8. Neuroprotective action of FSK

#### 8.1. FSK against neuroinflammation

An increase in intracellular cAMP levels through FSK to play an important role in modulating the cytokine production. Intracellular cAMP has been reported to depress the accumulation of tumor necrosis factor (TNF-α) an mRNA by inhibiting the transcriptional processes. Elevation of intracellular cAMP levels induced by PDE inhibitors, FSK, prostaglandin E2, or cell-permeable cAMP analogue also inhibited the secretion of IL-1b, whereas it increased IL-1b mRNA levels from lipopolysaccharide-stimulated human monocytes. Although the regulatory modality of IL-8 production by cAMP is still unclear and depends on the cell type, enhanced cAMP appears to have favorable effects at least on airway cells by suppressing IL-8 production [63]. Therefore, enhanced cAMP levels by have also FSK been recognized to reverse the increased pulmonary microvascular permeability associated with ischemia reperfusion (Figure 4) [64].

#### 8.2. Forskolin against neurooxidation

7.2. Role of FSK in brain

14 Recent Advances in Neurodegeneration

somes and bovine retinal slices [62].

8. Neuroprotective action of FSK

8.1. FSK against neuroinflammation

FSK may activate Ac by interacting with two sites, one which may be directly located on the cyclase molecule, and the other which is associated with OJ somehow formed by the interactions with the N, protein. FSK, a commonly used activator of Ac [55], elevates the stimulation-induced release of several transmitters, such as acetylcholine, noradrenaline and 5-hydrdoxytryptamine, from brain or synaptosomes and markedly increasing the rate of conversion of ATP to cyclic AMP [58]. FSK directly reduces certain K + potassium currents in addition to its action on Ac. cAMP could increase the apparent number of Na, K-ATPase sites by either direct or indirect mechanisms. cAMP could increase the number of Na, K-ATPase sites by increasing cell Na + or decreasing K + though there are reports of Na, K-ATPase stimulation that may be independent of cation changes. FSK elevates electrically evoked acetylcholine release in the hippocampus independently of Ac activation [58]. FSK appears to provide a new clue for elucidating the physiological role of cAMP in the synaptic transmission in the sympathetic ganglia. FSK exerts two opposite pharmacological actions at the synapse, i.e. a facilitation of transmitter release at the presynaptic site and a depressant action on nicotinic acetylcholine receptor at the postsynaptic site. FSK reduced the amplitude shock stimulation of preganglionic nerve. FSK induces a reversible AChR desensitization at the junctional and extrajunctional regions in rat [59]. FSK, an activator of Ac, could increase transmitter release presynaptically in CA1 neurons. FSK directly stimulates Ac and thereby increases cyclic AMP activity, which is known to influence neurite outgrowth and membrane trafficking in neurons. Increased cyclic AMP activity may have multiple effects on cells including changing the direction of growing neurites [60] and increasing the density of clathrin-coated pits and coated vesicles at plasma membranes coincident with an increased synthesis of clathrin light chain. The cAMP effector system enhanced by FSK is involved in the release of dopamine from dopaminergic nerve endings in the neostriatum [61]. FSK increased dopamine formation in rat striatal slices, rat striatal synaptosomes, rat hypothalamic synapto-

An increase in intracellular cAMP levels through FSK to play an important role in modulating the cytokine production. Intracellular cAMP has been reported to depress the accumulation of tumor necrosis factor (TNF-α) an mRNA by inhibiting the transcriptional processes. Elevation of intracellular cAMP levels induced by PDE inhibitors, FSK, prostaglandin E2, or cell-permeable cAMP analogue also inhibited the secretion of IL-1b, whereas it increased IL-1b mRNA levels from lipopolysaccharide-stimulated human monocytes. Although the regulatory modality of IL-8 production by cAMP is still unclear and depends on the cell type, enhanced cAMP appears to have favorable effects at least on airway cells by suppressing IL-8 production [63]. Therefore, enhanced cAMP levels by have also FSK been recognized to reverse the increased pulmonary

microvascular permeability associated with ischemia reperfusion (Figure 4) [64].

Oxidative stress may play a role in the development and clinical manifestations of autism. Both central and peripheral markers of oxidative stress have been reported in autism. Peripheral markers have included lipid peroxidation levels. Increases in these markers correlated with loss of previously acquired language skills in autism. Furthermore, metabolic markers of oxidative stress have been identified including abnormal levels of metabolites signifying impaired methylation and increased oxidative stress in autism [65]. The oxidative stress in autism may be caused by an imbalance between the generation of ROS and the defense mechanism against ROS by antioxidants. An increase in reactive oxygen species (ROS) results in damage to proteins, DNA, and lipids. Specifically, the interaction between ROS and nitric oxide (NO) results in the nitration of tyrosine residues in proteins and can alter protein conformation and function [66]. Oxidative DNA damage is also considered to play an important role in the pathology of a number of diseases like Parkinson's disease, tardive dyskinesia, metal intoxication syndromes, Down's syndrome, and possibly also in schizophrenia, Huntington's disease, and Alzheimer's disease. Reactive oxygen species including superoxide (O2.–), hydroxyl (.OH), hydrogen peroxide (H2O2), singlet oxygen (1O<sup>2</sup> ) and nitric oxide (NO•) can cause cellular injury when they are generated excessively or the enzymatic and nonenzymatic antioxidant defense systems are impaired [67].

