination.

2. Phenylacetaldehyde can form directly from phenylacetic acid in bacterium; however, if this also occurs in humans, then the possible hydroxylation at the 2,4,5 positions on the phenyl group, and subsequent reductive amination, may also lead to 6-hydroxydopamine. Evidence in humans indicates that the reaction of dopamine with the enzyme Monoamine oxidase also results in the formation of (3,4-dihydroxyphenyl) acetaldehyde, NH₃, and H₂O₂ (Summers et al. 1979).

If this process is found in humans, it will highlight the relationship between phenylacetic acid and 6-hydroxydopamine biosynthesis (see Figure 1).

Figure 1. Biosynthesis of 6-hydroxydopamine from phenylacetic acid.

The Role of Iron in 6-Hydroxydopamine Biosynthesis

Fe²⁺ is oxidized to Fe3+ in the presence of an electron acceptor (e.g., O₂) and then binds to apoferritin. Carboxylate resides (glutamate or aspartate) are abundant at the inner surface of the apoferritin; their conversion to ester groups causes the deposition and oxidation of more Fe ^II, forming ferritin (Mann et al. 1989). However, the autoxidation of Dopamine to 6-hydroxydopamine may result in its ability to act as a reducing agent that can cause the release of iron from cellular stores (accounting for oxidative damage to cell membranes or nucleic acids). Hemochromatosis seems likely to occur under these conditions and may contribute to increased skin pigmentation.

The Role of Iron in DNA Translation

The biosynthesis of nucleic acid may be adversely affected in schizophrenics. Their ability to transcribe mRNA also seems to be affected. Pyrimidine-deoxynucleoside 1’-dioxygenase catalyzes the reaction between 2-deoxyuridine and 2-oxoglutarate and requires iron and ascorbate to act as co-factors in the biosynthesis of uracil (found only in RNA species; Stubbe 1985). While one would expect high levels of iron to stimulate this reaction, this is not the case; the biosynthesis of 2-oxoglutarate is altered due to the reduction of acetyl-CoA and Mg²⁺. Furthermore, the biosynthesis of uridine is also changed because it has the same substrates as uracil, except that it is catalyzed by a different enzyme (Pyrimidine-deoxynucleoside 2’-dioxygenase; Bankel et al. 1972).

Mutagenesis of Trytophan Synthetase

Mutagenesis may occur in the gene coding for tryptophan synthetase and may be a genetic indicator of schizophrenia. According to DeMoss and Bonner (1959), genetically altered tryptophan synthetase prevents the enzyme from catalysing the formation of tryptophan and only catalyzes the breakdown of indole-3-glycerol phosphate to indole and triose phosphate. Catabolism of tryptophan results in the biosynthesis of NAD⁺, meaning that inhibition of tryptophan will cause pellagra. However, dietary intake of tryptophan may prevent this from happening, but a slight reduction of NAD⁺ may affect the performance of dopamine-b-hydroxylase. Fumarate is also involved in the stimulation of dopamine-b-hydroxylase, and fumarate is produced by the reaction of succinate plus the coenzyme FAD⁺ (Levin et al. 1960); however, the precursor to fumarate (2-oxoglutarate and succinyl CoA) requires the coenzyme NAD⁺ (Matthews and Von Holde 1996). So, low levels of NAD⁺ may lower the concentration of fumarate, thus acting as a negative allosteric effector. Dietary intake of tryptophan and high iron levels may favor excessive biosynthesis of serotonin. As H₄-biopterin may act as a cofactor for serotonin synthesis, iron may also act as a cofactor for the enzyme involved in serotonin synthesis, as is the case for phenylalanine hydroxylase.

