Neuroinflammation and Neurodegenerative Diseases: One Condition One Therapy

Does neuroinflammation fan the flame in neurodegenerative diseases?:

Microglial activation is the response to multiple traumatic insults whether triggered by infection, trauma or hypoxia. This common stress response can become self-feeding and can become chronic. The authors postulate that the particular presentation (PD, ALS, Huntingtons, etc) depends on genetic variation of environmental variability.

I believe and have so believed for more than a decade that all these conditions can be remitted by blocking the perpetuation of microglial activation by the use of dopamine and seotonin precursor therapy (PURSOR).

Summary

It is becoming increasingly evident that neuroinflammation plays a crucial role in the development and progression of many neurodegenerative diseases. Glia and in particular microglia are central to mediating the effects of neuroinflammation. While neuroinflammation and microglia provide an attractive therapeutic target in the treatment and prevention of neurodegenerative diseases investigators face several challenges ahead (Appendix 2) which must be overcome before one can advocate in favor of large-scale anti-inflammatory trials in the clinic. Some of these include developing approaches to improve the access of drugs to CNS tissue as well as developing therapies that maintain or optimize the beneficial effects of neuroinflammation while eliminating or minimizing its detrimental effects.

Key Observations

1. Neurodegenerative diseases are associated with signs of chronic neuroinflammation
2. A variety of initiating triggers (some as yet unknown) associated with the different neurodegenerative disorders converge at a common intersection point - activation of microglia.
3. While the initial neuroimmune response may be aimed at limiting the disease process, chronic neuroinflammation driven by persistent microglia activation is likely to aid in the progression of the disease and the hastening of neuronal demise.
4. How the inflammatory response affects specific neuronal and glial populations and contributes to specific neurodegenerative diseases remains a critical and unanswered question

Critical challenges involved in developing neuroprotective anti-inflammatory therapeutic strategies

1. Identify internal and external factors that trigger chronic neuroinflammatory responses, with a focus on how acute immune responses become chronic.
2. Identify inflammatory mediators that compromise survival of specific neuronal populations.
3. Develop therapeutic compounds that cross the blood brain barrier (BBB)
4. Selectively target destructive inflammatory mediators without compromising beneficial survival-promoting effects and overall immune function.
5. Develop inclusion and exclusion criteria for human subjects to be enrolled in clinical trials taking into account their immune status."

Why 5-HTP and the PURSOR Protocol May Improve Parkinson's Disease Rx

Summary

The inevitable progression of Parkinson’s Disease (PD) is unresponsive to treatment. Dopamine (DA) agonists may promote the underlying neurodegenerative process. Combined 5‑hydroxytryoptophan (5-HTP), the immediate precursor of serotonin (5-HT), and levodopa therapy should block DA induced PD progression because DA and 5­­-HT have countervailing actions in the immune system. While DA promotes inflammatory Th1 cytokines, neurotoxicity and neural apoptosis (programmed cell death), 5-HT promotes anti-inflammatory Th2 cytokines, acts as a neuroprotectant, and is antiapoptotic. Combined DA and 5-HT precursor therapy (PURSOR) with levodopa and 5-HTP suspensions titrated by taste, already associated with unprecedented partial remissions in another neurodegenerative disorder, amyotrophic lateral sclerosis, should markedly improve symptomatic Parkinson’s treatment, decrease the incidence of levodopa toxicity, and, by restoring Th1/Th2 balance and putatively decreasing QUIN induced excitatory neurotoxicity, alleviate or even halt the progression of PD.

Seven Reasons:

A.      The buccal mucosal route permits both precursors to pass through the blood-brain barrier directly without first passing through the general circulation. Since this markedly diminishes the decarboxylation of either precursor prior to its entering the CNS, carbidopa is no longer necessary.
B.       Maximum therapeutic levodopa doses to assuage nigrostriatal DA deficiency should now be realized promptly and safely. Prior to the proprietary PURSOR protocol, the responsible clinician, concerned that increasing the levodopa dose could at any time induce severe adverse effects, knowing that the only clinical endpoints were the onset of levodopa toxicity or PD clinical improvement, recognizing there was no procedure to ameliorate levodopa toxicity except the passage of time, increased levodopa dosage slowly and gingerly. One can assume that many a PD patient never achieves maximal levodopa intervention because of this understandable concern. The PURSOR protocol permits one to increase levodopa more acutely since the administration of 5-HTP reverses the toxic symptoms of levodopa excess
C.      The neurotoxicity associated with PD and increased by levodopa administration presumptively can be reversed by the increase of 5-HT, a glutamate antagonist and a neuroprotectant with the ability to diminish excessive QUIN toxicity and cellular apoptosis associated with hyperstimulation.
D.      The PURSOR protocol, by promoting CNS 5-HT levels, should decrease or ablate the Th1>Th2 imbalances associated with autoimmune disorders and suppress or halt the underlying neurodegenerative PD process.
E.       The unprecedented and rapid partial remissions noted by patients with ALS treated with the PURSOR protocol strongly suggests that 5-HT is modulating the EAA-associated neurotoxicity endemic in neurodegenerative disorders.
F.      Approximately 15% of DA treated PD patients develop obsessive/compulsive disorders. The addition of 5-HT to the regimen potentially ablates this as a problem.
G.       PD destroys both dopaminergic and serotoninergic cells. If for no other reason, the joint administration of both 5-HT and DA precursors makes empiric sense.

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