Neurological Disease

Background


Introduction of neurological disease

The Global Burden of Diseasw (GBD) study, a collaborative endeavor of the World Health Organization (WHO), the World Bank and the Harvard School of Public Health, drew the attention of the international health community to the burden of neurological disorders and many other chronic conditions. With awareness of the massive burden associated with neurological disorders came the recognition that neurological services and resources were disproportionately scarce, especially in low income and developing countries. The nervous system consists of the brain, the spinal cord, and peripheral nerve tissue attached to the cerebrospinal cord. The nervous system is the most complex system of human body structure and function. It is composed of nerve cells and plays a leading role in the body. It is divided into the central nervous system and the peripheral nervous system. The central nervous system includes the brain and spinal cord, and the peripheral nervous system includes cranial nerves, spinal nerves, and splanchnic nerves. The nervous system controls and regulates the activities of other systems to maintain unity outside the body. Common diseases of the nervous system are: neurodegenerative, epilepsy, ADHD, senile dementia, etc.

Mechanisms of Neurological Disease

Environmental cues, neuromodulators, synaptic activity, metabolic signals, and stress responses lead to the activation of diverse epigenetic mechanisms of neurological disease, including DNA methylation, histone modifications and chromatin remodeling, noncoding RNA (ncRNA) expression, and RNA editing. In turn, these processes mediate embryonic stem cell (ESC) and neural stem cell (NSC) maintenance and maturation, adult neurogenesis, neural network formation, and synaptic plasticity. DNA methylation refers to covalent modification of cytosine residues to form 5-methylcytosine (5mC). 5-Methylcytosine levels are dynamically regulated during development and adulthood. Enzymes that catalyze DNA methylation are DNA methyltransferases; those that catalyze DNA demethylation include DNA excision repair, cytidine deaminase, and Gadd45 proteins. Each nucleosome contains 2 of each core histone protein (H2A, H2B, H3, and H4). Specific classes of histone deacetylases (HDACs) as well as histone acetyltransferases, histone demethylases, histone methyltransferases, and others catalyze histone posttranslational modifications. Salient classes of short ncRNAs include microRNAs (miRNAs), endogenous short-interfering RNAs, PIWI-interacting RNAs, and small nucleolar RNAs. Each class is associated with specific biogenesis pathways, mechanisms of action, and functions. RNA editing is a mechanism for modifying RNA molecules. It modifies the information content of RNA molecules and affects their intracellular dynamics. For example, it can change codons in mRNAs, leading to expression of protein molecules different from those encoded in the genome. This process occurs primarily in proteins involved in neural excitability, such as ion channels and neurotransmitter receptors, and is thought to fine-tune synaptic responsiveness to environmental stimuli.

Treatment

During neurological disease, the processes regulating synaptic signaling and adaptation are hindered and as a result, physiological plasticity is lost. However, we could potentially prevent synaptic loss and even induce synaptic growth by pharmacologically altering synaptic function to regain the delicate balance of synaptic physiology. This is critically important given that synapse loss often occurs in the early prodromal phases before overt and irreversible neuron death has occurred. For example, AD (Alzheimer’s disease), PD (Parkinson’s disease), DLB (demential with Lewy bodies) and HD is the specific targeting of the pathological proteins (amyloid-tau, α-synuclein and huntingtin) associated with the disease and aiding clearance from the brain. These include increasing protein clearance by enhancing proteasomal function, dampening post-translational modifications associated with pathological forms of protein and preventing protein aggregation. Rivastigmine (cholinesterase inhibitor) is the favoured treatment for DLB and has produced significant improvement in patients’ hallucinations, cognition and behavioural changes in DLB patients over a 96-week treatment period. In PD, the treatments are more effective because loss of a single neurotransmitter, dopamine, does appear to drive the disease process. Levodopa inhibits the peripheral breakdown of levodopa allowing more drug to enter the brain, which is used in combination with carbidopa. Levodopa counteracts the loss of dopamine producing neurons in the substantia nigra by replacing dopamine in the brain. Another common therapeutic approach is to block excessive excitatory signaling. Memantine is a non-competitive NMDA receptor antagonist that appears to have specificity for open, extrasynaptic channels thus preventing glutamatergic excitotoxicity but leaving normal synaptic function unhindered, however the exact mechanism of action is still debated. Riluzole is used as a neuroprotective drug in ALS. It has many effects on neuronal physiology and certainly inhibits neurotransmitter release and glutamate receptors, leading to the hypothesis that its effects in ALS are to dampen excitotoxicity. Tetrabenazine has an unknown mode of action, but is believed to deplete levels of monoamines in the presynapse, by inhibiting vesicular monoamine transporter 2 (VMAT2) and is effective at controlling chorea in HD.

As one of the world leading suppliers of chemical reagents and kinase inhibitors, BOC Sciences has directed sincere efforts toward providing customers with high quality small molecule reagents for neurological disease research. Besides, BOC Sciences can provide the related impurities and metabolites to our customers for research.

References:

  1. Qureshi, I. A., & Mehler, M. F. (2013). Understanding neurological disease mechanisms in the era of epigenetics. JAMA neurology70(6), 703-710.
  2. Lo, E. H., Dalkara, T., & Moskowitz, M. A. (2003). Neurological diseases: Mechanisms, challenges and opportunities in stroke. Nature reviews neuroscience4(5), 399.
  3. Lindvall, O., & Kokaia, Z. (2006). Stem cells for the treatment of neurological disorders. Nature441(7097), 1094.