The Role of Magnesium

If there is no mutagenesis in tryptophan synthetase, the inability to produce NAD⁺ and Acetyl CoA from the Kynurenine pathway of tryptophan catabolism may be due to allosteric inhibition of the enzymes that involved in its breakdown. Namely, low Mg²⁺ seems likely to inhibit enzyme catalysis. For instance, tryptophan 2,3-dioxygenase is involved in the conversion of tryptophan to N-formyl-kynurenine and its cofactor is heme. However, heme biosynthesis may be affected in that its starting materials (succinyl CoA and glycine) may be at low concentrations due to low Mg 2+. Further investigation reveals that succinyl CoA requires Mg 2+, and if this were the case, one would expect the build up of the precursors of succinyl CoA. The biosynthesis of succinyl CoA occurs in the mitochondrial matrix and the cytosol of the cell. Its basic building block is either valine and/or isoleucine, probably depending on availability of either amino acid. If isoleucine is involved in the biosynthesis of succinyl CoA, then 2-oxoglutarate or pyuruvate will be needed in the first reaction that is catalyzed by the enzyme branched-chain amino acid aminotransferase (2.6.1.42). The products of this reaction are (S)-3-methyl-2-oxopentanoate, (S)-2-oxo-3-methylpentanoate, and ‘alpha’-keto-’beta’- methylvalerate. These products are then catalyzed by 3-methyl-2-oxobutanoate dehydrogenase (1.2.4.4) and the next reaction then requires Mg 2+, as the cofactor for (2.3.1.-), so a build up of the product catalyzed by (1.2.4.4), namely, S-(2-methylbutanoyl) dihydrolipoamide and S-(2-methylbutyryl) dihydrolipamide results. If valine is involved in the biosynthesis of succinyl CoA, then 2-oxoglutarate or pyruvate will be needed in the first reaction; as a result, low concentrations of these compounds will prevent valine and isoleucine from being incorporated into the biosynthesis of succinyl CoA. Once valine has been converted to 2-oxo-3-methylbutanoate, 2-oxoisovalerate, 3-methyl-2-oxobutanoate (requires 2-oxoglutarate in first reaction to obtain this compound) and ‘alpha’- ketoisovalerate, it is then ready to be catalyzed by (1.2.4.4), which requires Mg²⁺ as its cofactor. Therefore, a build up of these compounds will indicate three important factors:

1. Which amino acid is involved in succinyl CoA biosynthesis (this is determined by looking at the precursors).

2. Where succinyl CoA biosynthesis is occurring in the cell, either in the mitochondrial matrix and/or cytosol, as this is the case for the valine. If 3-methyl-2-oxobutanoate is present, then succinyl CoA must occur in the mitochondrial matrix, whereas 2-oxoisovalerate must occur in the cytosol of the cell.

3. Whether pyruvate and/or 2-oxoglutarate are required, as is the case for valine but not isoleucine (which have same products). If pyruvate is used, then 2-oxoisovalerate will be formed. If 2-oxoglutarate is used, then 3-methyl-2-oxobutanoate will be formed.

So, the inability to biosynthesize succinyl CoA will have an impact at not only this point, but on other important biochemical processes in the body as well.

There may be a reduction in the levels of Epinephrine in schizophrenics; however, this might not be the case at all, but the complete opposite (norepinephrine in controls was an average of 58.7 ng/g and in Schizophrenics was 60.25 ng/g from the amygdala of post-mortem brains; Reynolds 1983; Reynolds 1986). Therefore, one would not expect low concentrations of epinephrine to stimulate cAMP production that is activated by cAMP dependent protein kinase (further stimulating glycogen breakdown.) However, epinephrine in controls was 85 pg/ml. Patients on neuroleptic drugs were found to be 330 pg/ml and patients off neuroleptic drugs were 230 pg/ml [10]. In the schizophrenics’ case, activation may be achieved by Ca²⁺ stimulation of calmodulin (if epinephrine levels were low). The influx of Ca²⁺ through voltage-gated Ca²⁺ channels stimulates cells to secrete their neurotransmitters by activation of CaM-kinase II to phosphorylate. This makes tyrosine hydroxylase active, leading to the eventual biosynthesis of Epinephrine. However, the rate at which norepinephrine is produced affects the catalytic rate of tyrosine hydroxylase, thereby acting as a negative allosteric effector. But, in the schizophrenic case, the rate in which norepinephrine is synthesized remains constant; if phenylethanolamine N-methyl transferase is low, then the biosynthesis of norepinephrine will be favored instead of Epinephrine. But, this enzyme may be overactive and therefore account for high levels of Epinephrine as previously mentioned. This results in the uncontrollable production of Dopamine by keeping the norepinephrine levels constant.

