Administration of Nootropic Agents for Enhancing Neuroprotective Signaling in Parkinson’s Disease

Background

Parkinson’s Disease (PD) is a chronic, neurodegenerative disease, caused by the progressive loss of midbrain dopamine neurons in the substantia nigra, which sends axons to the striatum. Approximately 1% of Americans are afflicted with PD, which give rise to more than $14 billion in medical-related costs each year. Symptoms include irreversible and impaired motor function, bradykinesia, lack of initiation of movement, and loss of balance. A significant loss of cortical mass, decrease in utilization of nutrients, and increase in Lewy bodies and dementia are non-motor symptoms that are commonly observed in advanced stages of PD. With the increasing number of cases per year, and the lack of therapies which delay or reverse neurodegeneration in PD, it is essential to develop disease-modifying therapies.

Description

Our researchers at the University of Nevada, Reno have developed a novel treatment method for alleviating symptoms and neurodegeneration associated with PD. Our method involves the combined use of different formulations of nootropic drugs Forskolin and Noopept to promote neuronal and cognitive repair. Using these compounds in mouse and in vitro PD models, we observed a therapeutic effect in alleviating symptoms and neurodegeneration associated with the disease. Forskolin is conventionally used as a weight loss supplement, and has also been shown to enhance protein kinase A (PKA) signaling. Due to its poor solubility in water, Forskolin is unable to pass the blood brain barrier (BBB). Therefore, our method involves the intranasal delivery of several isoforms of Forskolin, allowing for effective BBB penetration, followed by an oral dose of Noopept, which has cognitive enhancing activity for memory and learning facilitation. The combined use of these compounds enhances both PKA and brain-derived neurotrophic factor (BDNF), which are associated with stimulating cognition, dopamine synthesis, increases neuronal metabolism (glycolysis) and neuronal and synergize mitochondrial function/survival. Current therapies for Parkinson’s disease, including the use of L-DOPA, monoamine oxidase B inhibitors, and dopamine receptor 2 agonists.  Unfortunately these methods are often associated with negative side effects and drug resistance. Additionally, these treatments only provide modest therapeutic effects in alleviating clinical symptoms, and unlike our treatment method, are not disease-modifying in targeting neurodegeneration.

Advantages

• Forskolin and Noopept can enhance the level of endogenous BDNF in the brain
• Forskolin can increase the endogenous level of dopamine in midbrain neurons and may be used to restore dopamine in PD
• Noopept can stimulate neurogenesis and may replace degenerated midbrain neurons in Parkinson’s disease
• Forskolin is commercially available, very safe for oral consumption  by humans and has low toxicity
• Forskolin does not induce glutamate-mediated excitotoxicity and calcium excitotoxicity
• Forskolin can enhance the level of dopamine in the brain

 Patents

• 17/055,349

Related Publications

• Kowal, S.L., et al., The current and projected economic burden of Parkinson's disease in the United States. Mov Disord, 2013. 28(3): p. 311-8.
• Vila, M. and S. Przedborski, Genetic clues to the pathogenesis of Parkinson's disease. Nat Med, 2004. 10(suppl): p. S58-S62.
• Dagda, R.K., T. Das Banerjee, and E. Janda, How Parkinsonian toxins dysregulate the autophagy machinery. Int J Mol Sci, 2013. 14(11): p. 22163-89.
• Dagda, R.K., J. Zhu, and C.T. Chu, Mitochondrial kinases in Parkinson's disease: converging insights from neurotoxin and genetic models. Mitochondrion, 2009. 9(5): p. 289-98.
• Dagda, R.K. and T. Das Banerjee, Role of protein kinase A in regulating mitochondrial function and neuronal development: implications to neurodegenerative diseases. Rev Neurosci, 2015. 26(3): p. 359-70.
• Das Banerjee, T., et al., PINK1 regulates mitochondrial trafficking in dendrites of cortical neurons through mitochondrial PKA. J Neurochem, 2017. 142(4): p. 545-559.
• Merrill, R.A., et al., Mechanism of neuroprotective mitochondrial remodeling by PKA/AKAP1. PLoS Biol, 2011. 9(4): p. e1000612
• Maeda, H., et al., Potential antidepressant properties of forskolin and a novel water-soluble forskolin (NKH477) in the forced swimming test. Life Sci, 1997. 61(25): p. 2435-42.
• Kumar, A. and N. Singh, Pharmacological activation of protein kinase A improves memory loss and neuropathological changes in a mouse model of dementia of Alzheimer's type. Behav Pharmacol, 2017. 28(2 and 3 - Special Issue): p. 187-198
• Ostrovskaya, R.U., et al., Noopept stimulates the expression of NGF and BDNF in rat hippocampus. Bull Exp Biol Med, 2008. 146(3): p. 334-7.
• Mao, L. and J.Q. Wang, Adult neural stem/progenitor cells in neurodegenerative repair. Sheng Li Xue Bao, 2003. 55(3): p. 233-44
• Lindgren et al., N. Regulation of tyrosine hydroxylase activity and phosphorylation at Ser 19 and Ser 40 via activation of glutamate NMDA receptors in rat stratum. J. Neurochem. 2000.74 (6). 2470-7

UNR18-012