Gauging The Role And Impact Of Drug Interactions And Repurposing in Neurodegenerative Disorders Part 9

Studies have been conducted to unveil the efficacy of phosphodiesterase IV inhibitors (roflumilast, rolipram, and PF-06266047) on CLN3 juvenile batten subtype proved to be effective in improving cognitive and motor abilities along with lysosomal pathway in mice which is diagnosed by blood sample examination (Aldrich et al., 2016). 

Phosphodiesterase (PDE) is an enzyme in cells that is mainly responsible for decomposing cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). It plays an important role in many biological processes, including the formation and maintenance of memory.

A large number of studies have shown that PDE plays an important role in the process of memory formation. When ganglion cells are stimulated, they secrete two neurotransmitters, cAMP and cGMP, making the connections between neurons closer. However, these two neurotransmitters are broken down by PDE and gradually lose their effectiveness. Therefore, if the activity of PDE is too high, it will inhibit the formation and maintenance of memory, leading to the weakening or loss of memory.

However, this does not mean that PDE is the enemy of memory. In contrast, moderate PDE activity is necessary for healthy memory. It can help regulate the content and duration of action of neurotransmitters, making the connections between neurons more stable and reliable. At the same time, PDE can also prevent neurons from being over-activated due to continued excitement.

Therefore, we should be aware of moderate PDE activity rather than trying to eliminate it. The correct way is to regulate the activity of PDE through diet, exercise, and other lifestyle changes, thereby protecting and improving your memory level. If you want to know more about the relationship between PDE and memory, you can consult a professional doctor or neurologist. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors. These substances are very important for memory and learning. In addition, Cistanche deserticola can also improve blood flow and promote oxygen delivery, which can ensure that the brain receives sufficient nutrients and energy, thereby improving brain vitality and endurance.

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Most of the pharmacological drugs (immunomodulators, antioxidants, neuroprotectants, NMDA, and AMPA receptor antagonists) have minimal effects on the actual disease pathophysiology and are mostly limited to symptomatic relief. 

Mycophenolate mofetil was initiated for a clinical trial in 2011 in mice for treating the CLN3 subtype and proved to have an improvement in motor activities but not have an effective clinical outcome on disease modification (Augustine et al., 2018). 

Teriflunomide, a pyrimidine antagonist reduced brain atrophy, neuronal loss, and retinal thinning by immunomodulation. Prednisolone reduced the levels of GAD65 autoantibodies and improved motor activities in older patients with CLN3 Batten disease but did not seem to be effective in younger patients (<13 years) (Åberg et al., 2008). 

Oxidative stress is the prominent feature in Batten disease where mutated CLN3 reduces lysosomal arginine levels triggering various metabolic cycles, resulting in the production of Reactive Oxygen Species (ROS) that finally damage DNA. 

N-acetyl cysteine has shown positive results as an antioxidant in decreasing oxidative stress in these patients. Resveratrol had a dose-dependent impact on apoptotic markers and also on oxidative stress in patients with Batten disease (Kauss et al., 2020). 

The other repurposed drugs that provide symptomatic relief for Batten disease are flupirtine, an anti-apoptotic drug, and N-(tert- butyl) hydroxylamine, an antioxidant that showed an increase in motor and cognitive activities in Ppt1 mutant mice (Dhar et al., 2002; Sarkar et al., 2013). 

6.5.5.4. Enzyme replacement therapy. This is the most effective strategy in treating lysosomal storage disorders, where the deficient lysosomal enzymes are replaced by purified recombinant enzymes administered via intrathecal, intracerebroventricular, or by an intravenous route which is now delivered to the receptor compartment by receptor-mediated uptake. 

CLN1, CLN2, CLN10, and CLN13 are the batten subtypes which are mainly caused due to lysosomal enzyme deficiencies like PPT1, TPP1, CTSD, and Cathepsin F (Mole and Cotman, 2015). 

Recombinant TPP1 is developed for the treatment of CLN2 type and administered intracerebroventricularly at a dose of 300 mg. Results showed that in 78% of patients, the disease progression is much slower and some patients are monitored to study the long-term effects of this therapy concerning safety and efficacy (Schulz et al., 2018). 

Baseline clinical scores (including both the Hamburg CLN2 scale (NCL-2 rating scales) and Weill Cornell CNS scale, which quantify the loss of language, seizures, visual and motor abilities), vital signs, electrocardiography, EEG, and MRI findings were recorded before surgical implantation of the cannula and reservoir in the lateral ventricle of the right hemisphere. 

Blood and CSF samples are collected and monitored for immunogenicity, biopharmaceutical characteristics, and kinetic profile.

7. Conclusion

Neurodegeneration is a progressive, complex, and multifactorial etiological process associated with significant morbidity and mortality across the globe. In the current scenario, Alzheimer's and Parkinson's are the most common forms of ND affecting the global population. 

The onset of such ND is erratic and difficult to predict since it is based on the cumulative effect of multiple factors like genetics, environment, diet, age, etc. As a result, the diagnosis of such ND is delayed and is only confirmed after the development of clinical symptoms. 

The current documented literature in the field of ND provides concrete evidence in support of the involvement of multi-pathophysiological mechanisms in neurodegeneration. 

However, it can be hypothesized that during the initial stage of disease progression, only one pathophysiological mechanism is predominant over the other and hence, early diagnosis and early therapeutic intervention might be able to prolong the progression of neurodegeneration. The present therapeutic regimen consists of various monotargeted ligands either administered alone or in combination with others. 

Such mono-targeted drug therapy when initiated during the early stages can modify the disease outcome but fail to do so in later stages of the disease. As a result, there has been an increased focus on multi-targeted drug ligands which are more than capable of targeting multiple pathological mechanisms at the same time. 

Such drugs by acting on multiple targets might effectively delay the disease progression than a single-targeted agent used alone. Additionally, MTDLs show better patient compliance and can overcome the drug-resistance problem faced by the traditional drug regimen. 

Drug repurposing represents an emerging field to combat the mentioned NDs to provide disease-modifying options. 

Such newer therapeutic regimens are currently offering multiple options of drugs as well as affordable therapies. The aforementioned fields have brighter futures and also provide opportunities to explore these fields in a wider way to obtain clinical success in the management of ND.

Credit authorship contribution statement

Dharmendra Kumar Khatri: Conceptualization, Writing – review & editing, review & editing, Supervision. Amey Kadbhane: Writing – review & editing. Monica Patel: Writing – review & editing. Shweta Nene: Writing – review & editing. 

Srividya Atmakuri: Writing – review & editing. Saurabh Srivastava: Writing – review & editing, Review & editing, Supervision, Visualization. Shashi Bala Singh: Supervision, Visualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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