As cAMP increases in the body, it results in a negative feedback mechanism that induces phosphorylation of B2-adrenergic receptors. This desensitizes the effect of epinephrine and prevents the depletion of glycogen stores (cAMP level in controls was 14.5 pmol/ml, in patients on neuroleptic drugs it was 9.2 pmol/ml, and in patients off neuroleptic drugs it was 7.5 pmol/ml [10]). Inability to synthesize cAMP from epinephrine stimulation may prevent this negative feedback mechanism from coming into play in schizophrenics. This may be likened to a “Neural Supernova” in that it burns fuel rapidly (i.e., there is glycogen breakdown by stimulation from Epinephrine) and goes out in a bang (i.e., psychosis and brain starvation causes neural death). The schizophrenic brain must work extra hard in glycogen metabolism to try and catch up to production of ATP in non-schizophrenics. Under normal conditions, glycolysis produces 4 ATP molecules and invests 2 ATP, giving a net output of 2 ATP molecules; more ATP molecules are synthesized via the citric acid cycle, fatty acid metabolism, and electron transport mechanism. Reduction in the concentration of NAD⁺ may result in the non-formation of acetyl-CoA from the b-oxidation pathway, preventing its incorporation into the citric acid cycle. Low concentrations of Mg²⁺ may prevent the formation of pyruvate (in glycolysis), which would lead to its subsequent conversion to acetyl-CoA. Precursors of acetyl-CoA may support this assumption.

Mutagenesis of Calmodulin

Possible mutagenesis of calmodulin may lead to Ca²⁺ sensitivity in schizophrenics. According to the “Neural Supernova” hypothesis, uncontrollable Ca²⁺ stimulation of glycogen breakdown will most likely lead to hypoglycaemia, contributing to cellular death. If Ca²⁺ concentration increases in the cytosol as expected, then the ATP produced by rapid glycogen breakdown will be needed to stimulate Ca²⁺-ATPase to pump it out of the cell, further depriving cells of much needed energy.

The Role of Insulin in “Neural Supernova”

As the hormone insulin is involved in glucose catabolism, it seems likely that it plays a role in schizophrenia. In patients with diabetes mellitus, deficiency in insulin results in the inability to catabolize glucose and is characterized by a build up of glucose in urine. In schizophrenics, increased levels of insulin, and/or insulin hypersensitivity due to the increase in the number of insulin receptors and/or IGF-I receptors, may further stimulate “Neural Supernova”. Therefore, the increase in the production of insulin receptors and/or IGF-I receptors may be due to male sex hormones, possibly accounting for a slight disposition toward males and the early onset of schizophrenia. However, increased levels of insulin may be due to by-products of “Neural Supernova”, namely, serotonin. Insulin inhibits the breakdown of glycogen and the conversion of amino acids or fatty acids to glucose. Stimulation of 5-HT₆ receptors by serotonin as previously stated may mediate cholinergic neurotransmission. Acetylcholine targets the pancreas to release insulin, so serotonin produced during “Neural Supernova” may inadvertently stimulate insulin release. Increased insulin levels may prevent glucose from being metabolised, thus depriving cells of much need energy. Under these conditions, ketone bodies may provide the necessary energy needed by the starving brain (with ketoacidosis side-effect.) As ketone bodies are anions, they will probably affect cations, namely, sodium and potassium, and may even account for possible depletion of magnesium in the schizophrenic.

Physiological Effects of “Neural Supernova”

The “Neural Supernova” feedback mechanism will now be activated in the brain, resulting in negative feedback. This leads to the stimulation of dopamine b-hydroxylase that will convert excess dopamine to norepinephrine and negate tyrosine hydroxylase. Glycogen breakdown will now be arrested and glycogen synthetase will be stimulated when glucose-6-phosphate levels have recovered. Evolutionary processes built into the mammalian brain have enabled it to survive hypoglycemia and reduce neural damage. This is achieved by the stimulation of hormones by the products of “Neural Supernova” (e.g. serotonin, tyrosine and possibly histamine). Therefore, histaminergic and serotoninergic neurons may induce adrenocorticotropin (ACTH) and b-endorphin release, resulting in the synthesis or activation of metabolic regulatory enzymes and other compounds capable of turning off the “Neural Supernova” stimulus. ACTH will cause the synthesis of tyrosine aminotransferase to help control the excess biosynthesis of tyrosine, and may contribute to the biosynthesis of fumarate, thus stimulating dopamine b-hydroxylase. ACTH also stimulates pro-opinomelanocortin, which stimulates various forms of melanocyte-stimulating hormone (MSH). MSH may help convert excess tyrosine and DOPA to polymeric black and red melains. The production of polymeric black melanins is catalyzed by tyrosinase, which is inhibited by tyrosine, so it seems that polymeric black melanins will be inhibited, favoring polymeric red melanin production. However, cysteine levels will affect polymeric red melanin production and, if cysteine were not available, then one would expect a build up of dopaquinone and DOPA. However, there will most likely be a greater build up of DOPA, as high levels of Cu²⁺ will act as a co-factor for tyrosinase, and “Neural Supernova” stimulus produces excess DOPA. If there are abundant levels of cysteine, increased melanin production may lead to the slight darkening of skin in schizophrenics.

