Frontiers in Clinical Drug Research - CNS and Neurological Disorders

The rapid increase in the incidence of dementia has enormous socioeconomic impacts and costs for governmental health systems all over the world. Despite this, finding an effective treatment for the different types of neurodegenerative diseases (NDs) so far represents a challenge for science. The biggest obstacles related to NDs are their multifactorial complexity and the lack of knowledge of the different pathophysiological pathways involved in the development of each disorder. The latest advances in science, especially those related to the systems biology concepts, have given new insights for a better comprehension of such multifactorial networks related to the onset and progression of NDs, and how Medicinal Chemists could act in the search for novel disease-modifying drug candidates capable of addressing the multiple pathological factors involved in neurodegeneration. The multi-target directed ligands (MTDLs) concept has captivated and opened new windows for the creativity and rationality of researchers worldwide in seeking innovative drug candidates capable of modulating different molecular targets by a single multifunctional molecule. In fact, in the last two decades, thousands of research groups have dedicated their efforts to the use of molecular hybridization as the main tool for the rational design of novel molecular scaffolds capable of expressing multi-target biological activity. In this way, this chapter addresses the most recent pathophysiological hallmarks of the most highimpact NDs, represented by Alzheimer’s, Parkinson’s, Huntington’s diseases, and amyotrophic lateral sclerosis, as well as the state-of-art in the design of new MTDLs, inspired mostly by natural products with improved druggability properties.

Behavioral and substance addictions share more similarities than differences in etiological, phenomenological, and clinical presentations. Interactions between the variables of predisposing (i.e., neurobiological and psychological constitutions) and moderating (i.e., coping style and cognitive and attentional biases), as well as variables of mediating (i.e., affective and cognitive reactions to situational triggers) in combination with reduced inhibitory control may accelerate or reduce the developing of specific versions of model for addictive behaviors. Around 50% individuals’ variability in becoming addicted to substance (nicotine, alcohol, or illicit drugs) is attributable to genetic factors. Genetic variations to addiction susceptibility and environmental factors such as stress or social defeat also alter brain-reward mechanisms impart vulnerability to addiction. The emergence and maintenance of addiction might be the consequences of chronic exposure to drugs remodeling the chromatin structure including FosB, Cdk5, G9a, and BDNF around genes. Only few drugs for substance use disorders (SUDs) are approved by the FDA, But QSP approaches provide valuable strategies for designing novel prevention or treatment towards drug addiction. Conjugate vaccines and monoclonal antibodies treatments generating high-affinity anti-drug IgG antibodies neutralizing drug doses in the serum might lead the immunotherapy for SUDs in the future.

 Neurodegenerative disorders are considered major global health problems associated with nervous system dysfunction, progressive neuronal cell loss with aging, and several pathological and sporadic factors. Parkinson’s disease, Alzheimer’s disease, Prion disease, Huntington’s disease, and multiple sclerosis are the main neurodegenerative diseases that raise significant concern among health scientists. The etiology of different neurodegenerative diseases is different, and they majorly affect the nervous system, including the brain, spinal cord, and peripheral nervous system. Neurodegenerative diseases are linked with motor dysfunction, anxiety, memory loss, depression, cognitive impairments, etc. These diseases can be hereditary or caused by toxicity, metabolic disorders, or pathological changes in the brain. Therefore, interest has been growing in the development of different neuroprotective agents of natural origin that could work effectively against these diseases. In that aspect, phytochemicals have shown high potential with minimal side effects in various in vitro and in vivo studies. Cinnamic acids with phenylpropenoic moiety are abundant in many natural resources. These are available in many forms, such as ferulic acid, caffeic acid, etc. They also have a variety of pharmacological properties, including anti-inflammatory, anti-oxidant, anti-amyloid, and neuroprotective properties. This chapter summarizes the role of naturally occurring cinnamic acids and their derivatives to develop the mechanistic aspects of neuroprotective therapeutics in neurodegenerative diseases. Future challenges are also discussed to provide beneficial information and therapeutic strategies.

Alzheimer’s disease (AD) is a progressive neurological disorder. Recent studies show that AD is the most common cause of dementia. There are several symptomatic treatments available to counterbalance the neurotransmitter disturbance. Currently, cholinesterase inhibitors are available for the treatment of mild to moderate AD. In addition to that, memantine (an N-methyl-D-aspartate receptor non-competitive antagonist) is also available for moderate to severe AD. Poor blood-brain barrier permeability is a limitation of existing drugs. These drugs may slow the disease progression, but there are chances of reoccurrence of the disease. Several medicinal plants such as Jasminum sambac, Rosmarinus officinalis, Eucalyptus globulus, Nigella sativa, and Acorus gramineus are reported to have neuroprotective effects. Salvia officinalis has cholinergic binding properties. Ginger root extract may prevent behavioral dysfunction in AD. Extensive research on these plants should be carried out. Drug delivery systems such as lipid nanoparticles, polymer nanoparticles, nanomicelles, nano-gels, liposomes, phytosomes, etc., could significantly improve the pharmacokinetics, stability, efficacy and reduce the side effects. Phytosomes have the advantage over other drug delivery systems to selectively target the drugs into the brain. In contrast to traditional approaches, polar phytoconstituents loaded phytosomes are more bioavailable on the site of brain tissue, as they can easily go for systemic circulation crossing the Blood-Brain Barrier (BBB). Phytosomes have a low hazard profile as toxicological outcomes are negligible and assure duration of action at a lowrisk profile due to upgraded absorption of the active constituents. In addition to this, the improved pharmacodynamic properties of phytosomes make them suitable for the treatment of neurological disorders.

Alzheimer’s disease is known to be the most common cause of dementia with increasing number of people suffering every year. In healthy adults, there are millions of neurons in the brain. Degeneration starts and extends in Alzheimer's disease many years before the initial symptoms show up. The neurons taking part in cognitive functions destroy gradually leading to functional disability and finally to death. β- amyloid plaques and tau protein are known as the most responsible causes of Alzheimer’s disease resulting in neurodegeneration. Inflammation, atrophy and dysfunction in glucose metabolism will follow. The three stages of the disease include mild, moderate and severe. The patient will have difficulty in cognitive functions, show changes in behavior and will need care for everyday needs, which increases by the disease progress. There are pharmacologic and non-pharmacologic approaches for treatment. The pharmacologic approaches comprise acetylcholinesterase (AChE) inhibitors such as donepezil or N-methyl-d-aspartate (NMDA) receptor blockers like memantine. None of them stops the disease but alleviate the symptoms. On the other hand, non-pharmacologic approaches are usually used to improve the patient’s quality of life or improve the behavioral aspects of the disease. Recently, involving physical activity as a non-pharmacologic method of treatment for Alzheimer’s disease has been the focus of many studies. This chapter will have a glance at the clinical trials that were conducted regarding the effect of physical exercise and its impact on Alzheimer’s disease.