Figure 4. Neuroprotective action of forskolin-mediated AC/cAMP/PKA/CREB activation.

Moreover, FSK-mediated cAMP/PKA/CREB activation were found to inhibit LPS- and cytokine-mediated production of NO as well as the expression of iNOS, whereas compounds (H-89 and (Rp)-cAMP) that decrease PKA activity stimulated the production of NO and the expression of iNOS in rat primary astrocytes [68].

9. Conclusion

Acknowledgements

ment.

Author details

References

Sidharth Mehan\*, Himanshi Khera and Ramit Sharma \*Address all correspondence to: sidh.mehan@gmail.com

Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India

In conclusion, the current study strongly confirms that the administration of propionic acid induces brain lesions that are similar to the behavioral, histological, morphological, biochemical, neurochemical, and pathological features of autism. After Chronic administration of propionic acid in the rats as proven by motor dysfunctions, biochemical and neurochemical alternations. The literature finding in the current study reveals that adenylyl cyclase activator, that is, FSKmediated cAMP/CREB activation, might be a unique platform for the prevention of neurodegenerative diseases. Thus in conclusion, neuroprotective and neuro restoration effects of FSK may be due to favorable modulation of CREB-mediated signaling. The involvement of cAMP/PKA/CREB pathway, anti-oxidant, anti-inflammatory and neuroprotective effect of test drug FSK may be the

Neuroprotective Strategies of Blood-Brain Barrier Penetrant "Forskolin" (AC/cAMP/PKA/CREB Activator)…

http://dx.doi.org/10.5772/intechopen.80046

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Furthermore, with cAMP/PKA/CREB signaling in regulation of neuronal functioning, the future studies can be designed to investigate the protective and therapeutic potency of forskolin in animal models of brain hemorrhage, Huntington's disease and Parkinson's disease and to find out if cAMP-mediated CREB pathway is equally implicated in the disease pathogenesis or progression. So, now we can finally conclude the significant mitochondrial restorative effects of the FSK may be due to showing its improved motor and cognitive functions as well as to restore the energy levels and antioxidant and anti-inflammatory defense system.

The authors express their gratitude to Chairman, Mr. Parveen Garg, and Director, Dr. G.D. Gupta, ISF College of Pharmacy, Moga (Punjab), India, for their great vision and support. Authors are really thankful to Dr. Vikramdeep Monga, for valuable support and encourage-

[1] Swerdlow RH. Mitochondrial DNA–related mitochondrial dysfunction in neurodegenerative diseases. Archives of Pathology & Laboratory Medicine. 2002;126:271-280

possible mechanisms at least in part underlying the observed effects (Figure 4).

## 8.3. Forskolin against mitochondrial dysfunctioning

The brain is strongly dependent on the ATP production of the cell energy-producing organelle, the mitochondrion. There is a large body of evidence involving mitochondrial dysfunctions in ASD. Palmieri and Persico, regarding ASD, oxidative phosphorylation (OXPHOS) in the mitochondrion requires at least 80 proteins, of which only 13 are encoded by the mtDNA, while mitochondrial functioning has been estimated to need the participation of approximately 1500 nuclear genes. Mitochondrial dysfunction is present in the brains of individuals with ASD and may play a role in its core cognitive and behavioral symptoms. Alternatively, mitochondria can be damaged by endogenous stressors associated with ASD such as elevated pro-inflammatory cytokines resulting from an activated immune system or other conditions associated with oxidative stress. Oxidative stress may be a key link between mitochondrial dysfunction and ASD as reactive oxygen species (ROS) generated from pro-oxidant environmental toxicants and activated immune cells can result in mitochondrial dysfunction. Excess production of free radicals or impaired antioxidant mechanisms may cause oxidative stress: impaired mitochondrial function then leads to further oxidative stress and a vicious negative cycle can ensue. Instead, abnormal functioning appears secondary to excessive Ca2+ levels. Mitochondrial dysfunctioning caused depletion of ATP, that further decrease the level of cAMP. Forskolin, increase in intracellular cAMP, through the phosphorylation of CREB which perform neuroprotective functioning associate with mitochondrial dysfunctioning [69].

### 8.4. Forskolin against cognitive dysfunction

Autistic brain which may reflect enhanced cortical plasticity which is defined as the process of microstructural construction of synapses occurring during development and the remodeling of these synapses during learning [70]. Enhanced synaptic plasticity triggers a regional reorganization of brain functions that account for both the unique aspects of autism and its variability [71]. Activation of cAMP/PKA has been mainly implicated in stimulating learning and memory. FSK activate cAMP/CREB in hippocampal region [72].

### 8.5. Possible involvement of FSK in PPA-induced autism

Summarizing the whole information given above, FSK confirmed a versatile role in autism where it activates the AC/cAMP-mediated PKA/CREB activation. Moreover, on other side FSK act as a co-activator in brain that follows the GS pathway through the activation of D1 receptor. There is least availability of selective AC activation and so far only limited reports suggest beneficial effect of FSK in neurodegeneration animal model.