Protein metabolism may be the only possible source for pyruvate and acetyl CoA to produce ATP – the end product is NH₃. Another source of NH₃ is the irreversible aminohydrolysis of 5’-AMP to equimolar amounts of 5’-IMP. Under ischaemic conditions, protein kinase C is activated and phosphorylates AMP aminohydrolase. However, normal concentrations of ATP inhibits it, but decreasing levels of ATP, due to ”Neural Supernova,” reduces its role as an inhibitor towards AMP aminohydrolase, adversely affecting the purine nucleotide cycle. Cerebral ischemia may be a major factor in the cause of Schizophrenia, primarily causing the release of high levels of Ca²⁺ ions and stimulating “Neural Supernova.” One possible use of NH₃ is in glutamine synthesis, which is ATP-dependent and highly regulated. The products of “Neural Supernova,” including serotonin, may stimulate ACTH, which in turn may stimulate the synthesis or activation of glutamine synthetase and tryptophan oxygenase. These enzymes are involved in tryptophan biosynthesis and its conversion to NAD⁺, favoring dopamine b-hydroxylase stimulation. Another product of “Neural Supernova” is tyrosine, which is involved in the stimulation of thyroid hormones that synthesize or activate the enzyme carbamoyl phosphate synthetase (involved in NH₃ assimilation). Intracellular acidosis caused by cerebral ischemia results in the production of carbonic acid, which deprotonates to form a carboanion that is required in the production of carbamoyl phosphate and glutamate. Ammonia or glutamine can serve as nitrogen donors. If the nitrogen donor is ammonia, then it will react with the carboanion and ATP to produce carbamoyl phosphate. Likewise, if the nitrogen donor is glutamine, then it will react to form carbamoyl phosphate and glutamate. The carbamoyl phosphate that is produced goes into the Kerbs-Henseleit urea cycle and forms urea, the end product of protein metabolism. Abnormal levels of urea in the urine of schizophrenics may imply high protein metabolism.

Increased Ca²⁺ /calmodulin caused by cerebral ischemia may result in the stimulation of NO synthetase that will produce NO and L-cistrulline. NO may counteract ischemia by relaxing blood vessels in the brain, thereby allowing better O₂ delivery to neurons. L-cistrulline produced will go into the Kerbs-Henseleit urea cycle to form urea; therefore, it may account for abnormal levels of urea in the urine of schizophrenics.

The brain of a person with an inherent disposition towards schizophrenia, when placed in a stressful situation, will activate the “Fight or Flight” response. Activation of this survival response in the schizophrenic will trigger “Neural Supernova,” the rapid metabolic breakdown of glucose leading to psychosis and neural death. Inefficient metabolism of glucose, during glycolysis, may be due to low Mg²⁺, which will favor chorismate production and lead to excess biosynthesis of tyrosine (the precursor of dopamine).

Dopamine and psychostimulants activate the reward system and expression of c-fos mRNA and other IEGs, but are blocked by dopamine receptor antagonists (i.e., antipsychotic drugs). Antipsychotic drugs counteract the stimulatory effects of dopamine, psychostimulants, and IEGs by actively binding to the dopamine receptor, resulting in a decrease in dopamine activity and recovery in people suffering from psychosis.

In humans, the breakdown of dopamine by monoamine oxidase results in the formation of homovanillic acid and the following intermediate products: 3,4-dihydroxyphenylacetic acid, 3,4-dihydroxyphenylacetaldehyde, NH₃, and H₂O₂. As dopamine is catabolized by monoamine oxidase in humans, it seems likely that the intermediate products of its breakdown could be converted back to dopamine or its analog 6-hydroxydopamine.

