Skip to Main Content
 

Global Search Box

 
 
 
 

ETD Abstract Container

Abstract Header

The Role of Nitric Oxide and Nitroxidative Stress in Amyotrophic Lateral Sclerosis

Jacoby, Adam M.

Abstract Details

2010, Doctor of Philosophy (PhD), Ohio University, Chemistry and Biochemistry (Arts and Sciences).
Amyotrophic lateral sclerosis (ALS) has been studied for many years, yet there have been few innovations in its therapy. This debilitating and fatal disease has proven elusive to all but a few treatments. These treatments have only extended life for short periods of time in ALS patients and have not succeeded in arresting the progression of ALS. Our approach to understanding the oxidative stress behind the disease was studied using nanosensors that directly measure nitric oxide and peroxynitrite concentrations in vivo. Nitric oxide (NO) was thought of as a nuisance in ALS patients, but new studies show that nitric oxide removal proves ineffective at preventing ALS progression. We determined that NO performs a much more vital role in ALS than previously understood. Our conclusions show that after ALS onset, the enzyme responsible for NO production, nitric oxide synthase (NOS), remains in a dysfunctional state. This proved that NO in ALS neurons was already depleted and that peroxynitrite was prevalent, in terms of global concentration, within the neurons. Dysfunctional NOS accounted for increased production of superoxide, which is a common pathological symptom in most ALS cases. We determined that one main malignant affector in ALS is the peroxynitrite produced from dysfunctional NOS. As a corollary, the restoration of coupled NOS and NO production would prove beneficial. The NOS cofactor and co-substrate levels were proven to be in a diminished state, failing to provide sufficient production of nitric oxide with respect to superoxide. The concentrations of the co-substrate L-arginine and the cofactor tetrahydrobiopterin were main targets for treatment in this study. The subsequent restoration of coupled NOS demonstrated that cofactor and co-substrate concentrations play an important role in ALS. Continued production of NO at a normal concentration was important to maintain the neuron function. The treatments with L-arginine and sepiapterin were beneficial and impeded some ALS progression, but did not curtail all the effects of the ALS progression. When added to the current ALS treatment riluzole, Larginine was more beneficial than treatment with riluzole alone. This was a major indicator that dysfunctional NOS only account for part of ALS pathology and that the cofactor and co-substrate treatments work through a different pathway than riluzole.
Tadeusz Malinski (Advisor)
153 p.

Recommended Citations

Citations

  • Jacoby, A. M. (2010). The Role of Nitric Oxide and Nitroxidative Stress in Amyotrophic Lateral Sclerosis [Doctoral dissertation, Ohio University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1273265480

    APA Style (7th edition)

  • Jacoby, Adam. The Role of Nitric Oxide and Nitroxidative Stress in Amyotrophic Lateral Sclerosis. 2010. Ohio University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1273265480.

    MLA Style (8th edition)

  • Jacoby, Adam. "The Role of Nitric Oxide and Nitroxidative Stress in Amyotrophic Lateral Sclerosis." Doctoral dissertation, Ohio University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1273265480

    Chicago Manual of Style (17th edition)