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Aβ cascade hypothesis being considered most evident event in AD pathology and even today it holds good. Dysregulation of catalytic events of Aβ regulating enzymes can possibly cause faulty Aβ trafficking; inequity of Aβ formation and clearance resulting in misfolded protein accumulation, neurodegeneration and cognitive impairment. Many novel approaches have been made on this pathway to discover new molecules, unfortunately couldn't reach the terminal phases of clinical trials. Over decades, studies have been more focused on enzyme chemistry and explored the relationship between structural features and catalytic function of Aβ regulating enzymes. However, the modulations of catalytic mechanisms of those enzymes have not been imposed so far to reduce the Aβ load. Hence, in this review, we have critically detailed the knowledge of basic structural dynamics and possible catalytic modulations of enzymes responsible for Aβ formation and clearance that will impart new perspectives in drug discovery process.

Gamma-amino butyric acid (GABA) is a major inhibitory neurotransmitter found in several regions of the brain and known to have various significant physiological roles as a potent bioactive compound. Malfunction of GABAergic neuronal signaling prompts to cause severe psychiatric symptoms in numerous mental disorders. Several drugs are available in clinical practice for neuropsychiatric disorders targeting through GABAergic pathway, with notable adverse effects. Interestingly, in recent years, researchers are focusing on natural compounds altering GABAergic neurotransmission for various psychiatric disorders due to its wide range of therapeutic efficacy and safety. The enormous variety of natural compounds, namely alkaloids, flavonoids, terpenoids, polyacetylenic alcohols, alkanes and fatty acids were reported to alter the GABAergic transmission through its receptors and or by influencing the transmission, synthesis and metabolism of GABA. Natural compounds are able to cross the blood brain barrier and influence the GABA functions in order to treat anxiety, mania, schizophrenia and cognitive disorders. Therefore, this current chapter describes on natural products which have the potential to alter the GABAergic neurotransmission and its therapeutical benefits in treating several neuropsychiatry disorders using various pharmacological methods.

Excitatory amino acid transporter-2 (EAAT-2) protein localized in the membrane of glial cells are responsible for the clearance of glutamate in synapse and it plays a key role among the five glutamate transporters (EAATs) in regulating synaptic transmission and preventing excitotoxicity in neurons. EAAT-2 dysfunction has been associated with the neuropathology of Alzheimer's disease (AD). Impairment of EAAT-2 transporter function results excess accumulation of glutamate in synaptic cleft that acts on post-synaptic glutaminergic receptors excessively resulting in influx of Na+ and Ca2+ ions into the neurons. This triggers excitotoxicity in post-synaptic neurons by activating apoptotic or necrotic pathways causing neurodegeneration in AD. The compounds that increase the EAAT-2 activity may have therapeutic potential for neuroprotection in AD. The positive allosteric site activation of EAAT-2 represents a promising entry point for the identification of novel pharmacological compounds for the management of neurodegenerative conditions involving glutamate-mediated excitotoxicity. We hypothesize, therefore, that the positive allosteric activators may enhance glutamate clearance from the synaptic cleft by promoting orthosteric binding of glutamate ligand in EAAT-2 transporter protein and attenuate the excitotoxicity in neurons and prevent the disease progression of AD.

Peroxisome proliferator-activated receptor gamma (PPAR-γ) is one of the ligand-activated transcription factors which regulates a number of central events and considered as a promising target for various neurodegenerative disease conditions. Numerous reports implicate that PPAR-γ agonists have shown neuroprotective effects by regulating genes transcription associated with the pathogenesis of neurodegeneration. In regards, this review critically appraises the recent knowledge of PPAR-γ receptors in neuroprotection in order to hypothesize potential neuroprotective mechanism of PPAR-γ agonism in chronic neurological conditions. Of note, the PPAR-γ's interaction dynamics with PPAR-γ coactivator-1α (PGC-1α) has gained significant attention for neuroprotection. Likewise, a plethora of studies suggest that the PPAR-γ pathway can be actuated by the endogenous ligands present in the CNS and thus identification and development of novel agonist for the PPAR-γ receptor holds a vow to prevent neurodegeneration. Together, the critical insights of this review enlighten the translational possibilities of developing novel neuroprotective therapeutics targeting PPAR-γ for various neurodegenerative disease conditions.

Neurological disorders such as Alzheimer’s Disease (AD), Parkinsons’s Disease (PD) and Cerebral Ischemic Stroke (CIS) are responsible for morbidities in almost a billion people and it is rising with increase in older population. AD is responsible for most dementia cases reported worldwide and is marked by the loss of memory and aggregation of Amyloid beta peptide (AsP) and Neurofibrillary tangle (NFT). Oxidative stress, apoptosis are few of the factors that influence the pathophysiology. PD is characterized by genetic abnormalities, mitochondrial dysfunction, oxidative stress, excitotoxicity, calcium and iron overload and neuroinflammation and manifests as rigidity and bradykinesia. CIS is caused by reduced cerebral blood flow and impaired metabolic processes. The generation of free radicals and elevation of Ca2+ levels along with inflammatory cytokines, carries out the process. The use of plants for various disease condition is as old as history. The recent advancements in scientific drug development has hastened the discovery process and has opened doors to new discoveries having potential in treatment of neurological disorders such as AD, PD and CIS. These investigations has resulted in discovery of plants and plant extracts with potential neuroprotective effects. However, these discoveries require further validation and scientific proofs to be applied in clinical scenario. Interestingly, these plant based treatments can be co-administered with existing drugs or can be even used as monotherapy, depending on the advancements in this field.

Cases of Diabetes mellitus around the world are increasing day by day. It has been predicted that India, China and United States will be having the largest number of diabetic patients by 2030. Therefore, the anti-diabetic study is attracted a huge number of scientists and various in-vitro and in-vivo models has been developed for anti-diabetic study. In drug development, the in-vitro techniques are an important method of confirming a particular biological activity of a compound before animal experiments. In vitro cell lines are alternative to animal models to study the particular activity of drugs. To produce more reproducible results, the in-vitro cell lines from clonal cells, cell lines are used. Characteristics of cell lines are constantly changing because of continuous growth of cells without any limits being its disadvantage. This review attempts to bring together all reported in-vitro cell line models to study the anti-diabetic activity. These cell lines may prove essential for the development of new drugs for the treatment of diabetes mellitus. Study of anti-diabetics activity of various agents in cell line models is important for improving the knowledge and in providing a clear understanding of pathogenesis leading to the discovery of new therapies for the disease. Many cell lines have been discovered in past few decades for the in-vitro studies involving diabetes mellitus. The generation of cell lines may bedecreased the number of animals used for in-vivo studies. Using cell lines for anti-diabetic studies also put aside the painful techniques in the in-vivo studies.