An increase in iron concentrations (most likely due to 6-hydroxydopamine acting as a reducing agent) will stimulate phenylalanine hydroxylase, converting phenylalanine to tyrosine. As a result, increasing levels of tyrosine will favor dopamine synthesis. Excess dopamine will be auto-oxidized to 6-hydroxydopamine, which will inhibit norepinephrine formation and favor epinephrine. Inhibition of norepinephrine will prevent it from acting as a regulator of dopamine concentration. Without this control mechanism, epinephrine will rapidly consume glycogen and lead to hypoglycaemia. The inability of the schizophrenic brain to produce enough ATP molecules will force it to rely on other metabolic pathways, thereby increasing the concentration of Ketone bodies. Consequently, an increase in ketone bodies will lower the concentration of Magnesium, further compounding the effects of “Neural Supernova.”

Mutagenesis of tryptophan synthetase could be a genetic indicator of schizophrenia because of its role in the biosynthesis of tryptophan. Insufficient levels of tryptophan will affect the concentration of fumarate, which, in turn, will inhibit dopamine-b-hydroxylase. However, increased levels of iron and dietary intake of tryptophan may favor serotonin synthesis. Therefore, serotonin produced during “Neural Supernova” may also stimulate the release of insulin from the pancreas. Insulin secretion will inhibit glycogen breakdown, further lowering the concentration of glucose in the brain.

Protein metabolism may be another source of energy during “Neural Supernova” as its end product is NH₃. Possible uses of NH₃ include being a nitrogen donor to inhibit the products of cerebral ischemia and being involved in glutamine synthesis. Furthermore, the products of “Neural Supernova” (i.e., serotonin) may stimulate ACTH to activate glutamine synthetase and tryptophan oxygenase. These enzymes are involved in tryptophan biosynthesis and its conversion to NAD⁺, further favoring dopamine-b-hydroxylase.

Possible mutagenesis of calmodulin may lead to calcium sensitivity in schizophrenics due to uncontrollable Ca²⁺ stimulation of glycogen breakdown, contributing to hypoglycemia and cellular death. Increased Ca²⁺/calmodulin may result in the stimulation of NO synthetase, which will counteract ischemia and may account for abnormal levels of urea in the urine of schizophrenics.

General Features of Neural Supernova

The general make-up of a schizophrenic may be the following:

1. Normal to below normal weight, due to high metabolism (from epinephrine stimulation of glycogen breakdown).

2. Slight disposition toward males, resulting from possible male sex hormone involvement in insulin receptor and/or IGF-I synthesis and hypersensitivity to insulin (which is further compounded by increased production of insulin by acetylcholine stimulation of pancreas to secrete insulin).

3. Slight increases in pigmentation of skin due to DOPA conversion to melanin.

4. Abnormal levels of urea, indicating high protein metabolism and/or NO counteracting cerebral ischemia which come into play during “Neural Supernova” and lead to hypoglycaemia.

A “Neural Supernova” may occur in cycles, indicating that psychotic episodes are cyclical; however, psychotic episodes get longer and recovery takes more time due to neural burnout. Treatment with neuroleptic drugs may result in weight increase due to the drugs’ ability to slow down metabolism (but this may be dose dependent).

In the end, schizophrenia may be due to dietary factors that affect their respective enzymes: low Mg²⁺ (ketone bodies may result in hypomagnesia) and high Fe (ferritin breakdown leads to free Fe in the cells.) Also involved is the possible mutagenesis of tryptophan synthetase, leading to subsequent deactivation of dopamine-b-hydroxylase and its inability to cope with the excessive amounts of dopamine being produced. Calmodulin mutagenesis leads to Ca²⁺ sensitivity and/or cerebral ischemia and results in the “Neural Supernova”, which eventually leads to hypoglycaemia. Finally, arrest in mRNA transcription leads to an inability to synthesize regulatory proteins and enzymes, further compounding the illness. For a complete overview of the Neural Supernova pathways, see Figure 2.

Figure 2. Overview of Neural Supernova pathways.

Future Research & Impact

Future research into the phenomena of “Neural Supernova” could lead to better ways of treating schizophrenia – perhaps even resulting in a cure. Therefore, if the observations presented here have enough validity regarding the aetiology of schizophrenia, new medicines, with fewer side effects, could be tested and used in this condition by addressing the faulty metabolism of glucose in the schizophrenic brain. A better understanding of the impaired function of glucose metabolism could lead to drugs specifically targeting this area. This could contribute to a more beneficial outcome with people diagnosed with schizophrenia, including quicker recovery from psychosis with less neural damage.

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