7. FSK and brain

management of skin infections and eruptions. The plant is also used traditionally in veterinary practice (Table 1). Essential oil in tubers of this plant has potential uses in food flavoring industry and can be used as an antimicrobial agent and has very attractive and delicate odor with spicy note. A labdane diterpenoid is considered the active secondary metabolite because of its ability to activate the enzyme adenylyl cyclase (Ac) thereby increasing the intracellular level of cAMP and leading to various physiological effects [52]. FSK is shown to exert a 6–400 fold increase in levels of cAMP. Cyclic AMP is a "second messenger" hormone signaling system as its synthesis triggers the action of various hormones, enzymes and other biological activities that have profound effects on local cells, as well as systemic effects, in some instances, on the entire body [53]. FSK by passes the adrenoreceptors, increasing cAMP levels directly, thereby stimulating lipolysis. FSK has also been shown to counteract the decreased response of fat cells to epinephrine, associated with aging. FSK also accelerates lipolysis through the activation of hormonesensitive lipase [54]. It is primarily via the increased synthesis of cyclic AMP that C. Forskohlii may exert its medicinal influences on a significant number of common health conditions.

S.No. Pharmacological activity Mechanism of action Ref. No

into cholinergic neurons

(NCP's) was achieved

there by decrease in IOP Reduction of intra ocular pressure

myocardial oxygen consumption.

dependent apoptosis in AML cell lines.

enhancement of the coupling between stimulatory GTPbinding protein (G protein) and AC catalytic molecules FSK stimulates AC and regulates brain-derived neurotrophic factor (BDNF) and TrkB expression in the rat brain

enables neurogenin-2 (Ngn2) to convert human fibroblasts

Neuronal differentiation of adult rat neural progenitor cells

and ERK activity and block proliferation and induce caspase-

Forskolin inhibited the in-vivo leukemogenesis of imatinib sensitive and resistant BCR/ABL+ 32Dcl3 cells in mice

epithelium to produce cyclic adenosine monophosphate (cAMP) that results in decreased aqueous humor inflow

It reduces diastolic blood pressure without increasing

mast cell degranulation, resulting in subsequent

Reduction of INa (cardiac Na + current) and overproduction of mitochondrial ROS in deoxycorticosterone acetate (DOCA) mouse myocytes by activating PKA and PKC

92

93

94

95

96

97

98

i. Anti-depressant FSK stimulated AC activity in rat brain and leads to

ii. Anti-Alzheimer's FSK-induced abipolar neuron-like cell morphology and it

iii. Anti-cancer Restoration of PP2A activity with forskolin that inhibit Akt

iv. Antispasmodic activity increase of cAMP inhibit cramping or smooth muscle contraction

vi. Cardioprotective amelioration of Mitochondrial dysfunction in

12 Recent Advances in Neurodegeneration

cardiomyopathy

v. Anti-Glaucoma Stimulates Adenylate cyclase which stimulates the ciliary

vii. Anti-asthmatic Forskolin activation of cAMP inhibits human basophil and

bronchodilation

#### 7.1. FSK-binding sites

3H-forskolin has, for example, been found to bind to both a high and a low affinity site in rat brain membranes [55] and the capacity of the high affinity forskolin-binding site has been shown to be increased by the activation of N-proteins by guanine nucleotides [56]. High affinity [3H] FSK-binding sites have been mapped autoradiographically in rat brain area such as caudate-putamen, nucleus accumbens, olfactory tubercle, globus pallidus, substantia nigra and the hilus of the area dentata [57] and exhibit a markedly heterogeneous distribution.

#### 7.2. Role of FSK in brain

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 synaptosomes and bovine retinal slices [62].

8.2. Forskolin against neurooxidation

(1O<sup>2</sup>

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

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

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

15

) 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.
